Sample records for nafld fibrosis score

  1. A comparison of FibroMeter™ NAFLD Score, NAFLD fibrosis score, and transient elastography as noninvasive diagnostic tools for hepatic fibrosis in patients with biopsy-proven non-alcoholic fatty liver disease.

    PubMed

    Aykut, Umut Emre; Akyuz, Umit; Yesil, Atakan; Eren, Fatih; Gerin, Fatma; Ergelen, Rabia; Celikel, Cigdem Ataizi; Yilmaz, Yusuf

    2014-11-01

    Noninvasive markers that purport to distinguish patients with non-alcoholic fatty liver disease (NAFLD) with fibrosis from those without must be evaluated rigorously for their classification accuracy. Herein, we seek to compare the diagnostic performances of three different noninvasive methods (FibroMeter™ NAFLD score, NAFLD Fibrosis score (NFSA), and Transient Elastrography [TE]) for the detection of liver fibrosis in NAFLD patients. A total of 88 patients with biopsy-proven NAFLD were included. The Kleiner system was used for grading fibrosis in liver biopsies. The FibroMeter™ NAFLD score was determined using a proprietary algorithm (regression score). The NFSA score was calculated based on age, hyperglycemia, body mass index, platelets, albumin and serum aminotransferase levels. TE was performed using the Fibroscan apparatus. The sensitivities/specificities for the FibroMeter™ NAFLD score, NFSA, and TE for the diagnosis of significant fibrosis (F2 + F3 + F4 fibrosis) were 38.6%/86.4%, 52.3%/88.6%, and 75.0%/93.2%, respectively. The areas under the receiver operating characteristic curves of TE were significantly higher than those of both the FibroMeter™ NAFLD score and NFSA. No significant differences were found between the FibroMeter™ NAFLD score and NFSA for the detection of significant and severe fibrosis, although the diagnostic performance of the FibroMeter™ NAFLD score was higher than that of the NFSA score for cirrhosis. In summary, TE showed the best diagnostic performance for the noninvasive assessment of liver fibrosis in NAFLD patients. The diagnostic performances of the FibroMeter™ NAFLD score and NFSA did not differ significantly for the detection of both significant and severe fibrosis.

  2. NAFLD fibrosis score: a prognostic predictor for mortality and liver complications among NAFLD patients.

    PubMed

    Treeprasertsuk, Sombat; Björnsson, Einar; Enders, Felicity; Suwanwalaikorn, Sompongse; Lindor, Keith D

    2013-02-28

    To study whether the severity of liver fibrosis estimated by the nonalcoholic fatty liver disease (NAFLD) fibrosis score can predict all-cause mortality, cardiac complications, and/or liver complications of patients with NAFLD over long-term follow-up. A cohort of well-characterized patients with NAFLD diagnosed during the period of 1980-2000 was identified through the Rochester Epidemiology Project. The NAFLD fibrosis score (NFS) was used to separate NAFLD patients with and without advanced liver fibrosis. We used the NFS score to classify the probability of fibrosis as < -1.5 for low probability, > -1.5 to < 0.67 for intermediate probability, and > 0.67 for high probability. Primary endpoints included all-cause death and cardiovascular- and/or liver-related mortality. From the 479 patients with NAFLD assessed, 302 patients (63%) greater than 18 years old were included. All patients were followed, and medical charts were reviewed until August 31, 2009 or the date when the first primary endpoint occurred. By using a standardized case record form, we recorded a detailed history and physical examination and the use of statins and metformin during the follow-up period. A total of 302/479 (63%) NAFLD patients (mean age: 47 ± 13 year) were included with a follow-up period of 12.0 ± 3.9 year. A low probability of advanced fibrosis (NFS < -1.5 at baseline) was found in 181 patients (60%), while an intermediate or high probability of advanced fibrosis (NSF > -1.5) was found in 121 patients (40%). At the end of the follow-up period, 55 patients (18%) developed primary endpoints. A total of 39 patients (13%) died during the follow-up. The leading causes of death were non-hepatic malignancy (n = 13/39; 33.3%), coronary heart disease (CHD) (n = 8/39; 20.5%), and liver-related mortality (n = 5/39; 12.8%). Thirty patients had new-onset CHD, whereas 8 of 30 patients (27%) died from CHD-related causes during the follow-up. In a multivariate analysis, a higher NFS at baseline and

  3. Hepatic artery resistive index (HARI) and non-alcoholic fatty liver disease (NAFLD) fibrosis score in NAFLD patients: cut-off suggestive of non-alcoholic steatohepatitis (NASH) evolution.

    PubMed

    Tana, Claudio; Tana, Marco; Rossi, Stefano; Silingardi, Mauro; Schiavone, Cosima

    2016-09-01

    Conventional ultrasound (US) is reliable to reveal the presence of non-alcoholic fatty liver disease (NAFLD), but it is neither sensitive nor specific to reveal fibrosis clues, except in advanced stages where signs of cirrhosis are evident. NALFD fibrosis score is a non-invasive parameter that predicts well the presence of significant fibrosis, but correlations with US parameters are lacking. The aim of this study was, therefore, to compare resistive index of hepatic artery (HARI) of NAFLD patients with different severity degrees of diffuse fatty liver disease vs HARI of controls, and to compare HARI of NAFLD patients with different NAFLD fibrosis scores vs HARI of controls. This was a spontaneous, no-profit observational study conducted in our US department between December 2013 and July 2014. Patients with NAFLD with different severity of disease and healthy controls were included. Echogenicity and size of liver and spleen, maximum portal vein velocity, RI, peak systolic velocity (PSV), and end diastolic velocity (EDV) of splenic artery, PSV, EDV, and RI of hepatic artery, and NAFLD fibrosis score were acquired and compared between groups. HARI was significantly lower in NAFLD patients than controls (p < 0.0001). A significant difference was also found between the groups of NAFLD severity (p < 0.0001). There was also a difference between HARI of NAFLD patients with different NAFLD fibrosis scores vs HARI of controls (p < 0.0001) with a positive correlation between HARI and NAFLD fibrosis score. Conventional Doppler US can be helpful to detect NAFLD patients with the risk of fibrous tissue accumulation. HARI tends to exceed the range of controls for patients with NAFLD fibrosis score greater than 0.675. The detection of HARI greater than 0.9 in NAFLD patients, regardless of the US degree of severity of steatosis, might suggest the execution of biopsy to predict the risk of progression to steatohepatitis and fibrous tissue accumulation. Low values of HARI may

  4. Cost-Effectiveness Analysis: Risk Stratification of Nonalcoholic Fatty Liver Disease (NAFLD) by the Primary Care Physician Using the NAFLD Fibrosis Score.

    PubMed

    Tapper, Elliot B; Hunink, M G Myriam; Afdhal, Nezam H; Lai, Michelle; Sengupta, Neil

    2016-01-01

    The complications of Nonalcoholic Fatty Liver Disease (NAFLD) are dependent on the presence of advanced fibrosis. Given the high prevalence of NAFLD in the US, the optimal evaluation of NAFLD likely involves triage by a primary care physician (PCP) with advanced disease managed by gastroenterologists. We compared the cost-effectiveness of fibrosis risk-assessment strategies in a cohort of 10,000 simulated American patients with NAFLD performed in either PCP or referral clinics using a decision analytical microsimulation state-transition model. The strategies included use of vibration-controlled transient elastography (VCTE), the NAFLD fibrosis score (NFS), combination testing with NFS and VCTE, and liver biopsy (usual care by a specialist only). NFS and VCTE performance was obtained from a prospective cohort of 164 patients with NAFLD. Outcomes included cost per quality adjusted life year (QALY) and correct classification of fibrosis. Risk-stratification by the PCP using the NFS alone costs $5,985 per QALY while usual care costs $7,229/QALY. In the microsimulation, at a willingness-to-pay threshold of $100,000, the NFS alone in PCP clinic was the most cost-effective strategy in 94.2% of samples, followed by combination NFS/VCTE in the PCP clinic (5.6%) and usual care in 0.2%. The NFS based strategies yield the best biopsy-correct classification ratios (3.5) while the NFS/VCTE and usual care strategies yield more correct-classifications of advanced fibrosis at the cost of 3 and 37 additional biopsies per classification. Risk-stratification of patients with NAFLD primary care clinic is a cost-effective strategy that should be formally explored in clinical practice.

  5. A novel 2-step approach combining the NAFLD fibrosis score and liver stiffness measurement for predicting advanced fibrosis.

    PubMed

    Chan, Wah-Kheong; Nik Mustapha, Nik Raihan; Mahadeva, Sanjiv

    2015-10-01

    The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is indeterminate in a proportion of NAFLD patients. Combining the NFS with liver stiffness measurement (LSM) may improve prediction of advanced fibrosis. We aim to evaluate the NFS and LSM in predicting advanced fibrosis in NAFLD patients. The NFS was calculated and LSM obtained for consecutive adult NAFLD patients scheduled for liver biopsy. The accuracy of predicting advanced fibrosis using either modality and in combination were assessed. An algorithm combining the NFS and LSM was developed from a training cohort and subsequently tested in a validation cohort. There were 101 and 46 patients in the training and validation cohort, respectively. In the training cohort, the percentages of misclassifications using the NFS alone, LSM alone, LSM alone (with grey zone), both tests for all patients and a 2-step approach using LSM only for patients with indeterminate and high NFS were 5.0, 28.7, 2.0, 2.0 and 4.0 %, respectively. The percentages of patients requiring liver biopsy were 30.7, 0, 36.6, 36.6 and 18.8 %, respectively. In the validation cohort, the percentages of misclassifications were 8.7, 28.3, 2.2, 2.2 and 8.7 %, respectively. The percentages of patients requiring liver biopsy were 28.3, 0, 41.3, 43.5 and 19.6 %, respectively. The novel 2-step approach further reduced the number of patients requiring a liver biopsy whilst maintaining the accuracy to predict advanced fibrosis. The combination of NFS and LSM for all patients provided no apparent advantage over using either of the tests alone.

  6. Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study.

    PubMed

    Sun, Wenjing; Cui, Hongli; Li, Ning; Wei, Yanling; Lai, Shujie; Yang, Yang; Yin, Xinru; Chen, Dong-Feng

    2016-08-01

    Non-alcoholic fatty liver disease (NAFLD)-related advanced hepatic fibrosis is associated with liver and cardiovascular morbidity and mortality. This study aims to compare the FIB-4 index, NAFLD fibrosis score (NFS) and BARD score for prediction of advanced liver fibrosis. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC) and Spearman's rank correlation coefficient were used to examine the accuracy of each non-invasive scoring system for predicting NAFLD-related advanced fibrosis. Four studies with 1038 adult patients were included in this meta-analysis. A total of 135 patients (13.0%) had advanced fibrosis. In the FIB-4 index group, pooled sensitivity and specificity with 95% confidence interval (CI), and the area under the ROC (AUROC) were 0.844 (0.772-0.901), 0.685 (0.654-0.716) and 0.8496 ± 0.0680, respectively, at a cut-off of 1.30. At a threshold of 3.25, the same parameters were 0.38 (0.30-0.47), 0.96 (0.95-0.98) and 0.8445 ± 0.0981. At a cut-off of -1.455, values were 0.77 (0.69-0.84), 0.70 (0.67-0.73) and 0.8355 ± 0.0667, respectively. At a 0.676 cut-off, pooled sensitivity and specificity with 95% CI were 0.27 (0.19-0.35) and 0.98 (0.96-0.98), respectively; and the AUROC was 0.647 ± 0.2208. In the BARD score group, pooled sensitivity and specificity with 95% CI were 0.74 (0.66-0.81) and 0.66 (0.63-0.69), respectively; and the AUROC was 0.7625 ± 0.0285. FIB-4 index with a 1.30 cut-off has better diagnostic accuracy than the FIB-4 index with a 3.25 cut-off, NFS and BARD score, despite showing its limited value for predicting NAFLD-related advanced fibrosis. © 2016 The Japan Society of Hepatology.

  7. Non-alcoholic fatty liver disease (NAFLD) fibrosis score predicts 6.6-year overall mortality of Chinese patients with NAFLD.

    PubMed

    Xun, Yun-Hao; Guo, Jian-Chun; Lou, Guo-Qiang; Jiang, Yan-Ming; Zhuang, Zhen-Jie; Zhu, Meng-Fei; Luo, Yan; Ma, Xiao-Jie; Liu, Jing; Bian, Dong-Xue; Shi, Jun-Ping

    2014-09-01

    The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has emerged as a useful predictor of long-term outcome in NAFLD patients. We evaluated the predictive performance of the NFS for overall mortality in a Chinese population with NAFLD. All NAFLD patients diagnosed ultrasonographically at Xixi Hospital of Hangzhou between 1996 and 2011 were retrospectively recruited to the study. Outcome was determined by interview and causes of death were confirmed by medical records. The area under the receiver operating characteristic curve (AUCROC ) was used to determine the predictive accuracy of the NFS, BARD (body mass index, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, diabetes) score, FIB-4 index and the AST/platelet ratio index (APRI) for mortality. Data from a total of 180 eligible patients (median age 39 years; 96 men) were analysed, with 12 deaths over a median follow-up period of 6.6 years (range 0.5-14.8 years). Using Cox model analysis, the NFS as a continuous variable was identified as the only predictor for all-cause mortality (hazard ratio 2.743, 95% confidence interval (CI) 1.670-4.504). The NFS yielded the highest AUCROC of 0.828 (95% CI 0.728-0.928, P < 0.05), followed by the FIB-4 index, APRI and BARD score (AUCROC 0.806 (P < 0.05), 0.732 (P < 0.05) and 0.632, respectively). The data indicated that the NFS is a useful predictor of 6.6-year all-cause mortality for Chinese patients with NAFLD. © 2014 Wiley Publishing Asia Pty Ltd.

  8. Cost-Effective Evaluation of Nonalcoholic Fatty Liver Disease With NAFLD Fibrosis Score and Vibration Controlled Transient Elastography.

    PubMed

    Tapper, Elliot B; Sengupta, Neil; Hunink, M G Myriam; Afdhal, Nezam H; Lai, Michelle

    2015-09-01

    The risk of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is traditionally assessed with a liver biopsy, which is both costly and associated with adverse events. We sought to compare the cost-effectiveness of four different strategies to assess fibrosis risk in patients with NAFLD: vibration controlled transient elastography (VCTE), the NAFLD fibrosis score (NFS), combination testing with NFS and VCTE, and liver biopsy (usual care). We developed a probabilistic decision analytical microsimulation state-transition model wherein we simulated a cohort of 10,000 50-year-old Americans with NAFLD undergoing evaluation by a gastroenterologist. VCTE performance was obtained from a prospective cohort of 144 patients with NAFLD. Both the NFS alone and the NFS/VCTE strategies were cost effective at $5,795 and $5,768 per quality-adjusted life years (QALY), respectively. In the microsimulation, the NFS alone and NFS/VCTE strategies were the most cost-effective (dominant) in 66.8 and 33.2% of samples given a willingness-to-pay threshold of $100,000 per QALY. In a sensitivity analysis, the minimum cost per liver biopsy at which the NFS is cost saving is $339 and the maximum cost per VCTE exam at which the NFS/VCTE strategy remains cost saving is $1,593. The expected value of further research on this topic is $526 million. Non-invasive risk stratification with both the NFS alone and the NFS/VCTE are cost-effective strategies for the evaluation and management of patients with NAFLD presenting to a gastroenterologist. Further research is needed to better define the natural history of NAFLD and the effect of novel treatments on decision making.

  9. The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease.

    PubMed

    Mansoor, Sana; Yerian, Lisa; Kohli, Rohit; Xanthakos, Stavra; Angulo, Paul; Ling, Simon; Lopez, Rocio; Christine, Carter-Kent; Feldstein, Ariel E; Alkhouri, Naim

    2015-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in children and can progress to liver cirrhosis during childhood. Patients with more advanced fibrosis on biopsy tend to have more liver complications. Noninvasive hepatic fibrosis scores have been developed for adult patients with NAFLD; however, these scores have not been validated in children. The aim of our study was to evaluate some of these scores in assessing the presence of fibrosis in children with biopsy-proven NAFLD. Our study consisted of 92 biopsy-proven NAFLD children from five major US centers. Fibrosis was determined by an experienced pathologist (F0-4). Clinically significant fibrosis was defined as fibrosis stage ≥ 2, and advanced fibrosis was defined as F3-4. The following fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 index. ROC was performed to assess the performance of different scores for prediction of presence of any, significant, or advanced fibrosis. A p value < 0.05 was considered statistically significant. Mean age was 13.3 ± 3 years, and 33 % were females. Eleven (12 %) subjects had no fibrosis, 35 (38 %) had fibrosis score of 1, 26 (28 %) had fibrosis score of 2, and 20 (22 %) had a score of 3. APRI had a fair diagnostic accuracy for the presence of any fibrosis (AUC of 0.80) and poor diagnostic accuracy for significant or advanced fibrosis. AST/ALT, NFS, and FIB-4 index all either had poor diagnostic accuracy or failed to diagnose the presence of any, significant, or advanced fibrosis. Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing significant fibrosis in children with NAFLD. Our results highlight the urgent need to develop a reliable pediatric fibrosis score.

  10. Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD

    PubMed Central

    Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A.; Kleiner, David; Brunt, Elizabeth M.; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James

    2015-01-01

    , international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. CONCLUSIONS Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. PMID:25887357

  11. Comparison of blood tests for liver fibrosis specific or not to NAFLD.

    PubMed

    Calès, Paul; Lainé, Fabrice; Boursier, Jérôme; Deugnier, Yves; Moal, Valérie; Oberti, Frédéric; Hunault, Gilles; Rousselet, Marie Christine; Hubert, Isabelle; Laafi, Jihane; Ducluzeaux, Pierre Henri; Lunel, Françoise

    2009-01-01

    To compare blood tests of liver fibrosis specific for NAFLD: the FibroMeter NAFLD and the NAFLD fibrosis score (NFSA) with a non-specific test, APRI. Two hundred and thirty-five NAFLD patients with liver Metavir staging and blood markers from two independent centres were randomly assigned to a test (n=121) or a validation population (n=114). The highest accuracy--91%--for significant fibrosis was obtained with the FibroMeter whose (i) AUROC (0.943) was significantly higher than those of NFSA (0.884, p=0.008) and APRI (0.866, p<10(-3); p=0.309 vs NFSA) in the whole population, and (ii) misclassification rate (9%) was significantly lower than those of NFSA (14%, p=0.04) and APRI (16%, p=0.002) and did not vary according to centre (14 vs 7%, p=0.07), unlike those of NFSA (25 vs 9%, p=0.001) and APRI (29 vs 11%, p<10(-3)). By using thresholds of 90% predictive values, liver biopsy could have been avoided in most patients: FibroMeter: 97.4% vs NFSA: 86.8% (p<10(-3)) and APRI: 80.0% (p<10(-3)). A new classification provided three reliable diagnosis intervals: F0/1, F0/1/2, F2/3/4 with 91.4% accuracy for FibroMeter, avoiding biopsy in all patients. FibroMeter NAFLD had high performance and provided reliable diagnosis for significant fibrosis, significantly outperforming NFSA and APRI.

  12. Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD.

    PubMed

    Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A; Kleiner, David; Brunt, Elizabeth M; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James; Loomba, Rohit

    2015-07-01

    an AUROC of 0.80 (95% CI 0.76-0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis.

    PubMed

    McPherson, Stuart; Hardy, Tim; Dufour, Jean-Francois; Petta, Salvatore; Romero-Gomez, Manuel; Allison, Mike; Oliveira, Claudia P; Francque, Sven; Van Gaal, Luc; Schattenberg, Jörn M; Tiniakos, Dina; Burt, Alastair; Bugianesi, Elisabetta; Ratziu, Vlad; Day, Christopher P; Anstee, Quentin M

    2017-05-01

    Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD. Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36-45 (n=96), 46-55 (n=197), 56-64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3-F4) for each group was assessed using liver biopsy as the standard. Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77-0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%). The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this

  14. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis

    PubMed Central

    McPherson, Stuart; Hardy, Tim; Dufour, Jean-Francois; Petta, Salvatore; Romero-Gomez, Manuel; Allison, Mike; Oliveira, Claudia P; Francque, Sven; Van Gaal, Luc; Schattenberg, Jörn M; Tiniakos, Dina; Burt, Alastair; Bugianesi, Elisabetta; Ratziu, Vlad; Day, Christopher P; Anstee, Quentin M

    2017-01-01

    OBJECTIVES: Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD. METHODS: Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36–45 (n=96), 46–55 (n=197), 56–64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3–F4) for each group was assessed using liver biopsy as the standard. RESULTS: Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77–0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77% NFS 0.12, sensitivity 80%). CONCLUSIONS: The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in

  15. The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Petta, Salvatore; Vanni, Ester; Bugianesi, Elisabetta; Di Marco, Vito; Cammà, Calogero; Cabibi, Daniela; Mezzabotta, Lavinia; Craxì, Antonio

    2015-05-01

    The accuracy of noninvasive tools for the diagnosis of severe fibrosis in patients with nonalcoholic fatty liver disease(NAFLD) in clinical practice is still limited. We aimed at assessing the diagnostic performance of combined noninvasive tools in two independent cohorts of Italian NAFLD patients. We analysed data from 321 Italian patients(179 Sicilian-training cohort, and 142 northern Italy-validation cohort) with an histological diagnosis of NAFLD. Severe fibrosis was defined as fibrosis ≥ F3 according to Kleiner classification. The APRI, AST/ALT, BARD, FIB-4, and NFS scores were calculated according to published algorithms. Liver stiffness measurement(LSM) was performed by FibroScan. Cut-off points of LSM, NFS and FIB-4 for rule-in or rule-out F3-F4 fibrosis were calculated by the reported formulas. In the Sicilian cohort AUCs of LSM, NFS, FIB-4, LSM plus NFS, LSM plus FIB-4, and NFS plus FIB-4 were 0.857, 0.803, 0.790, 0.878, 0.888 and 0.807, respectively, while in the northern Italy cohort the corresponding AUCs were 0.848, 0.730, 0.703, 0.844, 0.850, and 0.733 respectively. In the training cohort, the combination of LSM plus NFS was the best performing strategy, providing false positive, false negative and uncertainty area rates of 0%,1.1% and 48% respectively. Similar results were obtained in the validation cohort with false positive, false negative and uncertainty area rates of 0%,7.3% and 40.8%. The combination of LSM with NFS, two complementary, easy-to-perform, and widely available tools, is able to accurately diagnose or exclude the presence of severe liver fibrosis, also reducing of about 50-60% the number of needed diagnostic liver biopsies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Fibrosis Assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in 2016.

    PubMed

    Kaswala, Dharmesh H; Lai, Michelle; Afdhal, Nezam H

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver pathologies characterized by hepatic steatosis with a history of little to no alcohol consumption or secondary causes of hepatic steatosis. The prevalence of NAFLD is 20-25 % of the general population in the Western countries and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. The spectrum of disease ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Advanced fibrosis is the most significant predictor of mortality in NAFLD. It is crucial to assess for the presence and degree of hepatic fibrosis in order to make therapeutic decisions and predict clinical outcomes. Liver biopsy, the current gold standard to assess the liver fibrosis, has a number of drawbacks such as invasiveness, sampling error, cost, and inter-/intra-observer variability. There are currently available a number of noninvasive tests as an alternative to liver biopsy for fibrosis staging. These noninvasive fibrosis tests are increasingly used to rule out advanced fibrosis and help guide disease management. While these noninvasive tests perform relatively well for ruling out advanced fibrosis, they also have limitations. Understanding the strengths and limitations of liver biopsy and the noninvasive tests is necessary for deciding when to use the appropriate tests in the evaluation of patients with NAFLD.

  17. High Dietary Sodium Intake Assessed by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis.

    PubMed

    Huh, Ji Hye; Lee, Kyong Joo; Lim, Jung Soo; Lee, Mi Young; Park, Hong Jun; Kim, Moon Young; Kim, Jae Woo; Chung, Choon Hee; Shin, Jang Yel; Kim, Hyun-Soo; Kwon, Sang Ok; Baik, Soon Koo

    2015-01-01

    Although high sodium intake is associated with obesity and hypertension, few studies have investigated the relationship between sodium intake and non-alcoholic fatty liver disease (NAFLD). We evaluated the association between sodium intake assessed by estimated 24-h urinary sodium excretion and NAFLD in healthy Koreans. We analyzed data from 27,433 participants in the Korea National Health and Nutrition Examination Surveys (2008-2010). The total amount of sodium excretion in 24-h urine was estimated using Tanaka's equations from spot urine specimens. Subjects were defined as having NAFLD when they had high scores in previously validated NAFLD prediction models such as the hepatic steatosis index (HSI) and fatty liver index (FLI). BARD scores and FIB-4 were used to define advanced fibrosis in subjects with NAFLD. The participants were classified into three groups according to estimated 24-h urinary excretion tertiles. The prevalence of NAFLD as assessed by both FLI and HSI was significantly higher in the highest estimated 24-h urinary sodium excretion tertile group. Even after adjustment for confounding factors including body fat and hypertension, the association between higher estimated 24-h urinary sodium excretion and NAFLD remained significant (Odds ratios (OR) 1.39, 95% confidence interval (CI) 1.26-1.55, in HSI; OR 1.75, CI 1.39-2.20, in FLI, both P < 0.001). Further, subjects with hepatic fibrosis as assessed by BARD score and FIB-4 in NAFLD patients had higher estimated 24-h urinary sodium values. High sodium intake was independently associated with an increased risk of NAFLD and advanced liver fibrosis.

  18. High Dietary Sodium Intake Assessed by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis

    PubMed Central

    Huh, Ji Hye; Lee, Kyong Joo; Lim, Jung Soo; Lee, Mi Young; Park, Hong Jun; Kim, Moon Young; Kim, Jae Woo; Chung, Choon Hee; Shin, Jang Yel; Kim, Hyun-Soo; Kwon, Sang Ok; Baik, Soon Koo

    2015-01-01

    Background Although high sodium intake is associated with obesity and hypertension, few studies have investigated the relationship between sodium intake and non-alcoholic fatty liver disease (NAFLD). We evaluated the association between sodium intake assessed by estimated 24-h urinary sodium excretion and NAFLD in healthy Koreans. Methods We analyzed data from 27,433 participants in the Korea National Health and Nutrition Examination Surveys (2008–2010). The total amount of sodium excretion in 24-h urine was estimated using Tanaka’s equations from spot urine specimens. Subjects were defined as having NAFLD when they had high scores in previously validated NAFLD prediction models such as the hepatic steatosis index (HSI) and fatty liver index (FLI). BARD scores and FIB-4 were used to define advanced fibrosis in subjects with NAFLD. Results The participants were classified into three groups according to estimated 24-h urinary excretion tertiles. The prevalence of NAFLD as assessed by both FLI and HSI was significantly higher in the highest estimated 24-h urinary sodium excretion tertile group. Even after adjustment for confounding factors including body fat and hypertension, the association between higher estimated 24-h urinary sodium excretion and NAFLD remained significant (Odds ratios (OR) 1.39, 95% confidence interval (CI) 1.26–1.55, in HSI; OR 1.75, CI 1.39–2.20, in FLI, both P < 0.001). Further, subjects with hepatic fibrosis as assessed by BARD score and FIB-4 in NAFLD patients had higher estimated 24-h urinary sodium values. Conclusions High sodium intake was independently associated with an increased risk of NAFLD and advanced liver fibrosis. PMID:26571018

  19. IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

    PubMed

    Hagström, Hannes; Stål, Per; Hultcrantz, Rolf; Brismar, Kerstin; Ansurudeen, Ishrath

    2017-12-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4). Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02). This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.

  20. Differing clinical phenotype for higher alanine-aminotransferase (ALT) compared with high-risk NAFLD fibrosis score in type 2 diabetes mellitus.

    PubMed

    Williams, Kathryn H; Burns, Kharis; Twigg, Stephen M

    2018-03-01

    The impact of non-alcoholic fatty liver disease (NAFLD) presence and severity on the diabetes phenotype remains unclear. Our study aimed to explore and contrast the phenotypes associated with higher ALT and high-risk NAFLD fibrosis score (NFS) in type 2 diabetes. 324 patients with type 2 diabetes mellitus who were seen at a diabetes centre for a complications assessment with data for NFS were available for study. Data regarding co-morbidities and pathology were obtained at assessment and by file audit. Logistic regression was used to determine if there were significant relationships between pre-determined diabetes complications and co-morbidities and ALT or high-risk NFS (>0.675). Significant univariate associations with lower ALT included those of osteoporosis/osteopenia and inability to sense the monofilament. High-risk NFS was associated with arrhythmia, VPT ≥ 25 V and albuminuria. The associations of high-risk NFS with albuminuria and VPT ≥ 25 V remained after adjustment. In type 2 diabetes, the clinical phenotype of those with higher ALT is dissimilar, sometimes inverse, to those with high-risk NFS. More emphasis should be placed on liver fibrosis risk rather than on liver enzymes alone. Copyright © 2017. Published by Elsevier Inc.

  1. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD.

    PubMed

    Petta, S; Wong, V W-S; Cammà, C; Hiriart, J-B; Wong, G L-H; Vergniol, J; Chan, A W-H; Di Marco, V; Merrouche, W; Chan, H L-Y; Marra, F; Le-Bail, B; Arena, U; Craxì, A; de Ledinghen, V

    2017-09-01

    The accuracy of available non-invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited. To assess the diagnostic performance of paired or serial combination of non-invasive tools in NAFLD patients. We analysed data from 741 patients with a histological diagnosis of NAFLD. The GGT/PLT, APRI, AST/ALT, BARD, FIB-4, and NAFLD Fibrosis Score (NFS) scores were calculated according to published algorithms. Liver stiffness measurement (LSM) was performed by FibroScan. LSM, NFS and FIB-4 were the best non-invasive tools for staging F3-F4 fibrosis (AUC 0.863, 0.774, and 0.792, respectively), with LSM having the highest sensitivity (90%), and the highest NPV (94%), and NFS and FIB-4 the highest specificity (97% and 93%, respectively), and the highest PPV (73% and 79%, respectively). The paired combination of LSM or NFS with FIB-4 strongly reduced the likelihood of wrongly classified patients (ranging from 2.7% to 2.6%), at the price of a high uncertainty area (ranging from 54.1% to 58.2%), and of a low overall accuracy (ranging from 43% to 39.1%). The serial combination with the second test used in patients in the grey area of the first test and in those with high LSM values (>9.6 KPa) or low NFS or FIB-4 values (<-1.455 and <1.30, respectively) overall increased the diagnostic performance generating an accuracy ranging from 69.8% to 70.1%, an uncertainty area ranging from 18.9% to 20.4% and a rate of wrong classification ranging from 9.2% to 11.3%. The serial combination of LSM with FIB-4/NFS has a good diagnostic accuracy for the non-invasive diagnosis of severe fibrosis in NAFLD. © 2017 John Wiley & Sons Ltd.

  2. Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

    2018-04-01

    Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

  3. Continuous Grading of Early Fibrosis in NAFLD Using Label-Free Imaging: A Proof-of-Concept Study.

    PubMed

    Pirhonen, Juho; Arola, Johanna; Sädevirta, Sanja; Luukkonen, Panu; Karppinen, Sanna-Maria; Pihlajaniemi, Taina; Isomäki, Antti; Hukkanen, Mika; Yki-Järvinen, Hannele; Ikonen, Elina

    2016-01-01

    Early detection of fibrosis is important in identifying individuals at risk for advanced liver disease in non-alcoholic fatty liver disease (NAFLD). We tested whether second-harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy, detecting fibrillar collagen and fat in a label-free manner, might allow automated and sensitive quantification of early fibrosis in NAFLD. We analyzed 32 surgical biopsies from patients covering histological fibrosis stages 0-4, using multimodal label-free microscopy. Native samples were visualized by SHG and CARS imaging for detecting fibrillar collagen and fat. Furthermore, we developed a method for quantitative assessment of early fibrosis using automated analysis of SHG signals. We found that the SHG mean signal intensity correlated well with fibrosis stage and the mean CARS signal intensity with liver fat. Little overlap in SHG signal intensities between fibrosis stages 0 and 1 was observed. A specific fibrillar SHG signal was detected in the liver parenchyma outside portal areas in all samples histologically classified as having no fibrosis. This signal correlated with immunohistochemical location of fibrillar collagens I and III. This study demonstrates that label-free SHG imaging detects fibrillar collagen deposition in NAFLD more sensitively than routine histological staging and enables observer-independent quantification of early fibrosis in NAFLD with continuous grading.

  4. Continuous Grading of Early Fibrosis in NAFLD Using Label-Free Imaging: A Proof-of-Concept Study

    PubMed Central

    Pirhonen, Juho; Arola, Johanna; Sädevirta, Sanja; Luukkonen, Panu; Karppinen, Sanna-Maria; Pihlajaniemi, Taina; Isomäki, Antti; Hukkanen, Mika

    2016-01-01

    Background and Aims Early detection of fibrosis is important in identifying individuals at risk for advanced liver disease in non-alcoholic fatty liver disease (NAFLD). We tested whether second-harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy, detecting fibrillar collagen and fat in a label-free manner, might allow automated and sensitive quantification of early fibrosis in NAFLD. Methods We analyzed 32 surgical biopsies from patients covering histological fibrosis stages 0–4, using multimodal label-free microscopy. Native samples were visualized by SHG and CARS imaging for detecting fibrillar collagen and fat. Furthermore, we developed a method for quantitative assessment of early fibrosis using automated analysis of SHG signals. Results We found that the SHG mean signal intensity correlated well with fibrosis stage and the mean CARS signal intensity with liver fat. Little overlap in SHG signal intensities between fibrosis stages 0 and 1 was observed. A specific fibrillar SHG signal was detected in the liver parenchyma outside portal areas in all samples histologically classified as having no fibrosis. This signal correlated with immunohistochemical location of fibrillar collagens I and III. Conclusions This study demonstrates that label-free SHG imaging detects fibrillar collagen deposition in NAFLD more sensitively than routine histological staging and enables observer-independent quantification of early fibrosis in NAFLD with continuous grading. PMID:26808140

  5. Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

    PubMed Central

    Pasarín, Marcos; La Mura, Vincenzo; Gracia-Sancho, Jorge; García-Calderó, Héctor; Rodríguez-Vilarrupla, Aina; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G.

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation. PMID:22509248

  6. Non-alcoholic fatty liver disease (NAFLD) and significant hepatic fibrosis defined by non-invasive assessment in patients with type 2 diabetes.

    PubMed

    Sobhonslidsuk, Abhasnee; Pulsombat, Akharawit; Kaewdoung, Piyaporn; Petraksa, Supanna

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD), the most common liver problem in diabetes, is a risk factor for liver cancer. Diabetes, high body mass index (BMI) and old age can all contribute to NAFLD progression. Transient elastography (TE) is used for non-invasive fibrosis assessment. To identify the prevalence of NAFLD and significant hepatic fibrosis in diabetic patients and to assess associated factors. One hundred and forty-one diabetic and 60 normal subjects were screened. Fatty liver was diagnosed when increased hepatic echogenicity and vascular blunting were detected by ultrasonography. Liver stiffness measurement (LSM) representing hepatic fibrosis was assessed by TE. LSM ≥7 kPa was used to define significant hepatic fibrosis. Four cases were excluded due to positive hepatitis B viral markers and failed TE. Diabetic patients had higher BMI, systolic blood pressure, waist circumference and fasting glucose levels than normal subjects. Fatty liver was diagnosed in 82 (60.7%) diabetic patients but in none of the normal group. BMI (OR: 1.31; 95%CI: 1.02-1.69; p=0.038) and alanine aminotransferase (ALT)(OR: 1.14; 95%CI: 1.05-1.23; p=0.002) were associated with NAFLD. Diabetic patients with NAFLD had higher LSM than those without [5.99 (2.4) vs 4.76 (2.7) kPa, p=0.005)]. Significant hepatic fibrosis was more common in diabetic patients than in normal subjects [22 (16.1%) vs 1 (1.7%), p=0.002]. Aspartate aminotransferase (AST)(OR: 1.24; 95%CI: 1.07-1.42; p=0.003) was associated with significant hepatic fibrosis. Sixty and sixteen percent of diabetic patients were found to have NAFLD and significant hepatic fibrosis. High BMI and ALT levels are the predictors of NAFLD, and elevated AST level is associated with significant hepatic fibrosis.

  7. A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic Fatty liver disease.

    PubMed

    Mansoor, Sana; Collyer, Elizabeth; Alkhouri, Naim

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) and its spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis have been increasing in the pediatric population. The presence and severity of fibrosis in patients with NAFLD are important prognostic factors for the risk of disease progression to cirrhosis. The gold standard for staging liver fibrosis is a liver biopsy. However, given the risks of this procedure, especially in the pediatric population, the development of noninvasive markers to diagnose and monitor progression of NAFLD is desirable. This paper will review recently developed noninvasive methods for diagnosing liver fibrosis in children with NAFLD. These include simple fibrosis scores, advanced biochemical markers, and radiologic imaging studies. Simple fibrosis scores use readily available laboratory tests; available one include AST/ALT ratio, AST to platelet ratio index (APRI), fibrosis (FIB)-4 index, NAFLD fibrosis score (NFS), pediatric NAFLD fibrosis index (PNFI), and pediatric NALFD fibrosis score (PNFS). Advanced biochemical markers include biomarkers of hepatocyte cell death such as cytokeratin 18 fragment levels, and markers of extracellular matrix turnover such as the Enhanced Liver Fibrosis (ELF) test and hyaluronic acid. Radiologic imaging studies estimate liver stiffness as a surrogate for liver fibrosis; these include transient elastography (TE), magnetic resonance elastography (MRE), and acoustic radiation force impulse imaging (ARFI).

  8. Clinical risk scoring for predicting non-alcoholic fatty liver disease in metabolic syndrome patients (NAFLD-MS score).

    PubMed

    Saokaew, Surasak; Kanchanasuwan, Shada; Apisarnthanarak, Piyaporn; Charoensak, Aphinya; Charatcharoenwitthaya, Phunchai; Phisalprapa, Pochamana; Chaiyakunapruk, Nathorn

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) can progress from simple steatosis to hepatocellular carcinoma. None of tools have been developed specifically for high-risk patients. This study aimed to develop a simple risk scoring to predict NAFLD in patients with metabolic syndrome (MetS). A total of 509 patients with MetS were recruited. All were diagnosed by clinicians with ultrasonography-confirmed whether they were patients with NAFLD. Patients were randomly divided into derivation (n=400) and validation (n=109) cohort. To develop the risk score, clinical risk indicators measured at the time of recruitment were built by logistic regression. Regression coefficients were transformed into item scores and added up to a total score. A risk scoring scheme was developed from clinical predictors: BMI ≥25, AST/ALT ≥1, ALT ≥40, type 2 diabetes mellitus and central obesity. The scoring scheme was applied in validation cohort to test the performance. The scheme explained, by area under the receiver operating characteristic curve (AuROC), 76.8% of being NAFLD with good calibration (Hosmer-Lemeshow χ 2 =4.35; P=.629). The positive likelihood ratio of NAFLD in patients with low risk (scores below 3) and high risk (scores 5 and over) were 2.32 (95% CI: 1.90-2.82) and 7.77 (95% CI: 2.47-24.47) respectively. When applied in validation cohort, the score showed good performance with AuROC 76.7%, and illustrated 84%, and 100% certainty in low- and high-risk groups respectively. A simple and non-invasive scoring scheme of five predictors provides good prediction indices for NAFLD in MetS patients. This scheme may help clinicians in order to take further appropriate action. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Non-alcoholic fatty liver disease fibrosis score and FIB-4 scoring system could identify patients at risk of systemic complications.

    PubMed

    Takahashi, Yuka; Kurosaki, Masayuki; Tamaki, Nobuharu; Yasui, Yutaka; Hosokawa, Takanori; Tsuchiya, Kaoru; Nakanishi, Hiroyuki; Itakura, Jun; Izumi, Namiki

    2015-06-01

    To investigate the relation between systemic complications of non-alcoholic fatty liver disease (NAFLD) and non-invasive fibrosis scores. The NAFLD fibrosis score (NFS) and FIB-4 were measured in 1559 people who underwent a complete medical checkup at our hospital and were followed for more than 3 years. Correlation between these scores and prevalence and new incidence rates of diabetes or cerebral-cardiovascular diseases were analyzed. The 1559 cases were classified into two groups using the low cut-off values of NFS and FIB-4: group 1 (≥low cut-off score with fatty liver) and group 2 (the others). In group 1, the prevalence of diabetes and cerebral-cardiovascular diseases at baseline and additional incidences during the observation period was higher compared with group 2. Diabetes at baseline in group 1 versus group 2 were 31.5% versus 3.1% (NFS, P < 0.0001), 17.0% versus 4.7% (FIB-4, P < 0.0001), and cerebral-cardiovascular diseases at baseline were 7.7% versus 2.3% (NFS, P = 0.002) and 9.0% versus 2.3% (FIB-4, P = 0.0012). New incidences of diabetes were 4.5% versus 1.2% (NFS, P = 0.034) and 3.6% versus 1.2% (FIB-4, P = 0.11), and of cerebral-cardiovascular diseases were 5.0% versus 0.9% (NFS, P = 0.0019) and 5.4% versus 0.9% (FIB-4, P = 0.0034). NFS and FIB-4 are useful to extract cases with high risk of systemic complications of NAFLD in the public. © 2014 The Japan Society of Hepatology.

  10. Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

    PubMed Central

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients. PMID:27363523

  11. Steatosis Grade is the Most Important Risk Factor for Development of Endothelial Dysfunction in NAFLD

    PubMed Central

    Sapmaz, Ferdane; Uzman, Metin; Basyigit, Sebahat; Ozkan, Selcuk; Yavuz, Bunyamin; Yeniova, Abdullah; Kefeli, Ayse; Asilturk, Zeliha; Nazligül, Yasar

    2016-01-01

    Abstract It is shown that there are strong associations between nonalcoholic fatty liver disease (NAFLD) and endothelial dysfunction. The aim of our study was to reveal whether steatosis or fibrosis score is more important in the development of endothelial dysfunction in patients with NAFLD in a prospective manner. This cross-sectional study included 266 subjects. These subjects were divided into 2 groups depending on presence of hepatosteatosis sonographically. Patients with hepatosteatosis were also divided into 3 subgroups depending on degree of steatosis: grade 1, 2, and 3. In all patients, Aspartate aminotransferase-to-Platelet Ratio Index and Fibrosis-4 (FIB4) scores were calculated. In addition, flow-mediated dilatation (FMD) measurements were recorded. There was NAFLD in 176 (66.2%) of 266 patients included. There were no significant differences in sex and age distributions between patients with NAFLD (group 1) and controls without NAFLD (group 2) (P = 0.05). Mean Aspartate aminotransferase-to-Platelet Ratio Index score was significantly higher in group 1 compared with the control group (P = 0.001), whereas no significant difference was detected regarding FIB4 scores between groups (P = 0.4). Mean FMD value was found to be significantly lower in group 1 (P = 0.008). Patients with grade 3 hepatosteatosis had significantly lower FMD values than those with grade 1 steatosis and controls (P = 0.001). In univariate and multivariate analyses in group 1, no significant difference was detected regarding mean FMD measurements (P = 0.03). Again, no significant difference was detected in mean FMD measurement between FIB4 subgroups among patients with NAFLD and the whole study group (P = 0.09). The endothelial dysfunction is associated with steatosis in patients with NAFLD. PMID:27057890

  12. Knowledge-based identification of soluble biomarkers: hepatic fibrosis in NAFLD as an example.

    PubMed

    Page, Sandra; Birerdinc, Aybike; Estep, Michael; Stepanova, Maria; Afendy, Arian; Petricoin, Emanuel; Younossi, Zobair; Chandhoke, Vikas; Baranova, Ancha

    2013-01-01

    The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases.

  13. Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example

    PubMed Central

    Page, Sandra; Birerdinc, Aybike; Estep, Michael; Stepanova, Maria; Afendy, Arian; Petricoin, Emanuel; Younossi, Zobair; Chandhoke, Vikas; Baranova, Ancha

    2013-01-01

    The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases. PMID:23405244

  14. New scoring system combining the FIB-4 index and cytokeratin-18 fragments for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Saibara, Toshiji; Ono, Masafumi; Kage, Masayoshi

    To establish a new scoring system as a noninvasive tool for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). A total of 170 patients histologically diagnosed with nonalcoholic steatohepatitis (NASH) (n = 130) or nonalcoholic fatty liver (NAFL) (n = 40) were enrolled. We analyzed receiver operating characteristic (ROC) curves and performed multivariate analysis to predict steatohepatitis and liver fibrosis. Multivariate analysis showed that cytokeratin-18 fragment (CK18-F) levels (≥278 U/L) (odds ratio [OR], 4.46; 95% confidence interval [CI], 1.42-14.00; p = 0.010) and the FIB-4 index (≥1.46) (OR, 4.54; 95% CI, 1.93-29.50; p = 0.004) were independently associated with prediction of NASH. We then established a new scoring system (named the FIC-22 score) for predicting NASH using CK18-F levels and FIB-4 index. The areas under the ROC curve (AUROCs) of the FIC-22 score and NAFIC score were 0.82 (95% CI, 0.75-0.89) and 0.71 (95% CI, 0.62-0.78) (p = 0.044). Additionally, the AUROC of the FIC-22 score for predicting the presence of fibrosis (F ≥ 1) was 0.78 (95% CI, 0.70-0.85). In patients with NAFLD, the FIC-22 score had high predictive accuracy not only for steatohepatitis but also for the presence of liver fibrosis.

  15. The Expression of PNPLA3 Polymorphism could be the Key for Severe Liver Disease in NAFLD in Hispanic Population.

    PubMed

    Martínez, Leonardo A; Larrieta, Elena; Kershenobich, David; Torre, Aldo

    Nonalcoholic fatty liver disease (NAFLD) encompasses: fatty liver (SS), steatohepatitis (NASH) with or without fibrosis and cirrhosis. Patatine-like phosphatas in domain 3 (PNPLA3; adiponutrin; SNP rs738409 C/G, M148I) shows anabolic and catabolic activities on lipid metabolism and significant association to fatty liver content; however, I148M demographics and ethnics, as its role with NAFLD have not been fully elucidated. PNPLA3 genotyping from peripheral blood DNA by polymerase chain reaction (PCR) and direct sequencing, 211 patients diagnosed with NAFLD including SS, NASH and fibrosis spectrum. Eighty nine per cent showed the G risk allele [CC: 23 (10.5%), GC: 73 (34.7%), GG 115 (54.7%)], the allele frequency was 77%, NASH (71%), SS (80%) and fibrosis (73%). GG genotype carriers showed 3.8 times (CI 95%: 3.03 - 4.79) of increased risk of steatohepatitis and 2.3 times more (CI 95%: 1.77 ~ 3.23) risk of having liver fibrosis (CC). PNPLA3 (GC, GG) conditioned higher probability of low levels of HDL cholesterol (p < 0.010), SS even in normal weight (p < 0.007), insulin resistance by HOMA (p < 0.029), NAFLD fibrosis score showed > 0.675 (p < 0.001) and altered serum alanine aminotransferase (p < 0.05). PNPLA3 expression in Hispanics could be decisive in NAFLD pathogenesis, it's highly prevalent and it's a key to condition and determine the spectrum associated, SS, NASH and fibrosis.

  16. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States.

    PubMed

    Le, Michael H; Devaki, Pardha; Ha, Nghiem B; Jun, Dae Won; Te, Helen S; Cheung, Ramsey C; Nguyen, Mindie H

    2017-01-01

    In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988-1994. Our goal was to determine the NAFLD prevalence in the recent 1999-2012 NHANES, risk factors for advanced fibrosis (stage 3-4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93-5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality.

  17. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Arora, Anil; Sharma, Praveen

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation. PMID:25755423

  18. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

    PubMed

    Stål, Per

    2015-10-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

  19. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance

    PubMed Central

    Stål, Per

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD. PMID:26494963

  20. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis.

    PubMed

    Patel, Preya J; Banh, Xuan; Horsfall, Leigh U; Hayward, Kelly L; Hossain, Fabrina; Johnson, Tracey; Stuart, Katherine A; Brown, Nigel N; Saad, Nivene; Clouston, Andrew; Irvine, Katharine M; Russell, Anthony W; Valery, Patricia C; Williams, Suzanne; Powell, Elizabeth E

    2018-02-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis. To evaluate primary care clinicians' current approach to diagnosis, management and referral of NAFLD. A cross-sectional survey of primary care clinicians was undertaken through a structured questionnaire about NAFLD. A convenience sample of general practice clinics and general practice conferences in Metropolitan Brisbane and regional south east Queensland was selected. A total of 108 primary care clinicians completed the survey (participation rate 100%). Fifty-one percent of respondents considered the prevalence of NAFLD in the general population to be ≤10%. Twenty-four percent of respondents felt that liver enzymes were sufficiently sensitive to detect underlying NAFLD. Most respondents were unsure whether the Fibrosis 4 score (62.7% unsure) or Enhanced Liver Fibrosis score (63.7% unsure) could help to identify advanced fibrosis or cirrhosis. Although 47% of respondents said they would refer a patient to a Gastroenterologist/Hepatologist if they suspect the patient has NAFLD, 44.1% do not make any referrals. Of concern, 70.6% of clinicians said they were unlikely to refer a patient to Hepatology unless liver function tests are abnormal. Our findings demonstrate that many primary care clinicians underestimate the prevalence of NAFLD and under-recognise the clinical spectrum of NAFLD and how this is assessed. © 2017 Royal Australasian College of Physicians.

  1. Analytical, anthropometric and dietary factors associated with the development of fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Gómez de la Cuesta, Sara; Aller de la Fuente, Rocío; Tafur Sánchez, Carla; Izaola, Olatz; García Sánchez, Concepción; Mora, Natalia; González Hernández, Jose Manuel; de Luis Román, Daniel

    2018-05-01

    a prolonged non-alcoholic steatohepatitis (NASH) condition can lead to advanced stages of liver disease and the development of hepatocellular carcinoma. to evaluate analytical, anthropometric and dietary factors associated with the presence of fibrosis as this is the factor that most influences survival and evolution. seventy-six patients with liver biopsy-diagnosed non-alcoholic fatty liver disease (NAFLD) were included. Biopsies were scored considering the NASH criteria of Kleiner. Analytical, anthropometric and dietary (survey) parameters were obtained. NAFLD-FS is a non-invasive fibrosis index and was assessed for each patient. Leptin, adiponectin, resistin and TNF-alpha serum levels were determined. fifty-six patients were male (73.7%) and the mean age was 44.5 ± 11.3 years of age (19-68). Thirty-nine (51.3%) (F1-F2: 84.6%; F3-4: 15.4%) patients had fibrosis in the liver biopsy. Seventeen females (85%) had fibrosis versus 22 males (39%), which was statistically significant by univariate analysis (p < 0.01). Patients with advanced fibrosis were older, with lower platelet counts, lower serum albumin, greater homeostatic model assessment insulin resistance (HOMA-IR), lower dietary lipids percentage, higher serum leptin levels and higher NAFLD Fibrosis Score (NAFLD-FS) values. This index had a negative predictive value of 98% and a positive predictive value of 60% for the detection of fibrosis. Variables independently associated with fibrosis (logistic regression) included male gender (protective factor) (0.09, 95% CI 0.01-0.7; p < 0.05) and HOMA-IR (1.7, 95% CI, 1.03-2.79; p < 0.05). gender and HOMA-IR were the only independent factors associated with fibrosis. NAFLD-FS could be considered as an accurate scoring system to rule out advanced fibrosis.

  2. Association between liver fibrosis and coronary heart disease risk in patients with nonalcoholic fatty liver disease.

    PubMed

    Dogan, Serkan; Celikbilek, Mehmet; Yilmaz, Yunus K; Sarikaya, Savas; Zararsiz, Gokmen; Serin, Halil I; Borekci, Elif; Akyol, Lütfi; Pirti, Ilyas; Davarci, Sena E

    2015-03-01

    Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as the most common cause of chronic liver disease worldwide. It has been shown that NAFLD in adults is associated with increased risk of coronary heart disease (CHD). Because of the limitations of liver biopsy, noninvasive scoring indexes such as the NAFLD fibrosis score (NFS) were developed. The Framingham risk score (FRS) provides an estimate of CHD risk. In our study we aimed to investigate whether the severity of liver fibrosis estimated with the NFS is associated with a higher risk of CHD among individuals with ultrasonography-diagnosed NAFLD. A total of 155 patients and controls (81 patients with NAFLD and 74 controls) with ages ranging from 18 to 70 years were enrolled in this cross-sectional prospective study. Demographic, anthropometric, clinical, and laboratory data were obtained from each individual. The NAFLD patients were divided into subgroups on the basis of the severity of fatty liver. The FRS and NFS were adopted to predict the risk of CHD and the severity of hepatic fibrosis. In our study, we found that the FRS was higher in NAFLD patients than in controls (P<0.05). According to the FRS category, NFSs were higher in the intermediate/high probability CHD risk group in NAFLD (P<0.05). In multiple models, only age, sex, cholesterol, and HDL were independently associated with intermediate/high CHD risk (P<0.05). We also found a positive correlation between the NFS and the FRS (r=0.373, P<0.001). The optimum NFS cutoff point for identifying intermediate/high CHD risk in NAFLD patients was -2.1284, with a sensitivity and specificity of 95.20 and 48.30%, respectively. The predictive performance of the NFS in the determination of intermediate/high CHD risk in NAFLD patients was found to be 72% based on the area under the curve value. The FRS is associated with the NFS in NAFLD. The assessment of liver fibrosis may be useful for the risk stratification of CHD in the absence of liver

  3. Quantitative Imaging Biomarkers of NAFLD

    PubMed Central

    Kinner, Sonja; Reeder, Scott B.

    2016-01-01

    Conventional imaging modalities, including ultrasonography (US), computed tomography (CT), and magnetic resonance (MR), play an important role in the diagnosis and management of patients with nonalcoholic fatty liver disease (NAFLD) by allowing noninvasive diagnosis of hepatic steatosis. However, conventional imaging modalities are limited as biomarkers of NAFLD for various reasons. Multi-parametric quantitative MRI techniques overcome many of the shortcomings of conventional imaging and allow comprehensive and objective evaluation of NAFLD. MRI can provide unconfounded biomarkers of hepatic fat, iron, and fibrosis in a single examination—a virtual biopsy has become a clinical reality. In this article, we will review the utility and limitation of conventional US, CT, and MR imaging for the diagnosis NAFLD. Recent advances in imaging biomarkers of NAFLD are also discussed with an emphasis in multi-parametric quantitative MRI. PMID:26848588

  4. Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.

    PubMed

    Rastogi, Archana; Shasthry, Saggere Muralikrishna; Agarwal, Ayushi; Bihari, Chhagan; Jain, Priyanka; Jindal, Ankur; Sarin, Shiv

    2017-11-01

    Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow-up studies of non-alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS-CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS-CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS-CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3-4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt-out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0

  5. Suboptimal performance of simple noninvasive tests for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease.

    PubMed

    Xun, Yun Hao; Fan, Jian Gao; Zang, Guo Qing; Liu, Hong; Jiang, Yan Ming; Xiang, Jing; Huang, Qian; Shi, Jun Ping

    2012-11-01

    To evaluate the diagnostic accuracy of some noninvasive fibrosis models in Chinese patients with nonalcoholic fatty liver disease (NAFLD). Consecutive biopsy-proven NAFLD patients were recruited from a single center from January 2005 to December 2010. Advanced fibrosis (stage 3 and 4) was defined using Kleiner criteria. The area under the receiver operating characteristic curve (AUROC) was used to compare the diagnostic accuracy of the NAFLD fibrosis score (NFS), FIB-4 index, aspartate transaminase (AST)/platelet ratio index (APRI), AST/alanine transaminase (ALT) ratio (AAR) and body mass index (BMI)-AAR-Diabetes (BARD) score. Of the patients with NAFLD, 79.6% were males with a mean age of 37.1 years, mean BMI of 26.1 kg/m(2) and 41.4% of them had nonalcoholic steatohepatitis, and 24 (15.8%) had advanced fibrosis. The AUROC of the FIB-4 index, APRI, AAR, NFS and BARD score for advanced fibrosis were 0.756, 0.742, 0.670, 0.653 and 0.642 (P < 0.05 for all), respectively. A concordant negative predictive value of approximately 90% was indicated whereas the positive predictive values were modest for all tests, and only the FIB-4 index yielded a higher positive likelihood ratio of 7.65. Using these cut-off values of tests for excluding advanced fibrosis could reduce the use of liver biopsy in 56.6-74.3% of the patients, with a minor false negative rate of 5.3-9.9%. Although slightly less accurate than liver biopsy, simple noninvasive tests can reliably exclude advanced fibrosis in Chinese NAFLD patients in our center. FIB-4 index performs better than the other tests under examination. © 2012 The Authors. Journal of Digestive Diseases © 2012 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  6. Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms.

    PubMed

    Lykiardopoulos, Byron; Hagström, Hannes; Fredrikson, Mats; Ignatova, Simone; Stål, Per; Hultcrantz, Rolf; Ekstedt, Mattias; Kechagias, Stergios

    2016-01-01

    Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, King´s score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). Of established algorithms FIB-4 and King´s score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts.

  7. The impact of non-alcoholic fatty liver disease fibrosis score on cardiac prognosis in patients with chronic heart failure.

    PubMed

    Takahashi, Tetsuya; Watanabe, Tetsu; Shishido, Tetsuro; Watanabe, Ken; Sugai, Takayuki; Toshima, Taku; Kinoshita, Daisuke; Yokoyama, Miyuki; Tamura, Harutoshi; Nishiyama, Satoshi; Arimoto, Takanori; Takahashi, Hiroki; Yamanaka, Tamon; Miyamoto, Takuya; Kubota, Isao

    2018-07-01

    Liver abnormalities have a strong impact on clinical outcomes in patients with heart failure (HF), and are known as cardio-hepatic syndrome. The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has been developed to identify liver fibrosis in patients with NAFLD. It remains to be determined whether NFS is associated with cardiovascular prognosis in patients with chronic heart failure (CHF). We calculated NFS in 516 patients with CHF admitted to our hospital. The clinical endpoints were deaths due to progressive HF, myocardial infarction, stroke, and sudden cardiac death, and rehospitalization for worsening HF. There were 173 cardiovascular events noted during a median follow-up of 464 days. Patients with cardiovascular events showed a higher NFS as compared with those without. We divided the patients into four groups according to quartiles of NFS. The proportion of New York Heart Association functional class III/IV and serum brain natriuretic peptide levels were increased with increasing NFS. Kaplan-Meier analysis revealed that cardiovascular event rate was increased with increasing NFS in patients with CHF. In multivariate Cox proportional hazards analysis, NFS was independently associated with cardiovascular events after adjustment for confounding factors. Elevated NFS was associated with unfavorable outcomes in patients with CHF. Liver fibrosis assessed by NFS may provide valuable prognostic information in patients with CHF.

  8. The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

    PubMed Central

    Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu; Machado, Mariana; Fizanne, Lionel; Araujo-Perez, Felix; Guy, Cynthia D.; Seed, Patrick C.; Rawls, John F.; David, Lawrence A.; Hunault, Gilles; Oberti, Frédéric; Calès, Paul; Diehl, Anna Mae

    2016-01-01

    Background & aims Several animal studies have emphasized the role of gut microbiota in non-alcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remains scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, i.e. non-alcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Methods 57 patients with biopsy-proven NAFLD were enrolled. The taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Results 30 patients had F0/1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these 2 bacteria generated 3 patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, KEGG pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre/probiotics therapies. PMID:26600078

  9. Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

    PubMed

    Otgonsuren, Munkhzul; Estep, Michael J; Hossain, Nayeem; Younossi, Elena; Frost, Spencer; Henry, Linda; Hunt, Sharon; Fang, Yun; Goodman, Zachary; Younossi, Zobair M

    2014-12-01

    Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). A liver biopsy is considered the "gold standard" for diagnosing/staging NASH. Identification of NAFLD/NASH using non-invasive tools is important for intervention. The study aims were to: develop/validate the predictive performance of a non-invasive model (index of NASH [ION]); assess the performance of a recognized non-invasive model (fatty liver index [FLI]) compared with ION for NAFLD diagnosis; determine which non-invasive model (FLI, ION, or NAFLD fibrosis score [NFS]) performed best in predicting age-adjusted mortality. From the National Health and Nutrition Examination Survey III database, anthropometric, clinical, ultrasound, laboratory, and mortality data were obtained (n = 4458; n = 861 [19.3%] NAFLD by ultrasound) and used to develop the ION model, and then to compare the ION and FLI models for NAFLD diagnosis. For validation and diagnosis of NASH, liver biopsy data were used (n = 152). Age-adjusted Cox proportional hazard modeling estimated the association among the three non-invasive tests (FLI, ION, and NFS) and mortality. FLI's threshold score > 60 and ION's threshold score > 22 had similar specificity (FLI = 80% vs ION = 82%) for NAFLD diagnosis; FLI < 30 (80% sensitivity) and ION < 11 (81% sensitivity) excluded NAFLD. An ION score > 50 predicted histological NASH (92% specificity); the FLI model did not predict NASH or mortality. The ION model was best in predicting cardiovascular/diabetes-related mortality; NFS predicted overall or diabetes-related mortality. The ION model was superior in predicting NASH and mortality compared with the FLI model. Studies are needed to validate ION. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  10. Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Alazawi, William; Bernabe, Eduardo; Tai, David; Janicki, Tomasz; Kemos, Polychronis; Samsuddin, Salma; Syn, Wing-Kin; Gillam, David; Turner, Wendy

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups. We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy) underwent dental examination. Basic Periodontal Examination score was recorded. In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4) than without NASH (p = 0.009). Periodontitis was more common in patients with NASH and significant fibrosis (F2-4) than mild or no fibrosis (F0-1, p = 0.04). Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.

  11. Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation.

    PubMed

    Carotti, Simone; Vespasiani-Gentilucci, Umberto; Perrone, Giuseppe; Picardi, Antonio; Morini, Sergio

    2015-11-01

    We investigated whether portal tract inflammation observed in non-alcoholic fatty liver disease (NAFLD) is associated with hepatic progenitor cell compartment activation, as thoroughly evaluated with different markers of the staminal lineage. Fifty-two patients with NAFLD were studied. NAFLD activity score, fibrosis and portal inflammation were histologically evaluated. Putative hepatic progenitor cells, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for cytokeratin (CK)-7, CK-19 and epithelial cell adhesion molecule (EpCAM), and a hepatic progenitor cell compartment score was derived. Hepatic stellate cell and myofibroblast activity was determined by immunohistochemistry for α-smooth muscle actin. Portal inflammation was absent in a minority of patients, mild in 40% of cases and more than mild in about half of patients, showing a strong correlation with fibrosis (r=0.76, p<0.001). Portal inflammation correlated with CK-7-counted putative hepatic progenitor cells (r=0.48, p<0.001), intermediate hepatobiliary cells (r=0.6, p<0.001) and bile ductules/interlobular bile ducts (r=0.6, p<0.001), and with the activity of myofibroblasts (r=0.5, p<0.001). Correlations were confirmed when elements were counted by immunostaining for CK-19 and EpCAM. Lobular inflammation, ballooning, myofibroblast activity and hepatic progenitor cell compartment activation were associated with portal inflammation by univariate analysis. In the multivariate model, the only variable independently associated with portal inflammation was hepatic progenitor cell compartment activation (OR 3.7, 95% CI 1.1 to 12.6). Portal inflammation is frequent during NAFLD and strongly associated with activation of putative hepatic progenitor cells since the first steps of their differentiation, portal myofibroblast activity and fibrosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a

  12. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice

    PubMed Central

    Dulai, Parambir S.; Sirlin, Claude B.; Loomba, Rohit

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease, and its prevalence is rising worldwide. The occurrence of nonalcoholic steatohepatitis (NASH) is associated with a substantial increase in disease related morbidity and mortality. Accordingly, there has been a surge of innovation surrounding drug development in an effort to off-set the natural progression and long-term risks of this disease. Disease assessment within clinical trials and clinical practice for NAFLD is currently done with liver biopsies. Liver biopsy-based assessments, however, remain imprecise and are not without cost or risk. This carries significant implications for the feasibility and costs of bringing therapeutic interventions to market. A need therefore arises for reliable and highly accurate surrogate end-points that can be used in phase 2 and 3 clinical trials to reduce trial size requirements and costs, while improving feasibility and ease of implementation in clinical practice. Significant advances have now been made in magnetic resonance technology, and magnetic resonance imaging (MRI) and elastrography (MRE) have been demonstrated to be highly accurate diagnostic tools for the detection of hepatic steatosis and fibrosis. In this review article, we will summarize the currently available evidence regarding the use of MRI and MRE among NAFLD patients, and the evolving role these surrogate biomarkers will play in the rapidly advancing arena of clinical trials in NASH and hepatic fibrosis. Furthermore, we will highlight how these tools can be readily applied to routine clinical practice, where the growing burden of NAFLD will need to be met with enhanced monitoring algorithms. PMID:27312947

  13. Prognostic Value of Non-Invasive Fibrosis and Steatosis Tools, Hepatic Venous Pressure Gradient (HVPG) and Histology in Nonalcoholic Steatohepatitis.

    PubMed

    Sebastiani, Giada; Alshaalan, Rasha; Wong, Philip; Rubino, Maria; Salman, Ayat; Metrakos, Peter; Deschenes, Marc; Ghali, Peter

    2015-01-01

    Non-invasive diagnostic methods for liver fibrosis predict clinical outcomes in viral hepatitis and nonalcoholic fatty liver disease (NAFLD). We specifically evaluated prognostic value of non-invasive fibrosis methods in nonalcoholic steatohepatitis (NASH) against hepatic venous pressure gradient (HVPG) and liver histology. This was a retrospective cohort study of 148 consecutive patients who met the following criteria: transjugular liver biopsy with HVPG measurement; biopsy-proven NASH; absence of decompensation; AST-to-Platelets Ratio Index (APRI), fibrosis-4 (FIB-4), NAFLD fibrosis score, ultrasound, hepatic steatosis index and Xenon-133 scan available within 6 months from biopsy; a minimum follow-up of 1 year. Outcomes were defined by death, liver transplantation, cirrhosis complications. Kaplan-Meier and Cox regression analyses were employed to estimate incidence and predictors of outcomes, respectively. Prognostic value was expressed as area under the curve (AUC). During a median follow-up of 5 years (interquartile range 3-8), 16.2% developed outcomes, including 7.4% who died or underwent liver transplantation. After adjustment for age, sex, diabetes, the following fibrosis tools predicted outcomes: HVPG >10mmHg (HR=9.60; 95% confidence interval [CI] 3.07-30.12), histologic fibrosis F3-F4 (HR=3.14; 1.41-6.95), APRI >1.5 (HR=5.02; 1.6-15.7), FIB-4 >3.25 (HR=6.33; 1.98-20.2), NAFLD fibrosis score >0.676 (HR=11.9; 3.79-37.4). Prognostic value was as follows: histologic fibrosis stage, AUC=0.85 (95% CI 0.76-0.93); HVPG, AUC=0.81 (0.70-0.91); APRI, AUC=0.89 (0.82-0.96); FIB-4, AUC=0.89 (0.83-0.95); NAFLD fibrosis score, AUC=0.79 (0.69-0.91). Neither histologic steatosis nor non-invasive steatosis methods predicted outcomes (AUC<0.50). Non-invasive methods for liver fibrosis predict outcomes of patients with NASH. They could be used for serial monitoring, risk stratification and targeted interventions.

  14. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis.

    PubMed

    Xiao, Guangqin; Zhu, Sixian; Xiao, Xiao; Yan, Lunan; Yang, Jiayin; Wu, Gang

    2017-11-01

    Many noninvasive methods for diagnosing liver fibrosis (LF) have been proposed. To determine the best method for diagnosing LF in nonalcoholic fatty liver disease (NAFLD), we conducted a systemic review and meta-analysis to compare the performance of aspartate aminotransferase to platelets ratio index (APRI), fibrosis-4 index (FIB-4), BARD score, NAFLD fibrosis score (NFS), FibroScan, shear wave elastography (SWE), and magnetic resonance elastography (MRE) for diagnosing LF in NAFLD. We compared the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC) of these noninvasive methods for detecting significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis. Heterogeneity was explored using meta-regression. Sixty-four articles with a total of 13,046 NAFLD subjects were included. The overall mean prevalence of SF, AF, and cirrhosis was 45.0%, 24.0%, and 9.4% in NAFLD patients, respectively. With an APRI threshold of 1.0 and 1.5, the sensitivities and specificities were 50.0% and 84.0% and 18.3% and 96.1%, respectively, for AF. With a FIB-4 threshold of 2.67 and 3.25, the sensitivities and specificities were 26.6% and 96.5% and 31.8% and 96.0%, respectively, for AF. The summary sensitivities and specificities of BARD score (threshold of 2), NFS (threshold of -1.455), FibroScan M (threshold of 8.7-9), SWE, and MRE for detecting AF were 0.76 and 0.61, 0.72 and 0.70, 0.87 and 0.79, 0.90 and 0.93, and 0.84 and 0.90, respectively. The summary AUROC values using APRI, FIB-4, BARD score, NFS, FibroScan M probe, XL probe, SWE, and MRE for diagnosing AF were 0.77, 0.84, 0.76, 0.84, 0.88, 0.85, 0.95, and 0.96, respectively. MRE and SWE may have the highest diagnostic accuracy for staging fibrosis in NAFLD patients. Among the four noninvasive simple indexes, NFS and FIB-4 probably offer the best diagnostic performance for detecting AF. (Hepatology 2017;66:1486-1501). © 2017 by the

  15. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.

    PubMed

    Boursier, Jérôme; Vergniol, Julien; Guillet, Anne; Hiriart, Jean-Baptiste; Lannes, Adrien; Le Bail, Brigitte; Michalak, Sophie; Chermak, Faiza; Bertrais, Sandrine; Foucher, Juliette; Oberti, Frédéric; Charbonnier, Maude; Fouchard-Hubert, Isabelle; Rousselet, Marie-Christine; Calès, Paul; de Lédinghen, Victor

    2016-09-01

    NAFLD is highly prevalent but only a small subset of patients develop advanced liver fibrosis with impaired liver-related prognosis. We aimed to compare blood fibrosis tests and liver stiffness measurement (LSM) by FibroScan for the diagnosis of liver fibrosis and the evaluation of prognosis in NAFLD. Diagnostic accuracy was evaluated in a cross-sectional study including 452 NAFLD patients with liver biopsy (NASH-CRN fibrosis stage), LSM, and eight blood fibrosis tests (BARD, NAFLD fibrosis score, FibroMeter(NAFLD), aspartate aminotransferase to platelet ratio index (APRI), FIB4, FibroTest, Hepascore, FibroMeter(V2G)). Prognostic accuracy was evaluated in a longitudinal study including 360 NAFLD patients. LSM and FibroMeter(V2G) were the two best-performing tests in the cross-sectional study: AUROCs for advanced fibrosis (F3/4) were, respectively, 0.831±0.019 and 0.817±0.020 (p⩽0.041 vs. other tests); rates of patients with ⩾90% negative/positive predictive values for F3/4 were 56.4% and 46.7% (p<0.001 vs. other tests); Obuchowski indexes were 0.834±0.014 and 0.798±0.016 (p⩽0.036 vs. other tests). Two fibrosis classifications were developed to precisely estimate the histological fibrosis stage from LSM or FibroMeter(V2G) results without liver biopsy (diagnostic accuracy, respectively: 80.8% vs. 77.4%, p=0.190). Kaplan-Meier curves in the longitudinal study showed that both classifications categorised NAFLD patients into subgroups with significantly different prognoses (p<0.001): the higher was the class of the fibrosis classification, the worse was the prognosis. LSM and FibroMeter(V2G) were the most accurate of nine evaluated tests for the non-invasive diagnosis of liver fibrosis in NAFLD. LSM and FibroMeter(V2G) fibrosis classifications help physicians estimate both fibrosis stage and patient prognosis in clinical practice. The amount of liver fibrosis is the main determinant of the liver-related prognosis in patients with non-alcoholic fatty liver

  16. A composite model including visfatin, tissue polypeptide-specific antigen, hyaluronic acid, and hematological variables for the diagnosis of moderate-to-severe fibrosis in nonalcoholic fatty liver disease: a preliminary study.

    PubMed

    Chwist, Alina; Hartleb, Marek; Lekstan, Andrzej; Kukla, Michał; Gutkowski, Krzysztof; Kajor, Maciej

    2014-01-01

    Histopathological risk factors for end-stage liver failure in patients with nonalcoholic fatty liver disease (NAFLD) include nonalcoholic steatohepatitis (NASH) and advanced liver fibrosis. There is a need for noninvasive diagnostic methods for these 2 conditions. The aim of this study was to investigate new laboratory variables with a predictive potential to detect advanced fibrosis (stages 2 and 3) in NAFLD. The study involved 70 patients with histologically proven NAFLD of varied severity. Additional laboratory variables included zonulin, haptoglobin, visfatin, adiponectin, leptin, tissue polypeptide-specific antigen (TPSA), hyaluronic acid, and interleukin 6. Patients with NASH (NAFLD activity score of ≥5) had significantly higher HOMA-IR values and serum levels of visfatin, haptoglobin, and zonulin as compared with those without NASH on histological examination. Advanced fibrosis was found in 16 patients (22.9%) and the risk factors associated with its prevalence were age, the ratio of erythrocyte count to red blood cell distribution width, platelet count, and serum levels of visfatin and TPSA. Based on these variables, we constructed a scoring system that differentiated between NAFLD patients with and without advanced fibrosis with a sensitivity of 75% and specificity of 100% (area under the receiver operating characteristic curve, 0.93). The scoring system based on the above variables allows to predict advanced fibrosis with high sensitivity and specificity. However, its clinical utility should be verified in further studies involving a larger number of patients.

  17. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD.

    PubMed

    Permutt, Z; Le, T-A; Peterson, M R; Seki, E; Brenner, D A; Sirlin, C; Loomba, R

    2012-07-01

    Conventional magnetic resonance imaging (MRI) techniques that measure hepatic steatosis are limited by T1 bias, T(2)* decay and multi-frequency signal-interference effects of protons in fat. Newer MR techniques such as the proton density-fat fraction (PDFF) that correct for these factors have not been specifically compared to liver biopsy in adult patients with non-alcoholic fatty liver disease (NAFLD). To examine the association between MRI-determined PDFF and histology-determined steatosis grade, and their association with fibrosis. A total of 51 adult patients with biopsy-confirmed NAFLD underwent metabolic-biochemical profiling, MRI-determined PDFF measurement of hepatic steatosis and liver biopsy assessment according to NASH-CRN histological scoring system. The average MRI-determined PDFF increased significantly with increasing histology-determined steatosis grade: 8.9% at grade-1, 16.3% at grade-2, and 25.0% at grade-3 with P ≤ 0.0001 (correlation: r(2) = 0.56, P < 0.0001). Patients with stage-4 fibrosis, when compared with patients with stage 0-3 fibrosis, had significantly lower hepatic steatosis by both MRI-determined PDFF (7.6% vs. 17.8%, P < 0.005) and histology-determined steatosis grade (1.4 vs. 2.2, P < 0.05). NAFLD patients with grade 1 steatosis were more likely to have characteristics of advanced liver disease including higher average AST:ALT (0.87 vs. 0.60, P < 0.02), GGT (140 vs. 67, P < 0.01), and INR (1.06 vs. 0.99, P < 0.01), higher stage of fibrosis and hepatocellular ballooning. MRI-determined proton density-fat fraction correlates with histology-determined steatosis grade in adults with NAFLD. Steatosis is non-linearly related to fibrosis progression. In patients with NAFLD, a low amount of hepatic steatosis on imaging does not necessarily indicate mild disease. © 2012 Blackwell Publishing Ltd.

  18. Diagnosis of different liver fibrosis characteristics by blood tests in non-alcoholic fatty liver disease.

    PubMed

    Calès, Paul; Boursier, Jérôme; Chaigneau, Julien; Lainé, Fabrice; Sandrini, Jeremy; Michalak, Sophie; Hubert, Isabelle; Dib, Nina; Oberti, Frédéric; Bertrais, Sandrine; Hunault, Gilles; Cavaro-Ménard, Christine; Gallois, Yves; Deugnier, Yves; Rousselet, Marie C

    2010-10-01

    Our aim was to develop an accurate, non-invasive, blood-test-based method for identifying the main characteristics of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Fibrosis was staged according to NASH-CRN and Metavir systems in 226 patients with NAFLD. A fully automated algorithm measured the fractal dimension (FD) and the area of fibrosis (AOF). Independent predictors of diagnostic targets were determined using bootstrap methods. (i) Development. Significant fibrosis defined by NASH-CRN F ≥2 was diagnosed by weight, glycaemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and prothrombin index [area under the receiver operating characteristic (AUROC)=0.867]; significant fibrosis defined by Metavir F ≥2 was diagnosed by weight, age, glycaemia, AST, ALT, ferritin and platelets (FibroMeter AUROC=0.941, P<0.005). AOF was estimated by the combination of hyaluronic acid, glycaemia, AST, ALT, platelets and prothrombin index ((a) R(2) =0.530), while FD was estimated by hyaluronic acid, glycaemia, AST/ALT, weight and platelets ((a) R(2) =0.529). (ii) Evaluation. Although NASH-CRN was a better system for fibrosis staging, Metavir staging was a better reference for blood test. Thus, the patient rate with predictive values ≥90% by tests was 97.3% with Metavir reference vs. 66.5% with NASH-CRN reference (P<10(-3)). FibroMeter showed a significantly higher AUROC than the NAFLD fibrosis score for significant fibrosis, but not for severe fibrosis or cirrhosis, with both staging systems. Relationships between fibrosis lesions were well reflected by blood tests, e.g., the correlation between histological area and FD of fibrosis (r(s) =0.971, P<10(-3)) was well reflected by the relationship between respective blood tests (r(s) =0.852, P<10(-3)). Different characteristics of fibrosis in NAFLD can be diagnosed and quantified by blood tests with excellent accuracy. © 2010 John Wiley & Sons A/S.

  19. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis.

    PubMed

    Caussy, Cyrielle; Soni, Meera; Cui, Jeffrey; Bettencourt, Ricki; Schork, Nicholas; Chen, Chi-Hua; Ikhwan, Mahdi Al; Bassirian, Shirin; Cepin, Sandra; Gonzalez, Monica P; Mendler, Michel; Kono, Yuko; Vodkin, Irine; Mekeel, Kristin; Haldorson, Jeffrey; Hemming, Alan; Andrews, Barbara; Salotti, Joanie; Richards, Lisa; Brenner, David A; Sirlin, Claude B; Loomba, Rohit

    2017-06-30

    The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438). Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. 140084. National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

  20. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Kowdley, Kris V; Belt, Patricia; Wilson, Laura A; Yeh, Matthew M; Neuschwander-Tetri, Brent A; Chalasani, Naga; Sanyal, Arun J; Nelson, James E

    2012-01-01

    Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033). A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis. Copyright © 2011 American Association for the Study of Liver Diseases.

  1. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis

    PubMed Central

    Caussy, Cyrielle; Soni, Meera; Cui, Jeffrey; Bettencourt, Ricki; Schork, Nicholas; Chen, Chi-Hua; Ikhwan, Mahdi Al; Bassirian, Shirin; Cepin, Sandra; Gonzalez, Monica P.; Mendler, Michel; Vodkin, Irine; Mekeel, Kristin; Haldorson, Jeffrey; Hemming, Alan; Andrews, Barbara; Salotti, Joanie; Richards, Lisa; Brenner, David A.; Sirlin, Claude B.

    2017-01-01

    BACKGROUND. The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS. This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS. The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8–126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1–146.1, P = 0.0438). CONCLUSION. Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION. UCSD IRB: 140084. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases and

  2. In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis.

    PubMed

    Africa, Jonathan A; Behling, Cynthia A; Brunt, Elizabeth M; Zhang, Nan; Luo, Yunjun; Wells, Alan; Hou, Jiayi; Belt, Patricia H; Kohil, Rohit; Lavine, Joel E; Molleston, Jean P; Newton, Kimberly P; Whitington, Peter F; Schwimmer, Jeffrey B

    2018-03-01

    Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Treatment of NAFLD with diet, physical activity and exercise.

    PubMed

    Romero-Gómez, Manuel; Zelber-Sagi, Shira; Trenell, Michael

    2017-10-01

    Lifestyle intervention can be effective when treating non-alcoholic fatty liver diseases (NAFLD) patients. Weight loss decreases cardiovascular and diabetes risk and can also regress liver disease. Weight reductions of ⩾10% can induce a near universal non-alcoholic steatohepatitis resolution and fibrosis improvement by at least one stage. However, modest weight loss (>5%) can also produce important benefits on the components of the NAFLD activity score (NAS). Additionally, we need to explore the role of total calories and type of weight loss diet, micro- and macronutrients, evidence-based benefits of physical activity and exercise and finally support these modifications through established behavioural change models and techniques for long-term maintenance of lifestyle modifications. Following a Mediterranean diet can reduce liver fat even without weight loss and is the most recommended dietary pattern for NAFLD. The Mediterranean diet is characterised by reduced carbohydrate intake, especially sugars and refined carbohydrates (40% of the calories vs. 50-60% in a typical low fat diet), and increased monounsaturated and omega-3 fatty acid intake (40% of the calories as fat vs. up-to 30% in a typical low fat diet). Both TV sitting (a reliable marker of overall sedentary behaviour) and physical activity are associated with cardio-metabolic health, NAFLD and overall mortality. A 'triple hit behavioural phenotype' of: i) sedentary behaviour, ii) low physical activity, and iii) poor diet have been defined. Clinical evidence strongly supports the role of lifestyle modification as a primary therapy for the management of NAFLD and NASH. This should be accompanied by the implementation of strategies to avoid relapse and weight regain. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  4. Progression of liver fibrosis is associated with non‐liver‐related mortality in patients with nonalcoholic fatty liver disease

    PubMed Central

    Kumada, Takashi; Toyoda, Hidenori; Mizuno, Kazuyuki; Sone, Yasuhiro; Akita, Tomoyuki; Tanaka, Junko

    2017-01-01

    In patients with nonalcoholic fatty liver disease (NAFLD), prognosis and outcome, especially non‐liver‐related mortality, remain incompletely elucidated. We clarified the mortality from all causes in patients with NAFLD. A total of 4,073 patients with NAFLD diagnosed by ultrasonography were enrolled. We investigated the causes of death and analyzed the mortality from non‐liver‐related diseases according to the degrees of steatosis and fibrosis using the competing risk method. We used the NAFLD fibrosis score (NFS) to assess fibrosis severity and the ultrasonography fatty liver score to evaluate steatosis severity. The numbers of patients with NFS indicating low, intermediate, and high probabilities of advanced fibrosis were 2,451 (60.2%), 1,462 (35.9%), and 160 (3.9%), respectively. Of the 4,073 patients, 179 died during follow‐up, but only nine deaths were due to liver‐related diseases. Of the remaining 170 patients who died due to non‐liver‐related diseases, 83 (48.8%), 42 (24.7%), and 45 (26.5%) patients died due to malignancies, cerebrovascular and cardiovascular diseases, and benign diseases (excluding cerebrovascular and cardiovascular diseases), respectively. Multivariate analysis showed that the intermediate and high NFS groups were independently associated with each disease category: hazard ratio (HR) 2.163 (95% confidence interval [CI], 1.354‐3.457) and HR 4.814 (95% CI, 2.323‐9.977) for malignancies; HR 2.265 (95% CI, 1.141‐4.497) and HR 8.482 (95% CI, 3.558‐20.220) for cerebrovascular and cardiovascular diseases; and HR 3.216 (95% CI, 1.641‐6.303) and HR 5.558 (95% CI, 1.923‐16.070) for benign diseases, respectively. Conversely, the status of steatosis was not associated with risk of mortality in multivariate analysis. Conclusion: Progression of liver fibrosis severity was associated with mortality from various non‐liver‐related causes in patients with NAFLD. (Hepatology Communications 2017;1:928–945) PMID:29404500

  5. Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Kumagai, Erina; Mano, Yohei; Yoshio, Sachiyo; Shoji, Hirotaka; Sugiyama, Masaya; Korenaga, Masaaki; Ishida, Tsuyoshi; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Kawaguchi, Takumi; Torimura, Takuji; Nozaki, Yuichi; Watanabe, Sumio; Mizokami, Masashi; Kanto, Tatsuya

    2016-10-14

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = -0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.

  6. Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    McPherson, Stuart; Henderson, Elsbeth; Burt, Alastair D; Day, Christopher P; Anstee, Quentin M

    2014-05-01

    A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p<0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3-4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p<0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  7. Diagnostic accuracy of a noninvasive hepatic ultrasound score for non-alcoholic fatty liver disease (NAFLD) in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

    PubMed

    Goulart, Alessandra Carvalho; Oliveira, Ilka Regina Souza de; Alencar, Airlane Pereira; Santos, Maira Solange Camara dos; Santos, Itamar Souza; Martines, Brenda Margatho Ramos; Meireles, Danilo Peron; Martines, João Augusto dos Santos; Misciagna, Giovanni; Benseñor, Isabela Martins; Lotufo, Paulo Andrade

    2015-01-01

    Noninvasive strategies for evaluating non-alcoholic fatty liver disease (NAFLD) have been investigated over the last few decades. Our aim was to evaluate the diagnostic accuracy of a new hepatic ultrasound score for NAFLD in the ELSA-Brasil study. Diagnostic accuracy study conducted in the ELSA center, in the hospital of a public university. Among the 15,105 participants of the ELSA study who were evaluated for NAFLD, 195 individuals were included in this sub-study. Hepatic ultrasound was performed (deep beam attenuation, hepatorenal index and anteroposterior diameter of the right hepatic lobe) and compared with the hepatic steatosis findings from 64-channel high-resolution computed tomography (CT). We also evaluated two clinical indices relating to NAFLD: the fatty liver index (FLI) and the hepatic steatosis index (HSI). Among the 195 participants, the NAFLD frequency was 34.4%. High body mass index, high waist circumference, diabetes and hypertriglyceridemia were associated with high hepatic attenuation and large anteroposterior diameter of the right hepatic lobe, but not with the hepatorenal index. The hepatic ultrasound score, based on hepatic attenuation and the anteroposterior diameter of the right hepatic lobe, presented the best performance for NAFLD screening at the cutoff point ≥ 1 point; sensitivity: 85.1%; specificity: 73.4%; accuracy: 79.3%; and area under the curve (AUC 0.85; 95% confidence interval, CI: 0.78-0.91)]. FLI and HSI presented lower performance (AUC 0.76; 95% CI: 0.69-0.83) than CT. The hepatic ultrasound score based on hepatic attenuation and the anteroposterior diameter of the right hepatic lobe has good reproducibility and accuracy for NAFLD screening.

  8. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Hossain, Noreen; Afendy, Arian; Stepanova, Maria; Nader, Fatema; Srishord, Manirath; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair

    2009-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We investigated factors associated with advanced fibrosis in NAFLD. The study included 432 patients with histologically proven NAFLD (26.8% with nonalcoholic steatohepatitis [NASH] and 17.4% with moderate-to severe fibrosis). NASH was defined as steatosis, lobular inflammation, and ballooning degeneration with or without Mallory-Denk bodies and/or fibrosis. Fibrosis was classified into 2 groups: those with no or minimal fibrosis and those with moderate-to-severe fibrosis. Groups were compared using Mann-Whitney and chi-square method analyses. A model was constructed using a stepwise bidirectional method; its predictive power was measured using a 10-fold cross-validation technique. Patients with NASH were more likely to be male (P < .0001); have lower hip-to-waist ratios (P = .03); were less likely to be African American (P = .06); have higher levels of alanine aminotransferase (ALT; P < .0001), aspartate aminotransferase (AST; P < .0001), and serum triglycerides (P = .0154), but lower levels of high-density lipoprotein cholesterol (P < .0001). Patients with moderate-to-severe fibrosis were older (P = .0245); more likely to be male (P = .0189), Caucasian (P = .0382), have diabetes mellitus (P = .0238), and hypertension (P = .0375); and have a lower hip-to-waist ratio (P = .0077) but higher serum AST (P < .0001) and ALT (P < .0001) levels. The multivariate analysis model to predict moderate-to-severe fibrosis included male sex, Caucasian ethnicity, diabetes mellitus, and increased AST and ALT levels (model P value < .0001). In patients with NAFLD, diabetes mellitus and aminotransferase levels are independent predictors of moderate-to-severe fibrosis. They can be used to identify NAFLD patients at risk for advanced fibrosis.

  9. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Buzzetti, Elena; Pinzani, Massimo; Tsochatzis, Emmanuel A

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

    PubMed

    Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

    2011-04-01

    Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

  11. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease.

    PubMed

    Loomba, Rohit; Seguritan, Victor; Li, Weizhong; Long, Tao; Klitgord, Niels; Bhatt, Archana; Dulai, Parambir Singh; Caussy, Cyrielle; Bettencourt, Richele; Highlander, Sarah K; Jones, Marcus B; Sirlin, Claude B; Schnabl, Bernd; Brinkac, Lauren; Schork, Nicholas; Chen, Chi-Hua; Brenner, David A; Biggs, William; Yooseph, Shibu; Venter, J Craig; Nelson, Karen E

    2017-05-02

    The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0-2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of 40 features (p < 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: assessment of non-invasive indices predicting hepatic steatosis and fibrosis.

    PubMed

    Polyzos, Stergios A; Goulis, Dimitrios G; Kountouras, Jannis; Mintziori, Gesthimani; Chatzis, Panagiotis; Papadakis, Efstathios; Katsikis, Ilias; Panidis, Dimitrios

    2014-01-01

    Insulin resistance contributes to the pathogenesis of both polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). The main aim of the present study was the evaluation of non-invasive indices of hepatic steatosis and fibrosis in PCOS women with or without metabolic syndrome (MetS). In this cross-sectional study, three non-invasive indices for hepatic steatosis [NAFLD liver fat score, lipid accumulation product (LAP) and hepatic steatosis index (HIS)] and four for fibrosis [FIB-4, aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI), body mass index (BMI)-Age-Alanine aminotransferase (ALT)-Triglycerides (BAAT) and BMI AST/ALT Ratio Diabetes (BARD)] were calculated in 314 PCOS women (77 with, 237 without MetS) and 78 controls. All steatosis indices were significantly higher in the PCOS than the control group (NAFLD liver fat score: -0.139 ± 0.117 vs. -0.976 ± 0.159, p<0.001; LAP: 43.3 ± 1.9 vs. 34.7 ± 3.1, p=0.036; HIS: 44.6 ± 0.5 vs. 42.1 ± 0.8, p=0.016). FIB-4 and BAAT [fibrosis stage (F)2-4] were higher in the PCOS group (0.480 ± 0.020 vs. 0.400 ± 0.013, p<0.001; and 15.6% vs. 5.1%, respectively), whereas APRI and BARD were not. All steatosis indices were significantly higher in PCOS women with than without MetS (NAFLD liver fat score: 1.874 ± 0.258 vs. -0.793 ± 0.099, p<0.001; LAP: 76.8 ± 4.9 vs. 33.4 ± 1.4, p<0.001; and HIS: 49.8 ± 1 vs. 43 ± 0.5, p<0.001). Of the fibrosis indices, only BAAT (F2-4: 50.6% vs. 4.2%) was higher in PCOS women with MetS. Non-invasive indices of hepatic steatosis were significantly higher in PCOS, especially in the presence of MetS, whereas indices of hepatic fibrosis yielded controversial results. Further studies are warranted to evaluate the long-term outcomes of hepatic steatosis and fibrosis indices in PCOS women.

  13. Stage scoring of liver fibrosis using Mueller matrix microscope

    NASA Astrophysics Data System (ADS)

    Zhou, Jialing; He, Honghui; Wang, Ye; Ma, Hui

    2016-10-01

    Liver fibrosis is a common pathological process of varied chronic liver diseases including alcoholic hepatitis, virus hepatitis, and so on. Accurate evaluation of liver fibrosis is necessary for effective therapy and a five-stage grading system was developed. Currently, experienced pathologists use stained liver biopsies to assess the degree of liver fibrosis. But it is difficult to obtain highly reproducible results because of huge discrepancy among different observers. Polarization imaging technique has the potential of scoring liver fibrosis since it is capable of probing the structural and optical properties of samples. Considering that the Mueller matrix measurement can provide comprehensive microstructural information of the tissues, in this paper, we apply the Mueller matrix microscope to human liver fibrosis slices in different fibrosis stages. We extract the valid regions and adopt the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters for quantitative analysis. We also use the Monte Carlo simulation to analyze the relationship between the microscopic Mueller matrix parameters and the characteristic structural changes during the fibrosis process. The experimental and Monte Carlo simulated results show good consistency. We get a positive correlation between the parameters and the stage of liver fibrosis. The results presented in this paper indicate that the Mueller matrix microscope can provide additional information for the detections and fibrosis scorings of liver tissues and has great potential in liver fibrosis diagnosis.

  14. The Presence of White Matter Lesions Is Associated With the Fibrosis Severity of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Petta, Salvatore; Tuttolomondo, Antonino; Gagliardo, Cesare; Zafonte, Rita; Brancatelli, Giuseppe; Cabibi, Daniela; Cammà, Calogero; Di Marco, Vito; Galvano, Luigi; La Tona, Giuseppe; Licata, Anna; Magliozzo, Franco; Maida, Carlo; Marchesini, Giulio; Merlino, Giovanni; Midiri, Massimo; Parrinello, Gaspare; Torres, Daniele; Pinto, Antonio; Craxì, Antonio

    2016-01-01

    Abstract We tested whether nonalcoholic fatty liver disease (NAFLD) and/or its histological severity are associated with vascular white matter lesions (WML) in patients with biopsy-proven NAFLD and in non-NAFLD controls. Data were recorded in 79 consecutive biopsy-proven NAFLD, and in 82 controls with normal ALT and no history of chronic liver diseases, without ultrasonographic evidence of steatosis and liver stiffness value <6 KPa. All subjects underwent magnetic resonance assessment and WML were classified according to the Fazekas score as absent (0/III), or present (mild I/III; moderate II/III, and severe I/III). For the purpose of analyses, all controls were considered without NASH and without F2–F4 liver fibrosis. WML were found in 26.7% of the entire cohort (43/161), of moderate–severe grade in only 6 cases. The prevalence was similar in NAFLD versus no-NAFLD (29.1% vs 24.3%; P = 0.49), but higher in NASH vs no-NASH (37.7% vs 21.2%, P = 0.02) and F2–F4 vs F0-F1 fibrosis (47.3% vs 20.3%, P = 0.001). In both the entire cohort and in NAFLD, only female gender (OR 4.37, 95% CI: 1.79–10.6, P = 0.001; and OR 5.21, 95% CI: 1.39–19.6, P = 0.01), age > 45 years (OR 3.09, 95% CI: 1.06–9.06, P = 0.03; and OR 11.1, 95% CI: 1.14–108.7, P = 0.03), and F2–F4 fibrosis (OR 3.36, 95% CI: 1.29–8.73, P = 0.01; and OR 5.34, 95% CI: 1.40–20.3, P = 0.01) were independently associated with WML (mostly of mild grade) by multivariate analysis. Among NAFLD, the prevalence of WML progressively increased from patients without (1/18; 5.5%), or with 1 (1/17, 5.8%), to those with 2 (9/30; 30%) and further to those with 3 (12/14; 85.7%) risk factors. The presence of WML is not associated with NAFLD, but with metabolic diseases in general, and fibrosis severity of NAFLD. Clinical implications of this issue need to be assessed by longitudinal studies. PMID:27100443

  15. Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

    PubMed

    Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

    2015-10-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

  16. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values.

    PubMed

    Petta, Salvatore; Wong, Vincent Wai-Sun; Cammà, Calogero; Hiriart, Jean-Baptiste; Wong, Grace Lai-Hung; Marra, Fabio; Vergniol, Julien; Chan, Anthony Wing-Hung; Di Marco, Vito; Merrouche, Wassil; Chan, Henry Lik-Yuen; Barbara, Marco; Le-Bail, Brigitte; Arena, Umberto; Craxì, Antonio; de Ledinghen, Victor

    2017-04-01

    Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132-298, middle 299-338, higher 339-400 dB/m). Among patients with F0-F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3-F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848-0.982; 0.830, 0.753-0.908; 0.806, 0.723-0.890). As a consequence, in subjects with F0-F2 fibrosis, the rates of false-positive LSM results for F3-F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145-1155). © 2016 by the American Association for the Study of Liver Diseases.

  17. Nonalcoholic fatty liver disease associated with metabolic syndrome: Influence of liver fibrosis stages on characteristics of very low-density lipoproteins.

    PubMed

    Lucero, Diego; Miksztowicz, Verónica; Gualano, Gisela; Longo, Cristina; Landeira, Graciela; Álvarez, Estela; Zago, Valeria; Brites, Fernando; Berg, Gabriela; Fassio, Eduardo; Schreier, Laura

    2017-10-01

    We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. We studied 36 MetS patients with biopsy-proven NAFLD (MetS+NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS+NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0-F2, n=27) and severe (F3-F4, n=9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS+NAFLD type IV collagen 7S domain was measured. MetS+NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p<0.04). CETP activity tended to increase in MetS+NAFLD (p=0.058), while LPL activity was unchanged. Moreover, in MetS+NAFLD, adiponectin was decreased (p<0.001), and negatively correlated with VLDL-mass and VLDL particle number (p<0.05), independently of insulin-resistance. Within MetS+NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p<0.05), while type IV collagen was increased (p=0.009) and inversely correlated with large VLDL-% (p=0.045). In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats.

    PubMed

    Hayashizaki-Someya, Yuka; Kurosaki, Eiji; Takasu, Toshiyuki; Mitori, Hikaru; Yamazaki, Shunji; Koide, Kumi; Takakura, Shoji

    2015-05-05

    Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion by inhibiting renal glucose reabsorption and thereby causes a subsequent antihyperglycemic effect. As nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is closely linked to metabolic diseases such as obesity and diabetes, we investigated the effect of ipragliflozin on NAFLD in rats fed a choline-deficient l-amino acid-defined (CDAA) diet. Five weeks after starting the CDAA diet, rats exhibited hepatic triglyceride (TG) accumulation, fibrosis, and mild inflammation. Repeated oral administration of ipragliflozin (3mg/g, once daily for 5 weeks) prevented both hepatic TG accumulation (188 vs.290 mg/g tissue vehicle-treated group; P<0.001) and large lipid droplet formation. Further, ipragliflozin exerted a prophylactic effect on liver fibrosis, as indicated by a marked decrease in hydroxyproline content and fibrosis score. Pioglitazone, which is known to be effective on hepatic fibrosis in CDAA diet-fed rats as well as NASH patients with type 2 diabetes mellitus (T2DM), also exerted a mild prophylactic effect on fibrosis, but not on hepatic TG accumulation or inflammation. In conclusion, ipragliflozin prevented hepatic TG accumulation and fibrosis in CDAA-diet rats. These findings suggest the therapeutic potential of ipragliflozin for patients with NAFLD. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline.

    PubMed

    Aller, Rocío; Fernández-Rodríguez, Conrado; Lo Iacono, Oreste; Bañares, Rafael; Abad, Javier; Carrión, José Antonio; García-Monzón, Carmelo; Caballería, Joan; Berenguer, Marina; Rodríguez-Perálvarez, Manuel; Miranda, José López; Vilar-Gómez, Eduardo; Crespo, Javier; García-Cortés, Miren; Reig, María; Navarro, José María; Gallego, Rocío; Genescà, Joan; Arias-Loste, María Teresa; Pareja, María Jesús; Albillos, Agustín; Muntané, Jordi; Jorquera, Francisco; Solà, Elsa; Hernández-Guerra, Manuel; Rojo, Miguel Ángel; Salmerón, Javier; Caballería, Llorenc; Diago, Moisés; Molina, Esther; Bataller, Ramón; Romero-Gómez, Manuel

    2018-05-01

    Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

  20. Second Harmonic Generation Reveals Subtle Fibrosis Differences in Adult and Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Liu, Feng; Zhao, Jing-Min; Rao, Hui-Ying; Yu, Wei-Miao; Zhang, Wei; Theise, Neil D; Wee, Aileen; Wei, Lai

    2017-11-20

    Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  1.  High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients.

    PubMed

    Arab, Juan P; Barrera, Francisco; Gallego, Consuelo; Valderas, Juan P; Uribe, Sergio; Tejos, Cristian; Serrano, Cristóbal; Serrano, Cristóbal; Huete, Álvaro; Liberona, Jessica; Labbé, Pilar; Quiroga, Teresa; Benítez, Carlos; Irarrázaval, Pablo; Riquelme, Arnoldo; Arrese, Marco

    2016-01-01

     Background. Patients with type 2 diabetes mellitus (T2DM) are at risk for developing end-stage liver disease due to nonalcoholic steatohepatitis (NASH), the aggressive form of non-alcoholic fatty liver disease (NAFLD). Data on prevalence of advanced fibrosis among T2DM patients is scarce. To evaluate prevalence of steatosis, advanced fibrosis and cirrhosis using non-invasive methods in T2DM patients. 145 consecutive T2DM patients (> 55 years-old) were prospectively recruited. Presence of cirrhosis and advanced fibrosis was evaluated by magnetic resonance imaging (MRI) and NAFLD fibrosis score (NFS) respectively. Exclusion criteria included significant alcohol consumption, markers of viral hepatitis infection or other liver diseases. Results are expressed in percentage or median (interquartile range). 52.6% of patients were women, the median age was 60 years old (57-64), mean BMI was 29.6 ± 4.7 kg/m2 and diabetes duration was 7.6 ± 6.9 years. A high prevalence of liver steatosis (63.9%), advanced fibrosis assessed by NFS (12.8%) and evidence of liver cirrhosis in MRI (6.0%) was observed. In a multivariate analysis GGT > 82 IU/L (P = 0.004) and no alcohol intake (P = 0.032) were independently associated to advanced fibrosis. A high frequency of undiagnosed advanced fibrosis and cirrhosis was observed in non-selected T2DM patients. Screening of these conditions may be warranted in this patient population.

  2. Chemical shift magnetic resonance imaging is helpful in detecting hepatic steatosis but not fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Kalra, Naveen; Duseja, Ajay; Das, Ashim; Dhiman, Radha Krishan; Virmani, Vivek; Chawla, Yogesh; Singh, Paramjee; Khandelwal, Niranjan

    2009-01-01

    Imaging modalities have a role in the diagnosis of patients with nonalcoholic fatty liver disease. Aim of the present study was to evaluate the role of chemical shift magnetic resonance imaging in assessing hepatic steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Chemical shift magnetic resonance imaging was done in 10 biopsy proven patients (7 females, mean age 41 +/- 9.2 years) with nonalcoholic fatty liver disease. Objective measurements of signal intensity (SI) were done and a ratio was calculated (SI out-of- phase liver/ SI out-of- phase kidney)/ (SI in- phase liver/ SI in-phase kidney). A lower ratio indicated a higher signal drop and hence higher fat content. The ratio was correlated with hepatic steatosis on histology (< 33% and > 33%). Patients were classified as having histological NASH or no NASH and MRI was assessed in diagnosing hepatic fibrosis as seen on liver histology. Six patients had > 33% hepatic steatosis on histology. Five patients (50%) had evidence of histological NASH. MRI was not helpful in differentiating patients with and without histological NASH. One patient amongst NASH patients did not have fibrosis, one had stage 1, 2 had stage 2 and one had stage 4 fibrosis. SI ratio ranged between 0.35-0.69 in 6 patients with steatosis > 33% and was in the range of 0.69-1.20 in four patients with steatosis < 33% on histology. Fibrotic changes seen in 4 patients on biopsy were not detected on MRI. Chemical shift MRI provides objective data on fat infiltration in patients with NAFLD without giving information about hepatic fibrosis.

  3. Histological scoring and associated risk factors of non-alcoholic fatty liver disease.

    PubMed

    Majid, N; Ali, Z; Rahman, M R; Akhter, A; Rajib, R C; Ahmad, F; Sharmin, S; Akond, A K; Huq, N

    2013-10-01

    Non alcoholic steatohepatitis is a hepatic disorder with histological features of alcohol induced liver disease that occurs in individual who do not consume significant alcohol. Liver biopsy is an important part of the evaluation in term of both grade & stage. A cross sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka & department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from July 2007 to June 2009. Total 55 adult subjects of both sex were included on the basis of predefined inclusion & exclusion criteria in this study to evaluate the histological pattern of non alcoholic fatty liver disease (NAFLD) and its correlation with risk factors. Liver biopsy was done and H & E and Masson's Trichrome stain slides were examined to evaluate the grade and stage of NAFLD. Scoring and semiquantitative assessment of steatosis and NAFLD severity was done according to Kleiner scale known as NAFLD activity score (NAS). The results of Pearson correlation showed only BMI and triglyceride level significantly correlated with NAS score. The results of Spearman's rank correlation showed that BMI, central obesity, triglyceridaemia and age significantly correlated with staging of fibrosis. The results of multiple regression analysis showed that variation of NAS depend on BMI and triglyceride level. The study also revealed that risk factors contributed about 29% risk for the occurrence of non alcoholic steatohepatitis.

  4. Non-alcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model.

    PubMed

    Müller, Peter; Messmer, Marie; Bayer, Monika; Pfeilschifter, Josef M; Hintermann, Edith; Christen, Urs

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) and its more severe development non-alcoholic steatohepatitis (NASH) are increasing worldwide. In particular NASH, which is characterized by an active hepatic inflammation, has often severe consequences including progressive fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Here we investigated how metabolic liver injury is influencing the pathogenesis of autoimmune hepatitis (AIH). We used the CYP2D6 mouse model in which wild type C57BL/6 mice are infected with an Adenovirus expressing the major liver autoantigen cytochrome P450 2D6 (CYP2D6). Such mice display several features of human AIH, including interface hepatitis, formation of LKM-1 antibodies and CYP2D6-specific T cells, as well as hepatic fibrosis. NAFLD was induced with a high-fat diet (HFD). We found that pre-existing NAFLD potentiates the severity of AIH. Mice fed for 12 weeks with a HFD displayed increased cellular infiltration of the liver, enhanced hepatic fibrosis and elevated numbers of liver autoantigen-specific T cells. Our data suggest that a pre-existing metabolic liver injury constitutes an additional risk for the severity of an autoimmune condition of the liver, such as AIH. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

    PubMed

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-09-14

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

  6. THE NATURAL HISTORY OF NONALCOHOLIC FATTY LIVER DISEASE WITH ADVANCED FIBROSIS OR CIRRHOSIS: AN INTERNATIONAL COLLABORATIVE STUDY

    PubMed Central

    Bhala, Neeraj; Angulo, Paul; van der Poorten, David; Lee, Eric; Hui, Jason M.; Saracco, Giorgio; Adams, Leon A.; Charatcharoenwitthaya, Punchai; Topping, Joanne H.; Bugianesi, Elisabetta; Day, Christopher P.; George, Jacob

    2011-01-01

    Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis. We conducted this prospective cohort study including 247 patients with NAFLD and 264 patients with HCV infection that were either naïve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced (stage 3) fibrosis or cirrhosis (stage 4) confirmed by liver biopsy at enrolment. In the NAFLD cohort, followed-up for 85.6 months mean (range 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed-up for 74.9 months mean (range 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (p=0.03), including incident hepatocellular cancer (6 vs 18; p=0.03), but that of cardiovascular events (p=0.17) and overall mortality (p=0.6) was similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, and serum levels of cholesterol and ALT were associated with liver-related complications; an AST/ALT ratio >1 and older age were associated with overall mortality; and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. Conclusions Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict outcomes in patients with NAFLD. PMID:21688282

  7. Expression of inflammation-related genes is altered in gastric tissue of patients with advanced stages of NAFLD.

    PubMed

    Mehta, Rohini; Birerdinc, Aybike; Neupane, Arpan; Shamsaddini, Amirhossein; Afendy, Arian; Elariny, Hazem; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

    2013-01-01

    Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD.

  8. Noninvasive Assessment of Advanced Fibrosis Based on Hepatic Volume in Patients with Nonalcoholic Fatty Liver Disease.

    PubMed

    Hayashi, Tatsuya; Saitoh, Satoshi; Fukuzawa, Kei; Tsuji, Yoshinori; Takahashi, Junji; Kawamura, Yusuke; Akuta, Norio; Kobayashi, Masahiro; Ikeda, Kenji; Fujii, Takeshi; Miyati, Tosiaki; Kumada, Hiromitsu

    2017-09-15

    Noninvasive liver fibrosis evaluation was performed in patients with nonalcoholic fatty liver disease (NAFLD). We used a quantitative method based on the hepatic volume acquired from gadoxetate disodium-enhanced (Gd-EOB-DTPA-enhanced) magnetic resonance imaging (MRI) for diagnosing advanced fibrosis in patients with NAFLD. A total of 130 patients who were diagnosed with NAFLD and underwent Gd-EOB-DTPA-enhanced MRI were retrospectively included. Histological data were available for 118 patients. Hepatic volumetric parameters, including the left hepatic lobe to right hepatic lobe volume ratio (L/R ratio), were measured. The usefulness of the L/R ratio for diagnosing fibrosis ≥F3-4 and F4 was assessed using the area under the receiver operating characteristic (AUROC) curve. Multiple regression analysis was performed to identify variables (age, body mass index, serum fibrosis markers, and histological features) that were associated with the L/R ratio. The L/R ratio demonstrated good performance in differentiating advanced fibrosis (AUROC, 0.80; 95% confidence interval, 0.72 to 0.88) from cirrhosis (AUROC, 0.87; 95% confidence interval, 0.75 to 0.99). Multiple regression analysis showed that only fibrosis was significantly associated with the L/R ratio (coefficient, 0.121; p<0.0001). The L/R ratio, which is not influenced by pathological parameters other than fibrosis, is useful for diagnosing cirrhosis in patients with NAFLD.

  9. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis.

    PubMed

    Koo, Bo Kyung; Kim, Donghee; Joo, Sae Kyung; Kim, Jung Ho; Chang, Mee Soo; Kim, Byeong Gwan; Lee, Kook Lae; Kim, Won

    2017-01-01

    We explored whether sarcopenia is associated with the histological severity of non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH) and significant fibrosis. In a biopsy-proven NAFLD cohort, the appendicular skeletal muscle mass (ASM) was measured. Sarcopenia was defined as a ASM/body weight (ASM%) value beyond two standard deviations below the mean for healthy young adults. Among the entire set of 309 subjects, the prevalence of sarcopenia in subjects without NAFLD, with non-alcoholic fatty liver (NAFL), and with NASH were 8.7%, 17.9%, and 35.0%, respectively (p<0.001). ASM% was inversely correlated with the severity of fibrosis (p<0.001), and the prevalence of significant fibrosis (⩾F2) was higher in subjects with sarcopenia than in those without (45.7% vs. 24.7%; p<0.001). A crude analysis revealed that sarcopenia was associated with NAFLD (odds ratio [OR], 3.82; 95% confidence interval [CI], 1.58-9.25), which became insignificant after adjustment for body mass index (BMI), diabetes, and hypertension. Among NAFLD subjects, subjects with sarcopenia were more likely to have NASH than those without sarcopenia through a multivariate analysis adjusted for age, gender, BMI, hypertension, diabetes, and smoking status (OR, 2.28; 95% CI, 1.21-4.30), and this finding was obtained even after adjustment for insulin resistance (OR, 2.30; 95% CI, 1.08-4.93). Sarcopenia was also associated with significant fibrosis independent of BMI and insulin resistance (OR, 2.05; 95% CI, 1.01-4.16). In this large biopsy-proven NAFLD cohort, sarcopenia was significantly associated with NASH and significant fibrosis. Low muscle mass was found to be associated with histological severity in non-alcoholic fatty liver disease, and sarcopenia was significantly associated with non-alcoholic steatohepatitis and significant fibrosis, independent of obesity, inflammation, and insulin resistance. Clinical trial number: NCT 02206841. Copyright © 2016 European

  10. Prospective comparison among transient elastography, supersonic shear imaging, and ARFI imaging for predicting fibrosis in nonalcoholic fatty liver disease

    PubMed Central

    Joo, Sae Kyung; Woo, Hyunsik; Lee, Dong Hyeon; Jung, Yong Jin; Kim, Byeong Gwan; Lee, Kook Lae

    2017-01-01

    The diagnostic performance of supersonic shear imaging (SSI) in comparison with those of transient elastography (TE) and acoustic radiation force impulse imaging (ARFI) for staging fibrosis in nonalcoholic fatty liver disease (NAFLD) patients has not been fully assessed, especially in Asian populations with relatively lean NAFLD compared to white populations. Thus, we focused on comparing the diagnostic performances of TE, ARFI, and SSI for staging fibrosis in a head-to-head manner, and identifying the clinical, anthropometric, biochemical, and histological features which might affect liver stiffness measurement (LSM) in our prospective biopsy-proven NAFLD cohort. In this study, ninety-four patients with biopsy-proven NAFLD were included prospectively. Liver stiffness was measured using TE, SSI, and ARFI within 1 month of liver biopsy. The diagnostic performance for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis. Anthropometric data were evaluated as covariates influencing LSM by regression analyses. Liver stiffness correlated with fibrosis stage (p < 0.05); the area under the ROC curve of TE (kPa), SSI (kPa), and ARFI (m/s) were as follows: 0.757, 0.759, and 0.657 for significant fibrosis and 0.870, 0.809, and 0.873 for advanced fibrosis. Anthropometric traits were significant confounders affecting SSI, while serum liver injury markers significantly confounded TE and ARFI. In conclusion, the LSM methods had similar diagnostic performance for staging fibrosis in patients with NAFLD. Pre-LSM anthropometric evaluation may help predict the reliability of SSI. PMID:29176844

  11. Fibrosis in nonalcoholic fatty liver disease: Noninvasive assessment using computed tomography volumetry.

    PubMed

    Fujita, Nobuhiro; Nishie, Akihiro; Asayama, Yoshiki; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Okamoto, Daisuke; Shirabe, Ken; Yoshizumi, Tomoharu; Kotoh, Kazuhiro; Furusyo, Norihiro; Hida, Tomoyuki; Oda, Yoshinao; Fujioka, Taisuke; Honda, Hiroshi

    2016-10-28

    To evaluate the diagnostic performance of computed tomography (CT) volumetry for discriminating the fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD). A total of 38 NAFLD patients were enrolled. On the basis of CT imaging, the volumes of total, left lateral segment (LLS), left medial segment, caudate lobe, and right lobe (RL) of the liver were calculated with a dedicated liver application. The relationship between the volume percentage of each area and fibrosis stage was analyzed using Spearman's rank correlation coefficient. A receiver operating characteristic (ROC) curve analysis was performed to determine the accuracy of CT volumetry for discriminating fibrosis stage. The volume percentages of the caudate lobe and the LLS significantly increased with the fibrosis stage ( r = 0.815, P < 0.001; and r = 0.465, P = 0.003, respectively). Contrarily, the volume percentage of the RL significantly decreased with fibrosis stage ( r = -0.563, P < 0.001). The volume percentage of the caudate lobe had the best diagnostic accuracy for staging fibrosis, and the area under the ROC curve values for discriminating fibrosis stage were as follows: ≥ F1, 0.896; ≥ F2, 0.929; ≥ F3, 0.955; and ≥ F4, 0.923. The best cut-off for advanced fibrosis (F3-F4) was 4.789%, 85.7% sensitivity and 94.1% specificity. The volume percentage of the caudate lobe calculated by CT volumetry is a useful diagnostic parameter for staging fibrosis in NAFLD patients.

  12. qFibrosis: A fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients

    PubMed Central

    Tai, Dean C.S.; Wang, Shi; Cheng, Chee Leong; Peng, Qiwen; Yan, Jie; Chen, Yongpeng; Sun, Jian; Liang, Xieer; Zhu, Youfu; Rajapakse, Jagath C.; Welsch, Roy E.; So, Peter T.C.; Wee, Aileen; Hou, Jinlin; Yu, Hanry

    2014-01-01

    Background & Aims There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients. Methods qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison. Results qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p <0.001) and human biopsies (p <0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93–0.99 for animal samples: 1–16 mm2; AUC: 0.84–0.97 for biopsies: 10–44 mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15 mm) and under- and over-scoring by different pathologists (p <0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p = 0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts. Conclusions qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice. PMID:24583249

  13. Echocardiography and NAFLD (non-alcoholic fatty liver disease).

    PubMed

    Trovato, Francesca M; Martines, Giuseppe F; Catalano, Daniela; Musumeci, Giuseppe; Pirri, Clara; Trovato, Guglielmo M

    2016-10-15

    Non-alcoholic-fatty-liver-disease (NAFLD) is associated with atherosclerosis, increased cardiovascular risks and mortality. We investigated if, independently of insulin resistance, diet, physical activity and obesity, fatty liver involvement has any relationship with echocardiographic measurements in NAFLD. 660 NAFLD and 791 non-NAFLD subjects, referred to the same out-patients medical unit for lifestyle-nutritional prescription, were studied. Congestive heart failure, myocardial infarction, malignancies, diabetes mellitus, extreme obesity, underweight-bad-nourished subjects and renal insufficiency were exclusion criteria. Liver steatosis was assessed by Ultrasound-Bright-Liver-Score (BLS), left ventricular ejection fraction (LVEF), trans-mitral E/A doppler ratio (diastolic relaxation) and left ventricular myocardial mass (LVMM/m(2)) by echocardiography. Doppler Renal artery Resistive Index (RRI), insulin resistance (HOMA) and lifestyle profile were also included in the clinical assessment. LVMM/m(2) is significantly greater in NAFLD, 101.62±34.48 vs. 88.22±25.61, p<0.0001 both in men and in women. Ejection fraction is slightly smaller only in men with NAFLD; no significant difference was observed for the E/A ratio. BMI (30.42±5.49 vs. 24.87±3.81; p<0.0001) and HOMA (2.90±1.70 vs. 1.85±1.25; p: 0.0001) were significantly greater in NAFLD patients. By Multiple-Linear-Regression, NAFLD and unhealthy dietary profile are associated also in lean non-diabetic subjects with lower systolic function, independently of BMI, dietary profile, physical activity, RRI and insulin resistance. NAFLD may be a meaningful early clue suggestive of diminishing heart function, with similar determining factors. NAFLD is amenable to management and improvement by lifestyle change counseling, addressing a dual target: reducing fatty liver, which is easily monitored by ultrasound, and, independently, maintaining a normal heart function. Copyright © 2016 Elsevier Ireland Ltd. All rights

  14. Prevalence and Profile of Fibrosis in Diabetic Patients with Non-alcoholic Fatty Liver Disease and the Associated Factors.

    PubMed

    Prasetya, Ignatius Bima; Hasan, Irsan; Wisnu, Wismandari; Rumende, Cleopas Martin

    2017-04-01

    the risk of Non-Alcoholic Fatty Liver Disease (NAFLD) is increasing in patients with type-2 diabetes. Prevalence and factors related to the increased risk of NAFLD in diabetic patients in Indonesia has never been studied before. Data regarding the profile of fibrosis in the population has also been unknown. This study aimed to identify the difference on the profile of diabetic patients with and without NAFLD as well as the degree of fibrosis. the study was conducted using a cross-sectional method in type-2 diabetic patients who were treated at the outpatient clinic of endocrinology and metabolic division in Cipto Mangunkusumo Hospital. Sampling was done consecutively. Collected data comprised of age, duration of diabetes, body mass index (BMI), waist circumference, HDL, triglyceride, and HbA1C levels. Abdominal ultrasonography was conducted for all patients to determine the presence of NAFLD. Patients with NAFLD were subsequently underwent transient elastography in order to assess their degree of liver fibrosis. Chi-square or Fisher's-Exact tests were used for bivariate analysis and logistic regression was used for multivariate analysis. as many as 186 patients were analyzed in the study and 84 patients (45.2%) were demonstrated to have NAFLD. Transient elastography examinations were carried out in 68 patients and 17 patients (25.0%) were found with severe fibrosis. Univariate analysis showed significant differences on BMI (PR=1.878; 95%CI= 1.296-2.721; p<0.001) and waist circumference (PR=2.368; 95%CI= 1.117-5.017; p=0.018) between patients with and without NAFLD. However, the multivariate test showed that BMI was the only factor that had a significance difference between both groups (OR=2.989; 95%CI=1.625-5.499; p<0.001). prevalence of NAFLD among type-2 diabetic patients in Cipto Mangunkusumo Hospital has reached 45.2% and 25.0% among them had severe fibrosis. BMI is the only factor found to be associated with the occurrence of NAFLD.

  15. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance.

    PubMed

    Gaggini, Melania; Carli, Fabrizia; Rosso, Chiara; Buzzigoli, Emma; Marietti, Milena; Della Latta, Veronica; Ciociaro, Demetrio; Abate, Maria Lorena; Gambino, Roberto; Cassader, Maurizio; Bugianesi, Elisabetta; Gastaldelli, Amalia

    2018-01-01

    Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism

  16. Expression of Inflammation-Related Genes Is Altered in Gastric Tissue of Patients with Advanced Stages of NAFLD

    PubMed Central

    Mehta, Rohini; Birerdinc, Aybike; Neupane, Arpan; Shamsaddini, Amirhossein; Afendy, Arian; Elariny, Hazem; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M.

    2013-01-01

    Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD. PMID:23661906

  17. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease.

    PubMed

    Seko, Yuya; Yamaguchi, Kanji; Mizuno, Naoki; Okuda, Keiichiro; Takemura, Masashi; Taketani, Hiroyoshi; Hara, Tasuku; Umemura, Atsushi; Nishikawa, Taichiro; Moriguchi, Michihisa; Yasui, Kohichiroh; Kamaguchi, Mai; Nishioji, Kenichi; Mochizuki, Naomi; Kobayashi, Masao; Mori, Kojiroh; Tanaka, Saiyu; Matsuura, Kentaro; Tanaka, Yasuhito; Itoh, Yoshito

    2018-03-01

    Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis. In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.

  18. Laboratory parameter-based machine learning model for excluding non-alcoholic fatty liver disease (NAFLD) in the general population.

    PubMed

    Yip, T C-F; Ma, A J; Wong, V W-S; Tse, Y-K; Chan, H L-Y; Yuen, P-C; Wong, G L-H

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD) affects 20%-40% of the general population in developed countries and is an increasingly important cause of hepatocellular carcinoma. Electronic medical records facilitate large-scale epidemiological studies, existing NAFLD scores often require clinical and anthropometric parameters that may not be captured in those databases. To develop and validate a laboratory parameter-based machine learning model to detect NAFLD for the general population. We randomly divided 922 subjects from a population screening study into training and validation groups; NAFLD was diagnosed by proton-magnetic resonance spectroscopy. On the basis of machine learning from 23 routine clinical and laboratory parameters after elastic net regulation, we evaluated the logistic regression, ridge regression, AdaBoost and decision tree models. The areas under receiver-operating characteristic curve (AUROC) of models in validation group were compared. Six predictors including alanine aminotransferase, high-density lipoprotein cholesterol, triglyceride, haemoglobin A 1c , white blood cell count and the presence of hypertension were selected. The NAFLD ridge score achieved AUROC of 0.87 (95% CI 0.83-0.90) and 0.88 (0.84-0.91) in the training and validation groups respectively. Using dual cut-offs of 0.24 and 0.44, NAFLD ridge score achieved 92% (86%-96%) sensitivity and 90% (86%-93%) specificity with corresponding negative and positive predictive values of 96% (91%-98%) and 69% (59%-78%), and 87% of overall accuracy among 70% of classifiable subjects in the validation group; 30% of subjects remained indeterminate. NAFLD ridge score is a simple and robust reference comparable to existing NAFLD scores to exclude NAFLD patients in epidemiological studies. © 2017 John Wiley & Sons Ltd.

  19. Correlation between non-alcoholic fatty liver disease (NAFLD) and dyslipidemia in type 2 diabetes.

    PubMed

    Krishan, Saini

    2016-01-01

    Non-alcoholic fatty liver means the presence of hepatosteatosis without significant alcohol consumption; it is strongly associated with obesity and metabolic disorder like type 2 diabetes and dyslipideamia. NASH may progress to advanced stages of hepatic fibrosis and cirrhosis. Increased body mass index and viral genotype contribute to steatosis in chronic hepatitis. The sonographic features of NAFLD include the presence of bright hepatic echotexture deep attenuation, and vascular blurring either singly or in combination. Dyslipidemia in patients with NAFLD is atherogenic in nature and it is characterized by increased levels of serum triglycerides and decreased levels of HDL cholesterol. Statins are potent lipid-lowering agents which decrease LDL cholesterol by 20-60%, decrease triglycerides by 10-33% and increase HDL cholesterol by 5-10% for the patients with NAFLD. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  20. Liver fibrosis markers of nonalcoholic steatohepatitis

    PubMed Central

    Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH. PMID:26139988

  1. Liver fibrosis markers of nonalcoholic steatohepatitis.

    PubMed

    Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

    2015-06-28

    Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.

  2. Predictive value of the fibrosis scores in patients with chronic hepatitis C associated with liver fibrosis and metabolic syndrome.

    PubMed

    Miyaaki, Hisamitsu; Ichikawa, Tatsuki; Taura, Naota; Miuma, Satoshi; Shibata, Hidetaka; Isomoto, Hajime; Takeshima, Fuminao; Nakao, Kazuhiko

    2011-01-01

    We evaluated patients with chronic hepatitis C (CHC) and compared the clinical and pathological features of steatosis and metabolic syndrome to identify the risk factors for CHC with severe fibrosis. One hundred seventy-one patients with biopsy-confirmed CHC were included in the study: 90 males and 81 females, age 56.2 ± 12.8 years; 46 with obesity (BMI≥25 kg/m(2)); 51 with hypertension; 36 with type 2 diabetes mellitus; and 20 with hypertriglyceridemia. Steatosis was detected in 79 patients (46%); 92 patients (54%) showed no steatosis. Seventy-four patients (43%) showed mild fibrosis and 97 patients (56%) showed severe fibrosis. The variables that were significantly associated with steatosis were obesity [odds ratio 2.160 (1.010-4.727), p=0.046] and type 2 diabetes [odds ratio 3.667 (1.559-8.430), p=0.027]. The variables that were significantly associated with severe fibrosis were older age [odds ratio 2.675 (1.309-5.464), p=0.007], obesity [odds ratio 2.156 (1.006-4.619), p=0.048] and type 2 diabetes [odds ratio 8.739 (2.845-26.846), p=0.0002]. Nagasaki (N) score (the total number of specific risk factors, namely an older age, obesity, and type 2 diabetes) was higher in the severe fibrosis group than in the mild fibrosis group (mild fibrosis: severe fibrosis=1.48 ± 1.14 vs.2.66 ± 94, p<0.001). Metabolic syndrome factors, including obesity and diabetes, play a critical role in the pathogenesis of fibrosis in CHC. The N score was therefore found to be a significant predictor of severe fibrosis in CHC.

  3. Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress.

    PubMed

    Li, Bing-Hang; He, Fang-Ping; Yang, Xin; Chen, Yuan-Wen; Fan, Jian-Gao

    2017-02-01

    The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) has become one of the major public health threats in China and worldwide. However, during the development of NAFLD, the key mechanism underlying the progression of related fibrosis remains unclear, which greatly impedes the development of optimal NAFLD therapy. In the current study, we were endeavored to characterize a proinflammatory cytokine, CCL5, as a major contributor for fibrosis in NAFLD. The results showed that CCL5 was highly expressed in fatty liver and NASH patients. In NAFLD rats induced by 8-week-HFD, CCL5 and its receptor, CCR5, were significantly up-regulated and liver fibrosis exclusively occurred in this group. In addition, we showed that hepatocytes are the major source contributing to this CCL5 elevation. Interestingly, a CCL5 inhibitor Met-CCL5, significantly decreased liver fibrosis but not hepatic steatosis. Using a cell model of hepatic steatosis, we found that the conditioned medium of lipid-overloaded hepatocytes (Fa2N-4 cells) which produced excessive CCL5 stimulated the profibrotic activities of hepatic stellate cells (LX-2) as manifested by increased migration rate, proliferation and collagen production of LX-2 cells. CCL5 knockdown in Fa2N-4 cells, Met-CCL5 or CCR5 antibody treatment on LX-2 cells all significantly inhibited the conditioned medium of FFA-treated Fa2N-4 cells to exert stimulatory effects on LX-2 cells. Consistently, the conditioned medium of Fa2N-4 cells with CCL5 over-expression significantly enhanced migration rate, cell proliferation and collagen production of LX-2 cells. All these results support that CCL5 produced by steatotic hepatocytes plays an essential role in fibrotic signaling machinery of NAFLD. In addition, we were able to identify C/EBP-β as the up-stream regulator of CCL5 gene transcription in hepatocytes treated with free fatty acid (FFA). Our data strongly supported that CCL5 plays a pivotal regulatory role in

  4. Diagnosis of non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Yki-Järvinen, Hannele

    2016-06-01

    Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30 U/l in men and ≈20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by John Jones, DOI: 10.1007/s00125

  5. Omega-3 fatty acids: Mechanisms of benefit and therapeutic effects in pediatric and adult NAFLD.

    PubMed

    Nobili, Valerio; Alisi, Anna; Musso, Giovanni; Scorletti, Eleonora; Calder, Philip C; Byrne, Christopher D

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common liver disease in industrialized countries, and it is estimated that it will become the most frequent indication for liver transplantation in the next decade. NAFLD may be associated with moderate (i.e. steatosis) to severe (i.e. steatohepatitis and fibrosis) liver damage and affects all age groups. Furthermore, subjects with NAFLD may be at a greater risk of other obesity-related complications later in life, and people with obesity and obesity-related complications (e.g. metabolic syndrome, type 2 diabetes and cardiovascular disease) are at increased risk of developing NAFLD. To date, there is no licensed treatment for NAFLD and therapy has been mainly centered on weight loss and increased physical activity. Unfortunately, it is often difficult for patients to adhere to the advised lifestyle changes. Therefore, based on the known pathogenesis of NAFLD, several clinical trials with different nutritional supplementation and prescribed drugs have been undertaken or are currently underway. Experimental evidence has emerged about the health benefits of omega-3 fatty acids, a group of polyunsaturated fatty acids that are important for a number of health-related functions. Omega-3 fatty acids are present in some foods (oils, nuts and seeds) that also contain omega-6 fatty acids, and the best sources of exclusively omega-3 fatty acids are oily fish, krill oil and algae. In this review, we provide a brief overview of the pathogenesis of NAFLD, and we also discuss the molecular and clinical evidence for the benefits of different omega-3 fatty acid preparations in NAFLD.

  6. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.

    PubMed

    Noureddin, Mazen; Yates, Katherine P; Vaughn, Ivana A; Neuschwander-Tetri, Brent A; Sanyal, Arun J; McCullough, Arthur; Merriman, Raphael; Hameed, Bilal; Doo, Edward; Kleiner, David E; Behling, Cynthia; Loomba, Rohit

    2013-11-01

    The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis.

  7. Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH.

    PubMed

    Traussnigg, Stefan; Kienbacher, Christian; Halilbasic, Emina; Rechling, Christian; Kazemi-Shirazi, Lili; Hofer, Harald; Munda, Petra; Trauner, Michael

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a liver disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) with risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Associated metabolic conditions and comorbidities such as obesity, diabetes and cardiovascular diseases are common and require concerted management. Adiponutrin (PNPLA3) variants may help to identify NAFLD patients at higher risk for liver disease progression towards advanced fibrosis and HCC. The therapeutic options in NAFLD/NASH include lifestyle modification, pharmacological treatment, bariatric surgery for patients with morbid obesity and treatment of complications of liver cirrhosis and HCC, including liver transplantation. Insulin sensitizers and antioxidative treatment strategies with vitamin E are among the best-established pharmacological approaches, but both drugs have long-term safety issues and there is limited evidence in cirrhotic patients. Treatment of concomitant/underlying metabolic conditions with statins or metformin may also have beneficial effects on portal hypertension, complications of liver cirrhosis and HCC prevention. The bile acid receptor FXR may be a promising novel therapeutic target for the treatment of NAFLD/NASH, fibrosis and portal hypertension, but the prognostic implications of associated changes in low- and high-density lipoprotein cholesterol require further studies. Morbidly obese NASH patients can benefit from bariatric surgery which may reduce liver fibrosis but carries a risk of decompensation in patients with advanced liver cirrhosis. When carefully selected, patients with NASH cirrhosis undergoing liver transplantation have a good outcome. This review summarizes recent progress in the management of patients with liver cirrhosis due to NASH. © 2015 S. Karger AG, Basel.

  8. Systematic review with meta-analysis: the significance of histological disease severity in lean patients with nonalcoholic fatty liver disease.

    PubMed

    Sookoian, S; Pirola, C J

    2018-01-01

    Current evidence suggests that lean and obese patients with nonalcoholic fatty liver disease (NAFLD) share an altered metabolic and cardiovascular profile. However, there is an incomplete understanding of the natural history of "lean-NAFLD." Indeed, an unanswered question is whether lean (BMI ≤ 25 Kg/m 2 ) NAFLD-patients are protected from severe histological outcomes. To perform a meta-analysis with the goal of providing a quantitative estimation of the magnitude of fibrosis, as well as histological features associated with the disease severity, in lean versus overweight/obese-NAFLD patients. Through a systematic search up to July 2017, we identified eight studies that compared histological outcomes in lean (n = 493) versus overweight/obese (n = 2209) patients. Relative to lean-NAFLD, overweight/obese-NAFLD patients showed significantly (P = .032) higher fibrosis scores; the observed difference in means between the two groups, which is the absolute difference between the mean value of fibrosis score [0-4] ± standard error, was 0.28 ± 0.13. The risk of having nonalcoholic steatohepatitis-NASH (OR 0.58 95% CI 0.34-0.97) was significantly lower in lean-NAFLD (n = 322) than in overweight/obese-NAFLD (n = 1357), P = .04. Relative to lean-NAFLD, overweight/obese-NAFLD patients also have significantly greater NAFLD activity (difference in means ± SE: 0.58 ± 0.16, P = .0004) and steatosis (difference in means ± SE: 0.23 ± 0.07, P = .002) scores. Lean-NAFLD patients tend to show less severe histological features as compared to overweight/obese-NAFLD patients. Subsequent longitudinal assessment is needed to understand the clinical impact of these findings; however, the significant ~ 25% increment of mean fibrosis score in overweight/obese patients suggests that obesity could predict a worse long-term prognosis. © 2017 John Wiley & Sons Ltd.

  9. Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients.

    PubMed

    Kim, W Ray; Berg, Thomas; Asselah, Tarik; Flisiak, Robert; Fung, Scott; Gordon, Stuart C; Janssen, Harry L A; Lampertico, Pietro; Lau, Daryl; Bornstein, Jeffrey D; Schall, Raul E Aguilar; Dinh, Phillip; Yee, Leland J; Martins, Eduardo B; Lim, Seng Gee; Loomba, Rohit; Petersen, Jörg; Buti, Maria; Marcellin, Patrick

    2016-04-01

    While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Extrahepatic Diseases and NAFLD: The Triangular Relationship between NAFLD, Type 2-Diabetes and Dysbiosis.

    PubMed

    Scorletti, Eleonora; Byrne, Christopher D

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases from simple steatosis with hepatic lipid accumulation to end-stage liver disease with decompensated cirrhosis, liver failure and hepatocellular carcinoma. Recent data from the USA showed that in 2013, NAFLD was the second most frequent indication for liver transplantation behind hepatitis C. Since there are now effective treatments for hepatitis C and there is currently no licensed treatment for NAFLD, it has been predicted that over the next 10-15 years, NAFLD will replace hepatitis C as the most frequent indication for liver transplantation. Besides, increasing the risk of hepatocellular carcinoma and end-stage liver disease, it has recently become clear that NAFLD also increases risk of extrahepatic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, cardiac diseases and chronic kidney disease, to name but a few. Of each of these extrahepatic diseases, the evidence to date suggests that NAFLD is a strong risk factor for T2DM. When NAFLD occurs in combination with obesity and insulin resistance (as it frequently does), there is a marked increase in risk of incident T2DM with possible synergism occurring between liver fat accumulation, insulin resistance and obesity to further increase risk of development of T2DM. Thus, there is a reciprocal relationship between NAFLD as a risk factor for T2DM, and T2DM as a risk factor for liver disease progression in NAFLD. Moreover, recent evidence now points to the importance of perturbation of the intestinal microbiota (dysbiosis) in both T2DM and NAFLD. Consequently, there is a triangular relationship between dysbiosis and T2DM and NAFLD. This review will focus on T2DM as a key extrahepatic complication of NAFLD and will describe and discuss the triangular relationship between dysbiosis and T2DM and NAFLD and the factors and potential mechanisms underpinning this relationship. © 2016 S. Karger AG, Basel.

  11. The role of intestinal microbiota in the pathogenesis of NAFLD: starting points for intervention

    PubMed Central

    Vespasiani-Gentilucci, Umberto; Picardi, Antonio

    2016-01-01

    In recent years, close links between intestinal microbiota and host metabolism have been recognized. Intestinal bacteria can participate in the extraction of calories from food, and circulation of bacterial products, in particular lipopolysaccharides (LPS), is responsible for the “metabolic endotoxemia”, which contributes to insulin resistance and its complications, such as non-alcoholic fatty liver disease (NAFLD). Indeed, qualitative and quantitative intestinal dysbiotic changes have been clearly documented in NAFLD patients, and several mechanisms by which the intestinal microbiota can directly promote liver fat deposition, inflammation and fibrosis have also been described. Consistently, although with some differences concerning type and proportion of results, experimental and clinical studies are quite concordant in demonstrating beneficial effects of probiotic and/or prebiotic therapy in NAFLD. Although some physiopathological bases have been produced, major doubts still remain concerning how and when to intervene. Indeed, most of the available works were performed with mixtures of probiotics and/or prebiotics, and a baseline assessment of dysbiosis aimed at selecting the best candidates for treatment and predicting response has not been performed in any of the clinical studies in NAFLD. While future research is expected to solve these issues, the particularly favorable safety profile suggests that probiotic/prebiotic therapy could already be “tested” in NAFLD patients on an individual basis, at least once all the measures recommended by the latest guidelines have failed. PMID:29765460

  12. Long-term native liver fibrosis in biliary atresia: development of a novel scoring system using histology and standard liver tests.

    PubMed

    Tomita, Hirofumi; Masugi, Yohei; Hoshino, Ken; Fuchimoto, Yasushi; Fujino, Akihiro; Shimojima, Naoki; Ebinuma, Hirotoshi; Saito, Hidetsugu; Sakamoto, Michiie; Kuroda, Tatsuo

    2014-06-01

    Although liver fibrosis is an important predictor of outcomes for biliary atresia (BA), postsurgical native liver histology has not been well reported. Here, we retrospectively evaluated postsurgical native liver histology, and developed and assessed a novel scoring system - the BA liver fibrosis (BALF) score for non-invasively predicting liver fibrosis grades. We identified 259 native liver specimens from 91 BA patients. Of these, 180 specimens, obtained from 62 patients aged ≥1 year at examination, were used to develop the BALF scoring system. The BALF score equation was determined according to the prediction of histological fibrosis grades by multivariate ordered logistic regression analysis. The diagnostic powers of the BALF score and several non-invasive markers were assessed by area under the receiver operating characteristic curve (AUROC) analyses. Natural logarithms of the serum total bilirubin, γ-glutamyltransferase, and albumin levels, and age were selected as significantly independent variables for the BALF score equation. The BALF score had a good diagnostic power (AUROCs=0.86-0.94, p<0.001) and good diagnostic accuracy (79.4-93.3%) for each fibrosis grade. The BALF score revealed a strong correlation with fibrosis grade (r=0.77, p<0.001), and was the preferable non-invasive marker for diagnosing fibrosis grades ⩾F2. In a serial liver histology subgroup analysis, 7/15 patients exhibited liver fibrosis improvement with BALF scores being equivalent to histological fibrosis grades of F0-1. In postsurgical BA patients aged ⩾1year, the BALF score is a potential non-invasive marker of native liver fibrosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. High FIB-4 index as an independent risk factor of prevalent chronic kidney disease in patients with nonalcoholic fatty liver disease.

    PubMed

    Xu, Huang-Wei; Hsu, Yung-Chien; Chang, Chia-Hao; Wei, Kuo-Liang; Lin, Chun-Liang

    2016-03-01

    Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is linked to an increased risk for chronic kidney disease (CKD); liver fibrosis with biopsy-proven NAFLD has also been shown to associate with an increased risk of CKD. This study compares the diagnostic performance of simple noninvasive tests in identifying prevalent CKD among individuals with ultrasonography-diagnosed NAFLD. A total of 755 with ultrasonography-diagnosed NAFLD were included. Estimated glomerular filtration rate and noninvasive markers for hepatic fibrosis: aspartate transaminase to alanine transaminase ratio (AAR), aspartate transaminase to platelet ratio index (APRI), FIB-4 score, NAFLD fibrosis score (NFS) and BARD score were assessed. Binary logistic regression to generate a propensity score and receiver operating characteristic curves were developed for each of the noninvasive markers for predicting CKD, and the area under the receiver operating characteristic curve was greatest for FIB-4 score (0.750), followed by NFS (0.710), AAR (0.594), APRI (0.587), and BARD score (0.561). A cut-off value of 1.100 for FIB-4 score gave a sensitivity of 68.85% and a specificity of 71.07% for predicting CKD. The positive predictive value and negative predictive value were 37.50 and 90.05%, respectively. In multiple logistic regression analysis, only FIB-4 score ≧1.100 (OR 2.660, 95% CI 1.201-5.889; p = .016), older age, higher diastolic blood pressure and higher uric acid were independent predictors of CKD. High noninvasive fibrosis score is associated with an increased risk of prevalent CKD; the FIB-4 is the better predictor. With a cut-off value of 1.100 for FIB-4, it is useful in excluding the presence of CKD in patients with NAFLD.

  14. Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis.

    PubMed

    Papalavrentios, Lavrentios; Sinakos, Emmanouil; Chourmouzi, Danai; Hytiroglou, Prodromos; Drevelegas, Konstantinos; Constantinides, Manos; Drevelegas, Antonios; Talwalkar, Jayant; Akriviadis, Evangelos

    2015-01-01

    Limited data are available regarding the role of magnetic resonance imaging (MRI), particularly the new generation 3 Tesla technology, and especially diffusion-weighted imaging (DWI) in predicting liver fibrosis. The aim of our pilot study was to assess the clinical performance of the apparent diffusion coefficient (ADC) of liver parenchyma for the assessment of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). 18 patients with biopsy-proven NAFLD underwent DWI with 3 Tesla MRI. DWI was performed with single-shot echo-planar technique at b values of 0-500 and 0-1000 s/mm 2 . ADC was measured in four locations in the liver and the mean ADC value was used for analysis. Staging of fibrosis was performed according to the METAVIR system. The median age of patients was 52 years (range 23-73). The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm 2 (r= -0.30, P=0.27). However it was significantly associated with ADC at b value of 0-1000 s/mm 2 (r= -0.57, P=0.01). For this b value (0-1000 s/mm 2 ) the area under receiver-operating characteristic curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 ×10 -3 mm 2 /s. 3 Tesla DWI can possibly predict the presence of advanced fibrosis in patients with NAFLD.

  15. Phosphoproteomic biomarkers predicting histologic nonalcoholic steatohepatitis and fibrosis.

    PubMed

    Younossi, Zobair M; Baranova, Ancha; Stepanova, Maria; Page, Sandra; Calvert, Valerie S; Afendy, Arian; Goodman, Zachary; Chandhoke, Vikas; Liotta, Lance; Petricoin, Emanuel

    2010-06-04

    The progression of nonalcoholic fatty liver disease (NAFLD) has been linked to deregulated exchange of the endocrine signaling between adipose and liver tissue. Proteomic assays for the phosphorylation events that characterize the activated or deactivated state of the kinase-driven signaling cascades in visceral adipose tissue (VAT) could shed light on the pathogenesis of nonalcoholic steatohepatitis (NASH) and related fibrosis. Reverse-phase protein microarrays (RPMA) were used to develop biomarkers for NASH and fibrosis using VAT collected from 167 NAFLD patients (training cohort, N = 117; testing cohort, N = 50). Three types of models were developed for NASH and advanced fibrosis: clinical models, proteomics models, and combination models. NASH was predicted by a model that included measurements of two components of the insulin signaling pathway: AKT kinase and insulin receptor substrate 1 (IRS1). The models for fibrosis were less reliable when predictions were based on phosphoproteomic, clinical, or the combination data. The best performing model relied on levels of the phosphorylation of GSK3 as well as on two subunits of cyclic AMP regulated protein kinase A (PKA). Phosphoproteomics technology could potentially be used to provide pathogenic information about NASH and NASH-related fibrosis. This information can lead to a clinically relevant diagnostic/prognostic biomarker for NASH.

  16. Fibrillar collagen scoring by second harmonic microscopy: a new tool in the assessment of liver fibrosis.

    PubMed

    Gailhouste, Luc; Le Grand, Yann; Odin, Christophe; Guyader, Dominique; Turlin, Bruno; Ezan, Frédéric; Désille, Yoann; Guilbert, Thomas; Bessard, Anne; Frémin, Christophe; Theret, Nathalie; Baffet, Georges

    2010-03-01

    Imaging of supramolecular structures by multiphoton microscopy offers significant advantages for studying specific fibrillar compounds in biological tissues. In this study, we aimed to demonstrate the relevance of Second Harmonic Generation (SHG) for assessing and quantifying, without staining, fibrillar collagen in liver fibrosis. We first showed the relationship between SHG signal and collagen forms over-produced and accumulated during fibrosis progression. Taking this property into consideration, we developed an innovative method to precisely quantify the fibrosis area in histological slices by scoring of fibrillar collagen deposits (Fibrosis-SHG index). The scoring method was routinely applied to 119 biopsies from patients with chronic liver disease allowing a fast and accurate measurement of fibrosis correlated with the Fibrosis-Metavir score (rho=0.75, p<0.0001). The technique allowed discriminating patients with advanced (moderate to severe) fibrosis (AUROC=0.88, p<0.0001) and cirrhosis (AUROC=0.89, p<0.0001). Taking advantage of its continuous gradation, the Fibrosis-SHG index also allowed the discrimination of several levels of fibrosis within the same F-Metavir stage. The SHG process presented several advantages such as a high reliability and sensitivity that lead to a standardized evaluation of hepatic fibrosis in liver biopsies without staining and pathological examination. Second harmonic microscopy emerges as an original and powerful tool in the assessment of liver fibrosis and offers new possibilities for the evaluation of experimental protocols. We expect that this technology could easily be applicable in the study of other fibro-proliferative pathologies. Copyright (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  17. Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis

    PubMed Central

    Papalavrentios, Lavrentios; Sinakos, Emmanouil; Chourmouzi, Danai; Hytiroglou, Prodromos; Drevelegas, Konstantinos; Constantinides, Manos; Drevelegas, Antonios; Talwalkar, Jayant; Akriviadis, Evangelos

    2015-01-01

    Background Limited data are available regarding the role of magnetic resonance imaging (MRI), particularly the new generation 3 Tesla technology, and especially diffusion-weighted imaging (DWI) in predicting liver fibrosis. The aim of our pilot study was to assess the clinical performance of the apparent diffusion coefficient (ADC) of liver parenchyma for the assessment of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methods 18 patients with biopsy-proven NAFLD underwent DWI with 3 Tesla MRI. DWI was performed with single-shot echo-planar technique at b values of 0-500 and 0-1000 s/mm2. ADC was measured in four locations in the liver and the mean ADC value was used for analysis. Staging of fibrosis was performed according to the METAVIR system. Results The median age of patients was 52 years (range 23-73). The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm2 (r= -0.30, P=0.27). However it was significantly associated with ADC at b value of 0-1000 s/mm2 (r= -0.57, P=0.01). For this b value (0-1000 s/mm2) the area under receiver-operating characteristic curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 ×10-3 mm2/s. Conclusion 3 Tesla DWI can possibly predict the presence of advanced fibrosis in patients with NAFLD. PMID:25608776

  18. Fatty liver promotes fibrosis in monkeys consuming high fructose.

    PubMed

    Cydylo, Michael A; Davis, Ashley T; Kavanagh, Kylie

    2017-02-01

    Nonalcoholic fatty liver diseases (NAFLD) are related to development of liver fibrosis which currently has few therapeutic options. Rodent models of NAFLD inadequately model the fibrotic aspects of the disease and fail to demonstrate the spectrum of cardiometabolic diseases without genetic manipulation. This study aimed to document a monkey model of fatty liver and fibrosis, which naturally develop cardiometabolic disease pathophysiologies. Twenty-seven cynomolgus monkeys (Macaca fascicularis) fed diets either low or high in simple carbohydrates, supplied as fructose [control and high-fructose diet (HRr)], on low-fat, cholesterol-free background were studied. The HFr was consumed for up to 7 years, and liver tissue was histologically evaluated for fat and fibrosis extent. The HFr diet increased steatosis, and its extent was related to duration of fructose exposure. Lipid droplet size also increased with HFr duration; however, compared with control, the lipid droplets were smaller on average. Fibrosis extent was significantly greater with fructose feeding and was predicted by fructose exposure, extent of fatty liver, and age. These data are the first to demonstrate that high-carbohydrate diets alone can generate both liver fat and fibrosis and thus allow further study of mechanisms and therapeutic options in the translational animal model. © 2017 The Obesity Society.

  19. Transient elastography (FibroScan®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand?

    PubMed Central

    Mikolasevic, Ivana; Orlic, Lidija; Franjic, Neven; Hauser, Goran; Stimac, Davor; Milic, Sandra

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Currently, the routinely used modalities are unable to adequately determine the levels of steatosis and fibrosis (laboratory tests and ultrasonography) or cannot be applied as a screening procedure (liver biopsy). Among the non-invasive tests, transient elastography (FibroScan®, TE) with controlled attenuation parameter (CAP) has demonstrated good accuracy in quantifying the levels of liver steatosis and fibrosis in patients with NAFLD, the factors associated with the diagnosis and NAFLD progression. The method is fast, reliable and reproducible, with good intra- and interobserver levels of agreement, thus allowing for population-wide screening and disease follow-up. The initial inability of the procedure to accurately determine fibrosis and steatosis in obese patients has been addressed with the development of the obese-specific XL probe. TE with CAP is a viable alternative to ultrasonography, both as an initial assessment and during follow-up of patients with NAFLD. Its ability to exclude patients with advanced fibrosis may be used to identify low-risk NAFLD patients in whom liver biopsy is not needed, therefore reducing the risk of complications and the financial costs. PMID:27621571

  20. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study1[S

    PubMed Central

    Krawczyk, Marcin; Rau, Monika; Schattenberg, Jörn M.; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Boettler, Tobias; Lammert, Frank; Geier, Andreas

    2017-01-01

    The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16–88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2–S3 (P < 0.001) and fibrosis stages F2–F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis. PMID:27836992

  1. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study.

    PubMed

    Krawczyk, Marcin; Rau, Monika; Schattenberg, Jörn M; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Boettler, Tobias; Lammert, Frank; Geier, Andreas

    2017-01-01

    The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16-88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2-S3 (P < 0.001) and fibrosis stages F2-F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  2. Diagnostic performance of T lymphocyte subpopulations in assessment of liver fibrosis stages in hepatitis C virus patients: simple noninvasive score.

    PubMed

    Toson, El-Shatat A; Shiha, Gamal E; El-Mezayen, Hatem A; El-Sharkawy, Aml M

    2016-08-01

    Evaluation of liver fibrosis in patients infected with hepatitis C virus is highly useful for the diagnosis of the disease as well as therapeutic decision. Our aim was to develop and validate a simple noninvasive score for liver fibrosis staging in chronic hepatitis C (CHC) patients and compare its performance against three published simple noninvasive indexes. CHC patients were divided into two groups: an estimated group (n=70) and a validated group (n=52). Liver fibrosis was tested in biopsies using the Metavair score system. CD4 and CD8 count/percentage were assayed by fluorescence-activated cell sorting analysis. The multivariate discriminant analysis selects a function on the basis of absolute values of five biochemical markers: immune fibrosis index (IFI); score=3.07+3.06×CD4/CD8+0.02×α-fetoprotein (U/l)-0.07×alanine aminotransferase ratio-0.005×platelet count (10/l)-1.4×albumin (g/dl). The IFI score produced areas under curve of 0.949, 0.947, and 0.806 for differentiation of all patient categories [significant fibrosis (F2-F4), advanced fibrosis (F3-F4), and cirrhosis (F4)]. The IFI score, a novel noninvasive test, can be used easily for the prediction of liver fibrosis stage in CHC patients. Our score was more efficient than aspartate aminotransferase to platelet ratio index, fibrosis index, and fibroQ and more suitable for use in Egyptian hepatitis C virus patients.

  3. Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis

    PubMed Central

    Sevrain, David; Dubreuil, Matthieu; Dolman, Grace Elizabeth; Zaitoun, Abed; Irving, William; Guha, Indra Neil; Odin, Christophe; Le Grand, Yann

    2015-01-01

    In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools. PMID:25909005

  4. Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis.

    PubMed

    Sevrain, David; Dubreuil, Matthieu; Dolman, Grace Elizabeth; Zaitoun, Abed; Irving, William; Guha, Indra Neil; Odin, Christophe; Le Grand, Yann

    2015-04-01

    In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools.

  5. More Frequent Clinic Visits Are Associated with Improved Outcomes for Children with NAFLD

    PubMed Central

    Lam, Carol; Bandsma, Robert; Ling, Simon

    2016-01-01

    Objective. Adult data suggest that frequent monitoring of patients with nonalcoholic fatty liver disease (NAFLD) may be associated with improved outcomes. The optimal frequency of outpatient visits for the management of pediatric NAFLD remains unknown. Study Design. In this retrospective study, two cohorts of patients with NAFLD, one followed on a yearly basis and one followed on 3-month intervals, were included. Both received similar advice regarding lifestyle changes. Primary outcome was change in BMI z-scores over a year. Secondary outcomes were the change in serum transaminases and markers of metabolic dysregulation. Results. Fifty-six patients were included (28 per group). The majority (71%) were male with a mean (±SD) age of 12.2 (±2.7) years. At baseline, there were no differences in BMI z-scores (2.8 versus 2.9; p = 0.72) and ALT levels (101 versus 100 U/L; p = 0.95) between the groups (yearly versus three-month, resp.). Twelve months later, those followed on a 3-month basis demonstrated a significant decrease in BMI (net BMI z-score change = −0.06; p = 0.37), accompanied by a significant improvement in serum ALT (−25 U/L; p < 0.01) and AST (−13 U/L; p = 0.03) levels. There were no differences in fasting lipid profiles. Conclusion. Frequent clinic visits are associated with improved outcomes in pediatric NAFLD. PMID:28058253

  6. The influence of hepatic steatosis on the evaluation of fibrosis with non-alcoholic fatty liver disease by acoustic radiation force impulse.

    PubMed

    Yanrong Guo; Haoming Lin; Xinyu Zhang; Huiying Wen; Siping Chen; Xin Chen

    2017-07-01

    Acoustic radiation force impulse (ARFI) elastography is a non-invasive method for the assessment of liver by measuring liver stiffness. The aim of this study is to evaluate the accuracy of ARFI for the diagnosis of liver fibrosis and to assess impact of steatosis on liver fibrosis stiffness measurement, in rats model of non-alcoholic fatty liver disease (NAFLD). The rat models were conducted in 59 rats. The right liver lobe was processed and embedded in a fabricated gelatin solution. Liver mechanics were measured using shear wave velocity (SWV) induced by acoustic radiation force. In rats with NAFLD, the diagnostic performance of ARFI elastography in predicting severe fibrosis (F ≥ 3) and cirrhosis (F ≥ 4) had the areas under the receiver operating characteristic curves (AUROC) of 0.993 and 0.985. Among rats mean SWV values were significantly higher in rats with severe steatosis by histology compared to those mild or without steatosis for F0-F2 fibrosis stages (3.07 versus 2.51 m/s, P = 0.01). ARFI elastography is a promising method for staging hepatic fibrosis with NAFLD in rat models. The presence of severe steatosis is a significant factor for assessing the lower stage of fibrosis.

  7. Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data

    PubMed Central

    Saberi, Behnam; Dadabhai, Alia S; Nanavati, Julie; Wang, Lin; Shinohara, Russell T; Mullin, Gerard E

    2018-01-01

    AIM To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). METHODS Two individual reviewers identified relevant studies using the PubMed, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows: (1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and (2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P < 0.05 was considered statistically significant. RESULTS A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference = -0.86, P = 0.08 (-4.17, 2.46)]. A meta-regression evaluation of serum vitamin 25 (OH)D levels across the individual stages (F0-F4) of fibrosis did not show an association for the six included studies. CONCLUSION Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD. PMID:29399288

  8. Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data.

    PubMed

    Saberi, Behnam; Dadabhai, Alia S; Nanavati, Julie; Wang, Lin; Shinohara, Russell T; Mullin, Gerard E

    2018-01-27

    To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). Two individual reviewers identified relevant studies using the PubMed, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows: (1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and (2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P < 0.05 was considered statistically significant. A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference = -0.86, P = 0.08 (-4.17, 2.46)]. A meta-regression evaluation of serum vitamin 25 (OH)D levels across the individual stages (F0-F4) of fibrosis did not show an association for the six included studies. Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD.

  9. Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation.

    PubMed

    Nagpal, Sajan Jiv Singh; Kabbany, Mohammad Nasser; Mohamad, Bashar; Lopez, Rocio; Zein, Nizar N; Alkhouri, Naim

    2016-07-01

    Nonalcoholic fatty liver disease (NAFLD) is likely to replace Hepatitis C as the leading cause of cirrhosis resulting in liver transplantation (LT) within a few years. Unfortunately, due to the lack of established guidelines for the screening of NAFLD in high-risk populations, many patients present with portal hypertension complications as their first manifestation of NAFLD require a LT evaluation. We aimed to investigate what proportion of patients who underwent LT for NAFLD-cirrhosis had knowledge of their liver disease prior to presenting with portal hypertension complications and to identify differences in clinical parameters between those with and without knowledge of preexisting NAFLD. Consecutive patients who underwent LT for NAFLD-cirrhosis at a tertiary referral center were included in the study. Demographic and clinical data at the time of the first LT evaluation visit were collected, and patient knowledge of previous NAFLD was documented. Ascites, variceal bleeding, hepatic encephalopathy, and thrombocytopenia leading to diagnosis of underlying cirrhosis were considered as the presenting symptoms of portal hypertension. A p < 0.05 was considered statistically significant. A total of 124 subjects who received LT for NAFLD-cirrhosis were included, 58 % (n = 72) were male. At the time of the first LT evaluation visit, 60 % had diabetes, the mean body mass index was 33.2 [28.6, 37.6] kg/m(2), and the mean Model for End-Stage Liver Disease (MELD) score was 14.0 [11.0, 19.0]. More importantly, 85/124 patients (68.5 %) had no knowledge of preexisting NAFLD prior to presentation with symptoms of portal hypertension. The presenting symptoms were new-onset ascites in 61 %, hepatic encephalopathy in 25 %, variceal bleeding in 18 %, thrombocytopenia in 9 %, and other in 9 % (non-exclusive). Patients with no prior knowledge of NAFLD were less likely to have a diagnosis of hypercholesterolemia (30 vs. 50 %, p = 0.035) and had a trend toward having

  10. The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

    PubMed

    Irvine, Katharine M; Wockner, Leesa F; Shanker, Mihir; Fagan, Kevin J; Horsfall, Leigh U; Fletcher, Linda M; Ungerer, Jacobus P J; Pretorius, Carel J; Miller, Gregory C; Clouston, Andrew D; Lampe, Guy; Powell, Elizabeth E

    2016-03-01

    Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Current Management of NAFLD

    PubMed Central

    MUNTEANU, MIHAI ALEXANDRU; NAGY, GEORGIANA ANCA; MIRCEA, PETRU ADRIAN

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries. It affects about 1 billion individuals worldwide. While people with simple steatosis have no higher risk of death than the general population, people with non-alcoholic steatohepatitis are at increased risk of death compared to general population. Current management for NAFLD includes diet and lifestyle changes, management of underlying metabolic risk factors and pharmacological therapies. The objective of therapy is to prevent the complications. The problem with dietary and lifestyle interventions is that they are hard to implement. Compliance is the key. Until now, there is still no approved drug for the treatment of NAFLD. Insulin resistance is the main target of pharmacological therapy, but the question that we ask ourselves as physicians is who should receive medical treatment among NAFLD patients and for how long. PMID:27004021

  12. Mean Platelet Volume, Red Cell Distribution Width to Platelet Count Ratio, Globulin Platelet Index, and 16 Other Indirect Noninvasive Fibrosis Scores: How Much Do Routine Blood Tests Tell About Liver Fibrosis in Chronic Hepatitis C?

    PubMed

    Thandassery, Ragesh B; Al Kaabi, Saad; Soofi, Madiha E; Mohiuddin, Syed A; John, Anil K; Al Mohannadi, Muneera; Al Ejji, Khalid; Yakoob, Rafie; Derbala, Moutaz F; Wani, Hamidullah; Sharma, Manik; Al Dweik, Nazeeh; Butt, Mohammed T; Kamel, Yasser M; Sultan, Khaleel; Pasic, Fuad; Singh, Rajvir

    2016-07-01

    Many indirect noninvasive scores to predict liver fibrosis are calculated from routine blood investigations. Only limited studies have compared their efficacy head to head. We aimed to compare these scores with liver biopsy fibrosis stages in patients with chronic hepatitis C. From blood investigations of 1602 patients with chronic hepatitis C who underwent a liver biopsy before initiation of antiviral treatment, 19 simple noninvasive scores were calculated. The area under the receiver operating characteristic curves and diagnostic accuracy of each of these scores were calculated (with reference to the Scheuer staging) and compared. The mean age of the patients was 41.8±9.6 years (1365 men). The most common genotype was genotype 4 (65.6%). Significant fibrosis, advanced fibrosis, and cirrhosis were seen in 65.1%, 25.6, and 6.6% of patients, respectively. All the scores except the aspartate transaminase (AST) alanine transaminase ratio, Pohl score, mean platelet volume, fibro-alpha, and red cell distribution width to platelet count ratio index showed high predictive accuracy for the stages of fibrosis. King's score (cutoff, 17.5) showed the highest predictive accuracy for significant and advanced fibrosis. King's score, Göteborg university cirrhosis index, APRI (the AST/platelet count ratio index), and Fibrosis-4 (FIB-4) had the highest predictive accuracy for cirrhosis, with the APRI (cutoff, 2) and FIB-4 (cutoff, 3.25) showing the highest diagnostic accuracy.We derived the study score 8.5 - 0.2(albumin, g/dL) +0.01(AST, IU/L) -0.02(platelet count, 10/L), which at a cutoff of >4.7 had a predictive accuracy of 0.868 (95% confidence interval, 0.833-0.904) for cirrhosis. King's score for significant and advanced fibrosis and the APRI or FIB-4 score for cirrhosis could be the best simple indirect noninvasive scores.

  13. Interobserver Variability in Histologic Evaluation of Liver Fibrosis Using Categorical and Quantitative Scores.

    PubMed

    Pavlides, Michael; Birks, Jacqueline; Fryer, Eve; Delaney, David; Sarania, Nikita; Banerjee, Rajarshi; Neubauer, Stefan; Barnes, Eleanor; Fleming, Kenneth A; Wang, Lai Mun

    2017-04-01

    The aim of the study was to investigate the interobserver agreement for categorical and quantitative scores of liver fibrosis. Sixty-five consecutive biopsy specimens from patients with mixed liver disease etiologies were assessed by three pathologists using the Ishak and nonalcoholic steatohepatitis Clinical Research Network (NASH CRN) scoring systems, and the fibrosis area (collagen proportionate area [CPA]) was estimated by visual inspection (visual-CPA). A subset of 20 biopsy specimens was analyzed using digital imaging analysis (DIA) for the measurement of CPA (DIA-CPA). The bivariate weighted κ between any two pathologists ranged from 0.57 to 0.67 for Ishak staging and from 0.47 to 0.57 for the NASH CRN staging. Bland-Altman analysis showed poor agreement between all possible pathologist pairings for visual-CPA but good agreement between all pathologist pairings for DIA-CPA. There was good agreement between the two pathologists who assessed biopsy specimens by visual-CPA and DIA-CPA. The intraclass correlation coefficient, which is equivalent to the κ statistic for continuous variables, was 0.78 for visual-CPA and 0.97 for DIA-CPA. These results suggest that DIA-CPA is the most robust method for assessing liver fibrosis followed by visual-CPA. Categorical scores perform less well than both the quantitative CPA scores assessed here. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  14. Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice.

    PubMed

    Luo, Fangqiong; Ishigami, Masatoshi; Achiwa, Koichi; Ishizu, Yoji; Kuzuya, Teiji; Honda, Takashi; Hayashi, Kazuhiko; Ishikawa, Tetsuya; Katano, Yoshiaki; Goto, Hidemi

    2015-09-01

    The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in men than in women, but according to some epidemiological studies, this gender difference disappears after menopause. Estrogen therapy protects against NAFLD and nonalcoholic steatohepatitis (NASH) after menopause. We investigated the therapeutic effect of raloxifene, a second-generation selective estrogen-receptor modulator, on NASH induced by a choline-deficient high-fat (CDHF) diet in female ovariectomized (OVX) mice. Seven-week-old female C57BL/6J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + raloxifene (intraperitoneal injection, 3 mg/kg body weight/day; OVX + RLX group). These three groups of mice were fed a CDHF diet for 8 weeks; choline-sufficient high-fat (CSHF) diet was used as control diet. Serum biochemical indicators of hepatic function and liver histological changes were evaluated. Compared with CSHF diet, ovariectomy enhances liver injury and fibrosis in CDHF diet-fed mice. Serum alanine aminotransferase (ALT) levels were significantly lower in the OVX + RLX group than in the OVX group. The OVX group developed extensive steatosis with inflammation and fibrosis. Lobular inflammatory scores and fibrosis staging in the OVX + RLX group were significantly lower than in the OVX group. Furthermore, the OVX + RLX group exhibited significantly higher expression of hepatic estrogen receptor-α, which was significantly lower in the OVX group than in the SHAM group. Raloxifene may ameliorate progression of liver fibrosis of NASH induced by CDHF diet in ovariectomized female mice, and up-regulation of estrogen receptor-α may play an important role in the beneficial effects of raloxifene on NASH.

  15. Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.

    PubMed

    Chan, W-K; Treeprasertsuk, S; Imajo, K; Nakajima, A; Seki, Y; Kasama, K; Kakizaki, S; Fan, J-G; Song, M J; Yoon, S K; Dan, Y-Y; Lesmana, L; Ho, K-Y; Goh, K-L; Wong, V W-S

    2018-03-01

    The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m 2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 10 9 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH. © 2018 John Wiley & Sons Ltd.

  16. Low Hepatic Tissue Copper in Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Mendoza, Michael; Caltharp, Shelley; Song, Ming; Collin, Lindsay; Konomi, Juna V; McClain, Craig J; Vos, Miriam B

    2017-07-01

    Animal models and studies in adults have demonstrated that copper restriction increases severity of liver injury in nonalcoholic fatty liver disease (NAFLD). This has not been studied in children. We aimed to determine if lower tissue copper is associated with increased NAFLD severity in children. This was a retrospective study of pediatric patients who had a liver biopsy including a hepatic copper quantitation. The primary outcome compared hepatic copper concentration in NAFLD versus non-NAFLD. Secondary outcomes compared hepatic copper levels against steatosis, fibrosis, lobular inflammation, balloon degeneration, and NAFLD activity score (NAS). The study analysis included 150 pediatric subjects (102 with NAFLD and 48 non-NAFLD). After adjusting for age, body mass index z score, gamma glutamyl transferase, alanine aminotransferase, and total bilirubin, NAFLD subjects had lower levels of hepatic copper than non-NAFLD (P = 0.005). In addition, tissue copper concentration decreased as steatosis severity increased (P < 0.001). Copper levels were not associated with degree of fibrosis, lobular inflammation, portal inflammation, or balloon degeneration. In this cohort of pediatric subjects with NAFLD, we observed decreased tissue copper levels in subjects with NAFLD when compared with non-NAFLD subjects. In addition, tissue copper levels were lower in subjects with nonalcoholic steatohepatitis, a more severe form of the disease, when compared with steatosis alone. Further studies are needed to explore the relationship between copper levels and NAFLD progression.

  17. Comparing the efficiency of Fib-4, Egy-score, APRI, and GUCI in liver fibrosis staging in Egyptians with chronic hepatitis C.

    PubMed

    Cordie, Ahmed; Salama, Ahmed; El-Sharkawy, Marwa; El-Nahaas, Saeed M; Khairy, Marwa; Elsharkawy, Aisha; Hassany, Mohamed; Esmat, Gamal

    2018-06-01

    Assessment of hepatic fibrosis in chronic hepatitis C virus patients by liver biopsy is not widely accepted despite its accuracy, being invasive, carrying complications, and adding cost. This paved the way to development and use of non-invasive markers of fibrosis in diagnosis of hepatic fibrosis. We aimed at evaluating the efficiency of Fib-4, Egy-score, Aspartate-to-platelet ratio index (APRI), and Göteborg University Cirrhosis Index (GUCI) in comparison to liver biopsy, in the assessment of hepatic fibrosis in chronic hepatitis C patients. This was a cross sectional study including 200 chronic HCV patients were divided into two groups according to stage of fibrosis (Metavir score) into non-significant fibrosis (fibrosis (≥F2). Reference needle liver biopsy was compared to Fib-4, Egyscore, APRI, and GUCI. Older age (P < 0.001) and higher BMI (P = 0.005) were significantly related to significant fibrosis and positively correlated with fibrosis progression (r = 0.361, P = 0.000, and r = 0.165, P = 0.019 respectively). Fib-4 >1.27, APRI >0.48, Egy-score >0.73, and GUCI >0.57 significantly predict significant fibrosis (P < 0.01). Fib-4 carries the best performance and significant reliability with AUROC 0.783, sensitivity 74%, specificity 69%, PPV 0.55, and NPV 0.86. The addition of BMI to Fib-4 improved the significant fibrosis AUROC curve performance but did not reach statistical significant improvement. We concluded that age and BMI are good predictors of hepatic fibrosis. Fib-4 (>1.27) is the best method of prediction of significant fibrosis compared to Egy-score, APRI, and GUCI. Addition of BMI to Fib-4 did not improve diagnostic value of Fib-4. © 2018 Wiley Periodicals, Inc.

  18. Disease duration and Medsger's severity score are associated with significant liver fibrosis in patients with systemic sclerosis.

    PubMed

    Lee, Sang-Won; Kim, Beom Kyung; Park, Jun Yong; Kim, Do Young; Ahn, Sang Hoon; Song, Jason Jungsik; Park, Yong-Beom; Lee, Soo-Kon; Han, Kwang-Hyub; Kim, Seung Up

    2015-01-01

    We investigated the prevalence and predictors of significant liver fibrosis in patients with systemic sclerosis (SSc) who had no evidences of liver diseases due to viral infection, drug, and heavy alcohol consumption. A total of 44 SSc patients were recruited. In addition to the clinical and laboratory data, the 2013 College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria score, modified Rodnan skin score (mRSS), and Medsger's severity score (MSS) were analysed. Liver stiffness (LS) was measured using transient elastography to assess the degree of liver fibrosis and 7.4 kPa was adopted as the cut-off value for significant liver fibrosis. The median age of patients (38 women) was 54 years and the median disease duration was 41.0 months. The median LS value was 4.6 kPa. The median mRSS and MSS were 7.0 and 5.0, respectively. Six (13.6%) patients had significant liver fibrosis. Disease duration (standardised β=0.375, p=0.018) and MSS (standardised β=0.398, p=0.047) significantly correlated with LS values. In multivariate analysis, disease duration≥63 months (odds ratio (OR) 19.166, 95% confidence interval 1.090, 336.962, p=0.043) and MSS≥7 (OR 19.796, 95% confidence interval 1.439, 272.252, p=0.026) independently predicted the presence of significant liver fibrosis. The prevalence of significant liver fibrosis was relatively high (13.6%) and its independent predictors were disease duration and MSS.

  19. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography.

    PubMed

    Imajo, Kento; Kessoku, Takaomi; Honda, Yasushi; Tomeno, Wataru; Ogawa, Yuji; Mawatari, Hironori; Fujita, Koji; Yoneda, Masato; Taguri, Masataka; Hyogo, Hideyuki; Sumida, Yoshio; Ono, Masafumi; Eguchi, Yuichiro; Inoue, Tomio; Yamanaka, Takeharu; Wada, Koichiro; Saito, Satoru; Nakajima, Atsushi

    2016-03-01

    Noninvasive methods have been evaluated for the assessment of liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We compared the ability of transient elastography (TE) with the M-probe, and magnetic resonance elastography (MRE) to assess liver fibrosis. Findings from magnetic resonance imaging (MRI)-based proton density fat fraction (PDFF) measurements were compared with those from TE-based controlled attenuation parameter (CAP) measurements to assess steatosis. We performed a cross-sectional study of 142 patients with NAFLD (identified by liver biopsy; mean body mass index, 28.1 kg/m(2)) in Japan from July 2013 through April 2015. Our study also included 10 comparable subjects without NAFLD (controls). All study subjects were evaluated by TE (including CAP measurements), MRI using the MRE and PDFF techniques. TE identified patients with fibrosis stage ≥2 with an area under the receiver operating characteristic (AUROC) curve value of 0.82 (95% confidence interval [CI]: 0.74-0.89), whereas MRE identified these patients with an AUROC curve value of 0.91 (95% CI: 0.86-0.96; P = .001). TE-based CAP measurements identified patients with hepatic steatosis grade ≥2 with an AUROC curve value of 0.73 (95% CI: 0.64-0.81) and PDFF methods identified them with an AUROC curve value of 0.90 (95% CI: 0.82-0.97; P < .001). Measurement of serum keratin 18 fragments or alanine aminotransferase did not add value to TE or MRI for identifying nonalcoholic steatohepatitis. MRE and PDFF methods have higher diagnostic performance in noninvasive detection of liver fibrosis and steatosis in patients with NAFLD than TE and CAP methods. MRI-based noninvasive assessment of liver fibrosis and steatosis is a potential alternative to liver biopsy in clinical practice. UMIN Clinical Trials Registry No. UMIN000012757. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity.

    PubMed

    Fracanzani, Anna Ludovica; Petta, Salvatore; Lombardi, Rosa; Pisano, Giuseppina; Russello, Maurizio; Consonni, Dario; Di Marco, Vito; Cammà, Calogero; Mensi, Laura; Dongiovanni, Paola; Valenti, Luca; Craxì, Antonio; Fargion, Silvia

    2017-10-01

    age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2-106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4-4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms. Copyright © 2017. Published by Elsevier Inc.

  1. FibroMeters: a family of blood tests for liver fibrosis.

    PubMed

    Calès, P; Boursier, J; Oberti, F; Hubert, I; Gallois, Y; Rousselet, M-C; Dib, N; Moal, V; Macchi, L; Chevailler, A; Michalak, S; Hunault, G; Chaigneau, J; Sawadogo, A; Lunel, F

    2008-09-01

    FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

  2. Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease.

    PubMed

    Yamamoto, Hiroya; Kanno, Keishi; Ikuta, Takuya; Arihiro, Koji; Sugiyama, Akiko; Kishikawa, Nobusuke; Tazuma, Susumu

    2016-05-01

    We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  3. The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe.

    PubMed

    Simon, Tracey G; Corey, Kathleen E; Cannon, Christopher P; Blazing, Michael; Park, Jeong-Gun; O'Donoghue, Michelle L; Chung, Raymond T; Giugliano, Robert P

    2018-05-26

    The nonalcoholic fatty liver disease fibrosis score (NFS) is comprised of unique metabolic risk indicators that may accurately predict residual cardiovascular (CV) risk in patients with established coronary disease and metabolic dysfunction. We applied the NFS prospectively to 14,819 post-ACS patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), in the IMPROVE-IT trial, using validated NFS cutoffs. The primary endpoint included CV death, myocardial infarction, unstable angina, revascularization or stroke. Outcomes were compared between NFS categories and treatment arms using frequency of events, KM rates and adjusted Cox proportional hazard models. The ability of the NFS to predict recurrent CV events was independently validated in 5395 placebo-treated patients enrolled in the SOLID-TIMI 52 trial. Among 14,819 patients enrolled in IMPROVE-IT, 14.2% (N = 2106) were high-risk (NFS > 0.67). The high-risk group had a 30% increased risk of recurrent major CV events, compared to the low-risk NFS group (HR 1.30 [1.19-1.43]; p < 0.001). Among high-risk patients, ezetimibe/simvastatin conferred a 3.7% absolute reduction in risk of recurrent CV events, compared to placebo/simvastatin (HR 0.85 [0.74-0.98]), translating to a number-needed-to-treat of 27. Similar benefit was not found in the low-risk group (HR ezetimibe/simvastatin vs. placebo/simvastatin, 1.01 [0.91-1.12]; p-interaction = 0.053). The relationship between NFS category and recurrent CV events was independently validated in patients enrolled in SOLID-TIMI 52 (HR for NFS > 0.67 vs. NFS < -1.455 = 1.55 [1.32-1.81]; p < 0.001). Stratification of cardiovascular risk by NFS identifies an independent population of patients who are at highest risk of recurrent events, and most likely to benefit from dual lipid-lowering therapy. Clinical trials.gov: NCT00202878. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center.

    PubMed

    Agrawal, Swastik; Duseja, Ajay; Aggarwal, Ashutosh; Das, Ashim; Mehta, Manu; Dhiman, Radha K; Chawla, Yogesh

    2015-04-01

    The association of obstructive sleep apnea (OSA) with nonalcoholic fatty liver disease (NAFLD) has only been studied in selected subgroups such as the morbidly obese. We aimed to determine the prevalence and effect of OSA on NAFLD and vice versa in unselected patients attending the outpatient department. OSA was diagnosed by polysomnography, done in patients having symptoms of OSA, in patients with NAFLD attending the liver clinic. Polysomnography-proven patients with OSA attending the chest clinic were evaluated for NAFLD by ultrasonography. Anthropometry, liver function tests, metabolic syndrome evaluation and transient elastography were performed in all patients. Three (3%; 95% CI 1.03-8.45%) out of 100 patients with NAFLD (mean age 41 ± 11 years) had symptomatic OSA. Of 23 patients with OSA (mean age 46 ± 12 years,), 3 (13%) had mild, 5 (22%) moderate and 15 (65%) severe OSA. Twenty-one (91.3%; 95% CI 73.2-97.6%) patients with OSA had NAFLD, while raised hepatic transaminase levels were seen in seven (30.4%; 95% CI 15.6-50.9%). Body mass index (OR 1.21, 95% CI 1.02-1.44) and male gender (OR 4.79, 95% CI 1.12-20.48) were significant independent predictors of OSA in NAFLD. The apnea-hypopnea index (OR 1.084, 95% CI 1.002-1.172), a marker of OSA severity, was the only significant independent predictor of significant fibrosis in patients with NAFLD. Prevalence of symptomatic OSA in patients with NAFLD is low and is predicted by male gender and obesity. Prevalence of NAFLD in patients with OSA is very high. Significant hepatic fibrosis in patients with NAFLD is predicted by OSA independent of obesity and metabolic syndrome.

  5. Serum miR-29a and miR-122 as Potential Biomarkers for Non-Alcoholic Fatty Liver Disease (NAFLD).

    PubMed

    Jampoka, Kanisa; Muangpaisarn, Puth; Khongnomnan, Kritsada; Treeprasertsuk, Sombat; Tangkijvanich, Pisit; Payungporn, Sunchai

    2018-05-30

    Non-alcoholic fatty liver disease (NAFLD) is an over accumulation of triglyceride in the liver without alcohol consumption which its major cause is from insulin resistance. Patients with NAFLD can develop to be liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are non-coding RNAs that regulate post-transcriptional gene silencing. Previous research reported that miR-29 family (a, b and c) and miR-122 have an important role in regulating insulin resistance related to NAFLD. The purpose of this study was to investigate that miR-29 and miR-122 can be possible biomarkers for non-invasive diagnosis of NAFLD. Serum samples were collected from 58 NAFLD patients and 34 healthy controls. MiRNAs were extracted from serum by using microRNA purification kit followed by polyuridylation, reverse transcription and quantitative real-time PCR. Also, we analyzed the correlation between miR-29 and miR-122 and level of liver inflammation in NAFLD patients. We found that the serum miR-29a levels in NAFLD patients were significantly lower (P = 0.006) than the control group, while miR-29c levels were unchanged, and miR-29b levels were undetectable. However, we found that serum miR-122 levels in NAFLD patients were significantly higher (P < 0.001) than those found in the control group. For miR-29a, the area under curve (AUC) was 0.679 (P = 0.0065) with 60.87% sensitivity and 82.35% specificity. For miR-122, the AUC was 0.831 (P < 0.0001) with 75.00% sensitivity and 82.35% specificity. Interestingly, the level of serum miR-122 were significantly different between patients with not steatohepatitis (NAS < 4) and steatohepatitis (NAS ≥ 4), indicating that the levels of miR-122 were related to the severity of NAFLD. The levels of miR-29a and miR-122 might be beneficial and compelling as possible biomarkers for non-invasive diagnosis of NAFLD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan.

    PubMed

    Akuta, Norio; Kawamura, Yusuke; Arase, Yasuji; Suzuki, Fumitaka; Sezaki, Hitomi; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Suzuki, Yoshiyuki; Ikeda, Kenji; Kumada, Hiromitsu

    2016-05-23

    It is important to determine the noninvasive parameters of histological features in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the value of genetic variations as surrogate markers of histological features. The parameters that affected the histological features of NAFLD were investigated in 211 Japanese patients with biopsy-proven NAFLD. The relationships between genetic variations in PNPLA3 rs738409 or TM6SF2 rs58542926 and histological features were analyzed. Furthermore, the impact of genetic variations that affected the pathological criteria for the diagnosis of nonalcoholic steatohepatitis (NASH) (Matteoni classification and NAFLD activity score) was evaluated. The fibrosis stage of PNPLA3 GG was significantly more progressive than that of CG by multiple comparisons. Multivariate analysis identified PNPLA3 genotypes as predictors of fibrosis of stage 2 or more, but the impact tended to decrease at stage 3 or greater. There were no significant differences among the histological features of the three genotypes of TM6SF2. PNPLA3 genotypes partly affected the definition of NASH by the NAFLD activity score, but TM6SF2 genotypes did not affect the definition of NASH. In Japanese patients with biopsy-proven NAFLD, PNPLA3 genotypes may partly affect histological features, including stage of fibrosis, but the TM6SF2 genotype does not affect histological features.

  7. Role of aramchol in steatohepatitis and fibrosis in mice

    PubMed Central

    Iruarrizaga‐Lejarreta, Marta; Varela‐Rey, Marta; Fernández‐Ramos, David; Martínez‐Arranz, Ibon; Delgado, Teresa C; Simon, Jorge; Gutiérrez‐de Juan, Virginia; delaCruz‐Villar, Laura; Azkargorta, Mikel; Lavin, José L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buqué, Xabier; Delle Cave, Donatella; Peña, Arantza; Rodríguez‐Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcón‐Pérez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martínez‐Chantar, María Luz; Lu, Shelly C.

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in

  8. APRI, the FIB-4 score, and Forn's index have noninvasive diagnostic value for liver fibrosis in patients with chronic hepatitis B.

    PubMed

    Ucar, Fatma; Sezer, Sevilay; Ginis, Zeynep; Ozturk, Gulfer; Albayrak, Aynur; Basar, Omer; Ekiz, Fuat; Coban, Sahin; Yuksel, Osman; Armutcu, Ferah; Akbal, Erdem

    2013-09-01

    The aim of this study was to evaluate the potential use of serum transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), fetuin-A, and fibroblast growth factor 21 (FGF21) in the detection of liver fibrosis in patients with chronic hepatitis B (CHB). The value of the noninvasive fibrosis models - that is, the aspartate aminotransferase to platelet ratio index (APRI), the fibrosis index based on the four factors (FIB-4) score, and Forn's index - was also examined. CHB patients who underwent liver biopsy for the evaluation of fibrosis were included in the study. A total of 73 patients were divided into two groups according to their METAVIR scores (F0-1, no/minimal fibrosis; F2-4, significant fibrosis). Serum levels of TGF-β1, TIMP-1, fetuin-A, and FGF21 were measured besides APRI, FIB-4, and Forn's scores. The area under the receiver operating characteristic curve was measured for each parameter, followed by calculation of sensitivity, specificity, and positive and negative predictive values. APRI, FIB-4, and Forn's index scores were significantly higher in patients with significant fibrosis (P<0.05). There was no difference between no/minimal fibrosis and significant fibrosis groups in terms of serum levels of TGFβ-1, TIMP-1, fetuin-A, and FGF21 (P>0.05). The areas under the receiver operating characteristic curve for TGF-β1, TIMP-1, fetuin-A, FGF21, APRI, FIB-4, and Forn's index were 0.445, 0.483, 0.436, 0.585, 0.662, 0.687, and 0.680, respectively. Our results suggest that serum TGF-β1, TIMP-1, fetuin-A, and FGF21 are not useful for the assessment of the extent of liver fibrosis in CHB in this patient group. However, APRI, FIB-4, and Forn's index have a better diagnostic value in patients with significant fibrosis than in those with no/minimal fibrosis.

  9. [Correlation of liver stiffness measured by FibroTouch and FibroScan with Ishak fibrosis score in patients with chronic hepatitis B].

    PubMed

    Chen, G F; Ping, J; Gu, H T; Zhao, Z M; Zhou, Y; Xing, F; Tao, Y Y; Mu, Y P; Liu, P; Liu, C H

    2017-02-20

    Objective: To investigate the correlation of liver stiffness measured by FibroTouch (FT) and FibroScan (FS) with Ishak fibrosis score in patients with chronic hepatitis B. Methods: A total of 313 patients with chronic hepatitis B who visited Department of Liver Cirrhosis in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2014 to May 2016 were enrolled. All the patients underwent liver biopsy, and FT and FS were used to determine liver stiffness measurement (LSM). Serum biochemical parameters were measured, and the aspartate aminotransferase-to-platelet ratio index (APRI) in a multi-parameter model of liver fibrosis and fibrosis-4 (FIB-4) index were calculated. The consistency between the results of four noninvasive examinations and Ishak fibrosis score was compared. The t-test was used for comparison of LSM determined by FT and FS. Pearson correlation analysis was used investigate the correlation between LSM determined by FT and FS; Spearman correlation analysis was used to investigate the correlation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and Knodell score with LSM determined by FT and FS; the correlation between LSM determined by FT and FS and fibrosis stage was analyzed by partial correlation analysis adjusted by Knodell score for liver inflammatory activity; Spearman correlation analysis was used for APRI, FIB-4, and fibrosis stage. Based on the Ishak fibrosis score, the receiver operating characteristic (ROC) curve was used to analyze the values of four noninvasive methods in the diagnosis of liver fibrosis. Results: There was no significant difference in LSM measured by FT and FS in all patients (15.75±9.42 kPa vs 15.42±10.52 kPa, P > 0.05) and Pearson correlation analysis indicated a significant positive correlation between them ( r = 0.858, P < 0.01); serum ALT and AST levels and liver inflammatory activity were correlated with LSM determined by FT and FS. There

  10. Prediction of acute pancreatitis risk based on PIP score in children with cystic fibrosis.

    PubMed

    Terlizzi, V; Tosco, A; Tomaiuolo, R; Sepe, A; Amato, N; Casale, A; Mercogliano, C; De Gregorio, F; Improta, F; Elce, A; Castaldo, G; Raia, V

    2014-09-01

    Currently no tools to predict risk of acute (AP) and recurrent pancreatitis (ARP) in children with cystic fibrosis (CF) are available. We assessed the prevalence of AP/ARP and tested the potential role of Pancreatic Insufficiency Prevalence (PIP) score in a cohort of children with CF. We identified two groups of children, on the basis of presence/absence of AP/ARP, who were compared for age at diagnosis, clinical features, genotypes and sweat chloride level. PIP score was calculated for each patient. 10/167 (5.9%) experienced at least one episode of AP during follow up; 10/10 were pancreatic sufficient (PS). Patients with AP/ARP showed a PIP score ≤0.25 more frequently (6/10) than patients without AP/ARP. The odds ratio (95% CI) of developing pancreatitis was 4.54 (1.22-16.92) for patients with PIP <0.25 when compared with those who have a PIP score >0.25 (p 0.0151). PIP score was correlated with sweat chloride test (p < 0.01). PIP score, PS status and normal/borderline sweat chloride levels could be applied to predict pancreatitis development in children with CF. ARP could lead to pancreatic insufficiency. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  11. Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis

    PubMed Central

    Zhang, Xiaoyan; Li, Sha; Zhou, Yunfeng; Su, Wen; Ruan, Xiongzhong; Wang, Bing; Zheng, Feng; Warner, Margaret; Gustafsson, Jan-Åke; Guan, Youfei

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a high-fat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD. PMID:28270609

  12. Minimally invasive percutaneous endovascular therapies in the management of complications of non-alcoholic fatty liver disease (NAFLD): A case report.

    PubMed

    Salsamendi, Jason; Pereira, Keith; Kang, Kyungmin; Fan, Ji

    2015-09-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from simple steatosis to inflammation leading to fibrosis, cirrhosis, and even hepatocellular carcinoma. With the progressive epidemics of obesity and diabetes, major risk factors in the development and pathogenesis of NAFLD, the prevalence of NAFLD and its associated complications including liver failure and hepatocellular carcinoma is expected to increase by 2030 with an enormous health and economic impact. We present a patient who developed Hepatocellular carcinoma (HCC) from nonalcoholic steatohepatitis (NASH) cirrhosis. Due to morbid obesity, she was not an optimal transplant candidate and was not initially listed. After attempts for lifestyle modifications failed to lead to weight reduction, a transarterial embolization of the left gastric artery was performed. This is the sixth such procedure in humans in literature. Subsequently she had a meaningful drop in BMI from 42 to 36 over the following 6 months ultimately leading to her being listed for transplant. During this time, the left hepatic HCC was treated with chemoembolization without evidence of recurrence. In this article, we wish to highlight the use of minimally invasive percutaneous endovascular therapies such as transarterial chemoembolization (TACE) in the comprehensive management of the NAFLD spectrum and percutaneous transarterial embolization of the left gastric artery (LGA), a novel method, for the management of obesity.

  13. Non-Invasive Evaluation of Cystic Fibrosis Related Liver Disease in Adults with ARFI, Transient Elastography and Different Fibrosis Scores

    PubMed Central

    Oltmanns, Annett; Güttler, Andrea; Petroff, David; Wirtz, Hubert; Mainz, Jochen G.; Mössner, Joachim; Berg, Thomas; Tröltzsch, Michael; Keim, Volker; Wiegand, Johannes

    2012-01-01

    Background Cystic fibrosis-related liver disease (CFLD) is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. Aim We evaluated transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and fibrosis indices for CFLD detection. Methods TE and ARFI were performed in 55 adult CF patients. In addition, AST/Platelets-Ratio-Index (APRI), and Forns' score were calculated. Healthy probands and patients with alcoholic liver cirrhosis served as controls. Results Fourteen CF patients met CFLD criteria, six had liver cirrhosis. Elastography acquisition was successful in >89% of cases. Non-cirrhotic CFLD individuals showed elastography values similar to CF patients without liver involvement. Cases with liver cirrhosis differed significantly from other CFLD patients (ARFI: 1.49 vs. 1.13 m/s; p = 0.031; TE: 7.95 vs. 4.16 kPa; p = 0.020) and had significantly lower results than individuals with alcoholic liver cirrhosis (ARFI: 1.49 vs. 2.99 m/s; p = 0.002). APRI showed the best diagnostic performance for CFLD detection (AUROC 0.815; sensitivity 85.7%, specificity 70.7%). Conclusions ARFI, TE, and laboratory based fibrosis indices correlate with each other and reliably detect CFLD related liver cirrhosis in adult CF patients. CF specific cut-off values for cirrhosis in adults are lower than in alcoholic cirrhosis. PMID:22848732

  14. Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway.

    PubMed

    Pandey, Anuradha; Raj, Priyank; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Sharma, Nisha; Gaikwad, Anil Bhanudas

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  15. Nonalcoholic fatty liver disease (NAFLD) in the Veterans Administration population: development and validation of an algorithm for NAFLD using automated data.

    PubMed

    Husain, N; Blais, P; Kramer, J; Kowalkowski, M; Richardson, P; El-Serag, H B; Kanwal, F

    2014-10-01

    In practice, nonalcoholic fatty liver disease (NAFLD) is diagnosed based on elevated liver enzymes and confirmatory liver biopsy or abdominal imaging. Neither method is feasible in identifying individuals with NAFLD in a large-scale healthcare system. To develop and validate an algorithm to identify patients with NAFLD using automated data. Using the Veterans Administration Corporate Data Warehouse, we identified patients who had persistent ALT elevation (≥2 values ≥40 IU/mL ≥6 months apart) and did not have evidence of hepatitis B, hepatitis C or excessive alcohol use. We conducted a structured chart review of 450 patients classified as NAFLD and 150 patients who were classified as non-NAFLD by the database algorithm, and subsequently refined the database algorithm. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the initial database definition of NAFLD were 78.4% (95% CI: 70.0-86.8%), 74.5% (95% CI: 68.1-80.9%), 64.1% (95% CI: 56.4-71.7%) and 85.6% (95% CI: 79.4-91.8%), respectively. Reclassifying patients as having NAFLD if they had two elevated ALTs that were at least 6 months apart but within 2 years of each other, increased the specificity and PPV of the algorithm to 92.4% (95% CI: 88.8-96.0%) and 80.8% (95% CI: 72.5-89.0%), respectively. However, the sensitivity and NPV decreased to 55.0% (95% CI: 46.1-63.9%) and 78.0% (95% CI: 72.1-83.8%), respectively. Predictive algorithms using automated data can be used to identify patients with NAFLD, determine prevalence of NAFLD at the system-wide level, and may help select a target population for future clinical studies in veterans with NAFLD. © 2014 John Wiley & Sons Ltd.

  16. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease.

    PubMed

    Sundaram, Shikha S; Sokol, Ronald J; Capocelli, Kelley E; Pan, Zhaoxing; Sullivan, Jillian S; Robbins, Kristen; Halbower, Ann C

    2014-04-01

    To determine whether obstructive sleep apnea (OSA) and/or nocturnal hypoxemia are associated with the severity of liver injury in patients with pediatric nonalcoholic fatty liver disease (NAFLD). Obese children aged 10-18 years with liver biopsy-proven NAFLD were enrolled. Demographic, clinical, and laboratory data were collected, polysomnography was performed, and liver histology was scored. Subjects were divided into those with OSA/hypoxemia and those without OSA/hypoxemia for analysis. Of 25 subjects with NAFLD, OSA/hypoxemia was present in 15 (60%) (mean age, 12.8 ± 1.9 years; 68% male; 88% Hispanic; mean body mass index z-score, 2.3 ± 0.3). Subjects with and without OSA/hypoxemia had similar levels of serum aminotransferases, serum lipids, and inflammatory and insulin resistance markers. Although there were no differences between groups in the histological severity of steatosis, inflammation, ballooning degeneration, NAFLD activity score, or histological grade, subjects with OSA/hypoxemia had significantly more severe hepatic fibrosis. Moreover, oxygen saturation nadir during polysomnography was related to hepatic fibrosis stage (r = -0.49; P = .01) and aspartate aminotransferase level (r = 0.42; P < .05). Increasing percentage of time with oxygen saturation ≤90% was related to NAFLD inflammation grade (r = 0.44; P = .03), degree of hepatic steatosis (r = -0.50; P = .01), NAFLD activity score (r = 0.42; P = .04), aspartate aminotransferase level (r = 0.56; P = .004), and alanine aminotransferase level (r = 0.44; P = .03). Moderate OSA/hypoxemia is common in pediatric patients with biopsy-proven NAFLD. OSA and the severity/duration of hypoxemia are associated with biochemical and histological measures of NAFLD severity. Copyright © 2014 Mosby, Inc. All rights reserved.

  17. Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus.

    PubMed

    Mantovani, Alessandro; Rigolon, Riccardo; Pichiri, Isabella; Bonapace, Stefano; Morani, Giovanni; Zoppini, Giacomo; Bonora, Enzo; Targher, Giovanni

    2017-01-01

    Recent studies suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiac tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus. The aim of this study was to examine whether an association also exists between NAFLD and heart block. We have retrospectively evaluated a hospital-based cohort of 751 patients with type 2 diabetes discharged from our Division of Diabetes and Endocrinology during years 2007-2014. Standard electrocardiograms were performed on all patients. Diagnosis of NAFLD was based on ultrasonography, whereas the severity of advanced hepatic fibrosis was based on the fibrosis (FIB)-4 score and other non-invasive fibrosis markers. Overall, 524 (69.8%) patients had NAFLD and 202 (26.9%) had heart block (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block) on electrocardiograms. Patients with NAFLD had a remarkably higher prevalence of any persistent heart block than those without NAFLD (31.3% vs. 16.7%, p<0.001); this prevalence was particularly increased among those with higher FIB-4 score. NAFLD was associated with a threefold increased risk of prevalent heart block (adjusted-odds ratio 3.04, 95% CI 1.81-5.10), independently of age, sex, hypertension, prior ischemic heart disease, hemoglobin A1c, microvascular complication status, use of medications and other potentially confounding factors. In conclusion, this is the largest cross-sectional study to show that NAFLD and its severity are independently associated with an increased risk of prevalent heart block in hospitalized patients with type 2 diabetes.

  18. Value of Egy-Score in diagnosis of significant, advanced hepatic fibrosis and cirrhosis compared to aspartate aminotransferase-to-platelet ratio index, FIB-4 and Forns' index in chronic hepatitis C virus.

    PubMed

    Alboraie, Mohamed; Khairy, Marwa; Elsharkawy, Marwa; Asem, Noha; Elsharkawy, Aisha; Esmat, Gamal

    2015-05-01

    Serum markers and developed scores are of rising importance in non-invasive diagnosis of hepatic fibrosis. Aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forns' index are validated scores used for diagnosis of liver fibrosis. The Egy-Score is a newly developed score for detection of hepatic fibrosis with promising results. We aimed to assess the accuracy of the Egy-Score in the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis compared to APRI, FIB-4 and Forns' in chronic hepatitis C virus (HCV) patients. A retrospective study including 100 chronic hepatitis C naïve Egyptian patients was performed. Patients were classified according to stages of fibrosis into three groups: significant fibrosis (≥ F2), advanced fibrosis (≥ F3) and cirrhosis (F4). Egy-Score, APRI, FIB-4 and Forns' index were calculated. Regression analysis and receiver-operator curves were plotted to assess the sensitivity, specificity and predictive values for the significant scores with the best cut-off for diagnosis. An Egy-Score of 3.28 or more was superior to APRI, FIB-4 and Forns' index for detecting advanced fibrosis with a sensitivity of 91% and specificity of 78%. An Egy-Score of 3.67 or more was superior to APRI, FIB-4 and Forns' index for detecting cirrhosis with a sensitivity of 82% and specificity of 87%. Forns' index was superior to Egy-Score, FIB-4 and APRI for detecting significant fibrosis. The Egy-Score is a promising, accurate, easily calculated, cost-effective score in the prediction of hepatic fibrosis in chronic HCV patients with superiority over APRI, FIB-4 and Forns' index in advanced hepatic fibrosis and cirrhosis. © 2014 The Japan Society of Hepatology.

  19. Minimally invasive percutaneous endovascular therapies in the management of complications of non-alcoholic fatty liver disease (NAFLD): A case report

    PubMed Central

    Salsamendi, Jason; Pereira, Keith; Kang, Kyungmin; Fan, Ji

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from simple steatosis to inflammation leading to fibrosis, cirrhosis, and even hepatocellular carcinoma. With the progressive epidemics of obesity and diabetes, major risk factors in the development and pathogenesis of NAFLD, the prevalence of NAFLD and its associated complications including liver failure and hepatocellular carcinoma is expected to increase by 2030 with an enormous health and economic impact. We present a patient who developed Hepatocellular carcinoma (HCC) from nonalcoholic steatohepatitis (NASH) cirrhosis. Due to morbid obesity, she was not an optimal transplant candidate and was not initially listed. After attempts for lifestyle modifications failed to lead to weight reduction, a transarterial embolization of the left gastric artery was performed. This is the sixth such procedure in humans in literature. Subsequently she had a meaningful drop in BMI from 42 to 36 over the following 6 months ultimately leading to her being listed for transplant. During this time, the left hepatic HCC was treated with chemoembolization without evidence of recurrence. In this article, we wish to highlight the use of minimally invasive percutaneous endovascular therapies such as transarterial chemoembolization (TACE) in the comprehensive management of the NAFLD spectrum and percutaneous transarterial embolization of the left gastric artery (LGA), a novel method, for the management of obesity. PMID:26629307

  20. Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

    PubMed Central

    Guo, Feng; Ma, Yinyan; Kadegowda, Anil K. G.; Betters, Jenna L.; Xie, Ping; Liu, George; Liu, Xiuli; Miao, Hongming; Ou, Juanjuan; Su, Xiong; Zheng, Zhenlin; Xue, Bingzhong; Shi, Hang; Yu, Liqing

    2013-01-01

    Triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) preludes the development of advanced nonalcoholic fatty liver diseases (NAFLDs) such as steatohepatitis, fibrosis, and cirrhosis. Mutations in human Comparative Gene Identification-58 (CGI-58) cause cytosolic TG-rich lipid droplets to accumulate in almost all cell types including hepatocytes. However, it is unclear if CGI-58 mutation causes hepatic steatosis locally or via altering lipid metabolism in other tissues. To directly address this question, we created liver-specific CGI-58 knockout (LivKO) mice. LivKO mice on standard chow diet displayed microvesicular and macrovesicular panlobular steatosis, and progressed to advanced NAFLD stages over time, including lobular inflammation and centrilobular fibrosis. Compared with CGI-58 floxed control littermates, LivKO mice showed 8-fold and 52-fold increases in hepatic TG content, which was associated with 40% and 58% decreases in hepatic TG hydrolase activity at 16 and 42 weeks, respectively. Hepatic cholesterol also increased significantly in LivKO mice. At 42 weeks, LivKO mice showed increased hepatic oxidative stress, plasma aminotransferases, and hepatic mRNAs for genes involved in fibrosis and inflammation, such as α-smooth muscle actin, collagen type 1 α1, tumor necrosis factor α, and interleukin-1β. In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis. PMID:23733885

  1. Lipolysis stimulating peptides of potato protein hydrolysate effectively suppresses high-fat-diet-induced hepatocyte apoptosis and fibrosis in aging rats.

    PubMed

    Chiang, Wen-Dee; Huang, Chih Yang; Paul, Catherine Reena; Lee, Zong-Yan; Lin, Wan-Teng

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common outcomes of obesity and is characterized by the accumulation of triglycerides, increased tissue apoptosis, and fibrosis. NAFLD is more common among elderly than in younger age groups, and it causes serious hepatic complications. In this study, alcalase treatment derived potato protein hydrolysate (APPH) with lipolysis-stimulating property has been evaluated for its efficiency to provide hepato-protection in a high-fat-diet (HFD)-fed aging rats. Twenty-four-month-old SD rats were randomly divided into six groups (n=8): aged rats fed with standard chow, HFD-induced aged obese rats, HFD with low-dose (15 mg/kg/day) APPH treatment, HFD with moderate (45 mg/kg/day) APPH treatment, HFD with high (75 mg/kg/day) APPH treatment, and HFD with probucol. APPH was found to reduce the NAFLD-related effects in rat livers induced by HFD and all of the HFD-fed rats exhibited heavier body weight than those with control chow diet. However, the HFD-induced hepatic fat accumulation was effectively attenuated in rats administered with low (15 mg/kg/day), moderate (45 mg/kg/day), and high (75 mg/kg/day) doses of APPH. APPH oral administration also suppressed the hepatic apoptosis- and fibrosis-related proteins induced by HFD. Our results thus indicate that APPH potentially attenuates hepatic lipid accumulation and anti-apoptosis and fibrosis effects in HFD-induced rats. APPH may have therapeutic potential in the amelioration of NAFLD liver damage.

  2. Controlled attenuation parameter is correlated with actual hepatic fat content in patients with non-alcoholic fatty liver disease with none-to-mild obesity and liver fibrosis.

    PubMed

    Fujimori, Naoyuki; Tanaka, Naoki; Shibata, Soichiro; Sano, Kenji; Yamazaki, Tomoo; Sekiguchi, Tomohiro; Kitabatake, Hiroyuki; Ichikawa, Yuki; Kimura, Takefumi; Komatsu, Michiharu; Umemura, Takeji; Matsumoto, Akihiro; Tanaka, Eiji

    2016-09-01

    Non-invasive steatosis-quantifying methods are required for non-alcoholic fatty liver disease (NAFLD) patients in order to monitor disease severity and assess therapeutic efficacy. Controlled attenuation parameter (CAP) evaluated with vibration-controlled transient elastography can predict the presence of steatosis, but its application to absolute hepatic fat quantitation remains unclear. The aim of this st\\udy was to examine whether CAP is correlated with real hepatic fat content in NAFLD patients. Eighty-two NAFLD patients who had undergone percutaneous liver biopsy were enrolled. CAP was measured using FibroScan(®) just before liver biopsy. The percentage of fat droplet area to hepatocyte area in biopsied specimen was determined morphometrically using computerized optical image analyzing system. The correlation between CAP and liver histology was examined. CAP showed an excellent correlation with actual liver fat percentage in the NAFLD patients with body mass index (BMI) of less than 28 kg/m(2) (r = 0.579, P < 0.0001), especially less than 25 kg/m(2) (r = 0.708, P < 0.01), but the meaningful correlation disappeared in the patients with BMI of 28 kg/m(2) or more. In the patients with BMI of less than 28 kg/m(2) , CAP quantitativeness was affected by the presence of stage 2-4 fibrosis, but not the presence of hepatocyte ballooning and severity of lobular inflammation. CAP may be a promising tool for quantifying hepatic fat content in NAFLD patients with none-to-mild obesity and liver fibrosis. Further improvement of CAP performance is needed for the NAFLD patients with BMI of more than 28 kg/m(2) or significant hepatic fibrosis. © 2016 The Japan Society of Hepatology.

  3. Fibromax-based nonalcoholic fatty liver disease in chronic obstructive pulmonary disease patients with obstructive sleep apnea: Methodological considerations

    PubMed Central

    Monneret, Denis

    2017-01-01

    The relationship between nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) has been well demonstrated, but remains to be evidenced in chronic obstructive pulmonary disease (COPD). Recently, Viglino et al. (Eur Respir J, 2017) attempted to determine the prevalence of liver fibrosis, steatosis and nonalcoholic steatohepatitis (NASH) in COPD patients, some of whom had OSA, basing the NAFLD diagnostic on three circulating biomarker-based liver scores: the FibroTest, SteatoTest and NashTest, from the Fibromax® panel. Among the main findings, the absence of OSA treatment emerged as independently associated with liver fibrosis and steatosis, when compared to effective treatment. However, besides the low number of treated patients, no polysomnographic respiratory data was provided, making it difficult to differentiate the impact of OSA from that of COPD in NAFLD prevalence. Furthermore, NAFLD diagnosis relied exclusively on circulating biomarker-based liver scores, without histological, imagery or other liver exploratory methods. Therefore, in this article, some methodological points are reminded and discussed, including the choice of OSA measurements, and the significance of ActiTest and AshTest scores from Fibromax® in this pathophysiological context. PMID:29225775

  4. Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound grades of fatty liver in obese NAFLD patients.

    PubMed

    Ali Khan, Rashid; Kapur, Prem; Jain, Abhinav; Farah, Farrukh; Bhandari, Uma

    2017-01-01

    Orlistat is recommended in the treatment of obesity, which is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). The reported findings of orlistat in NAFLD are divisive. Recently, periostin is identified as an important regulatory molecule in the pathogenesis of obesity-induced fatty liver. Therefore, this study aimed to evaluate the potential effects of orlistat in the treatment of NAFLD. A 16-week prospective observational study was conducted, with obese NAFLD patient (n=77) receiving orlistat (120 mg capsules, three times a day) with hypocaloric diet or hypocaloric diet only. Grades of fatty liver were determined using ultrasound (US) echogenicity of liver; serum levels of periostin, adiponectin, tumor necrosis factor (TNF)-α and interleukin-6 were determined using ELISA kits at 0 and 16 weeks. Correlations of US grades of fatty liver with these biomarkers were also determined. Orlistat significantly reversed the US grades of fatty liver ( P =0.016), decreased serum levels of periostin ( P =0.030) and TNF-α ( P =0.040), and increased serum adiponectin levels ( P <0.001) when compared with hypocaloric diet only. Serum interleukin-6 levels were not found to be significantly different in both groups after the treatment. In the orlistat group, the degree of reduction in grades of fatty liver was found to be positively correlated with the changes in serum levels of periostin (r s =0.306, P =0.041) and adiponectin (r s =0.314, P =0.036), whereas the associations were insignificant with the change in serum levels of TNF-α (r s =0.053, P =0.729). Mild gastrointestinal side effects (20%) were reported in the orlistat group. In conclusion, orlistat is effective in the treatment of NAFLD patients without fibrosis. This study demonstrated a positive association between the reduction of fatty infiltration in the liver and the changes in serum levels of periostin and adiponectin in obese NAFLD patients.

  5. Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound grades of fatty liver in obese NAFLD patients

    PubMed Central

    Ali Khan, Rashid; Kapur, Prem; Jain, Abhinav; Farah, Farrukh; Bhandari, Uma

    2017-01-01

    Orlistat is recommended in the treatment of obesity, which is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). The reported findings of orlistat in NAFLD are divisive. Recently, periostin is identified as an important regulatory molecule in the pathogenesis of obesity-induced fatty liver. Therefore, this study aimed to evaluate the potential effects of orlistat in the treatment of NAFLD. A 16-week prospective observational study was conducted, with obese NAFLD patient (n=77) receiving orlistat (120 mg capsules, three times a day) with hypocaloric diet or hypocaloric diet only. Grades of fatty liver were determined using ultrasound (US) echogenicity of liver; serum levels of periostin, adiponectin, tumor necrosis factor (TNF)-α and interleukin-6 were determined using ELISA kits at 0 and 16 weeks. Correlations of US grades of fatty liver with these biomarkers were also determined. Orlistat significantly reversed the US grades of fatty liver (P=0.016), decreased serum levels of periostin (P=0.030) and TNF-α (P=0.040), and increased serum adiponectin levels (P<0.001) when compared with hypocaloric diet only. Serum interleukin-6 levels were not found to be significantly different in both groups after the treatment. In the orlistat group, the degree of reduction in grades of fatty liver was found to be positively correlated with the changes in serum levels of periostin (rs=0.306, P=0.041) and adiponectin (rs=0.314, P=0.036), whereas the associations were insignificant with the change in serum levels of TNF-α (rs=0.053, P=0.729). Mild gastrointestinal side effects (20%) were reported in the orlistat group. In conclusion, orlistat is effective in the treatment of NAFLD patients without fibrosis. This study demonstrated a positive association between the reduction of fatty infiltration in the liver and the changes in serum levels of periostin and adiponectin in obese NAFLD patients. PMID:28260907

  6. Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease.

    PubMed

    Sumida, Yoshio; Yonei, Yoshikazu; Tanaka, Saiyu; Mori, Kojiroh; Kanemasa, Kazuyuki; Imai, Shunsuke; Taketani, Hiroyoshi; Hara, Tasuku; Seko, Yuya; Ishiba, Hiroshi; Okajima, Akira; Yamaguchi, Kanji; Moriguchi, Michihisa; Mitsuyoshi, Hironori; Yasui, Kohichiroh; Minami, Masahito; Itoh, Yoshito

    2015-07-01

    Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance. Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH. © 2014 The Japan Society of Hepatology.

  7. New trends on obesity and NAFLD in Asia.

    PubMed

    Fan, Jian-Gao; Kim, Seung-Up; Wong, Vincent Wai-Sun

    2017-10-01

    Traditionally, obesity and its related diseases have been considered a problem in Western countries. However, in the past two decades, urbanisation in many Asian countries has led to a sedentary lifestyle and overnutrition, setting the stage for the epidemic of obesity. This article reviews the epidemiological trend of obesity in Asia, with special emphasis on the emerging condition of non-alcoholic fatty liver disease (NAFLD). Currently, the population prevalence of NAFLD in Asia is around 25%, like many Western countries. While hepatocellular carcinoma and end-stage liver disease secondary to NAFLD remain uncommon, a rising trend has emerged. Around 8-19% of Asians with body mass indexes less than 25kg/m 2 are also found to have NAFLD, a condition often described as "lean" or "non-obese" NAFLD. Although this condition is generally less severe than that in more obese patients, steatohepatitis and fibrotic disease are well recognized. Central adiposity, insulin resistance and weight gain are major risk factors, and genetic predisposition, such as the PNPLA3 polymorphism appears to be more important in the development of NAFLD in the non-obese population. Lifestyle modification remains the cornerstone of management for obesity and NAFLD, but few patients can achieve adequate weight reduction and even fewer can maintain the weight in the long run. While pharmacological agents have entered phase III development for steatohepatitis, Asian patients are under-represented in most drug trials. Future studies should define the optimal management of obesity and NAFLD in Asia. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Simpler score of routine laboratory tests predicts liver fibrosis in patients with chronic hepatitis B.

    PubMed

    Zhou, Kun; Gao, Chun-Fang; Zhao, Yun-Peng; Liu, Hai-Lin; Zheng, Rui-Dan; Xian, Jian-Chun; Xu, Hong-Tao; Mao, Yi-Min; Zeng, Min-De; Lu, Lun-Gen

    2010-09-01

    In recent years, a great interest has been dedicated to the development of noninvasive predictive models to substitute liver biopsy for fibrosis assessment and follow-up. Our aim was to provide a simpler model consisting of routine laboratory markers for predicting liver fibrosis in patients chronically infected with hepatitis B virus (HBV) in order to optimize their clinical management. Liver fibrosis was staged in 386 chronic HBV carriers who underwent liver biopsy and routine laboratory testing. Correlations between routine laboratory markers and fibrosis stage were statistically assessed. After logistic regression analysis, a novel predictive model was constructed. This S index was validated in an independent cohort of 146 chronic HBV carriers in comparison to the SLFG model, Fibrometer, Hepascore, Hui model, Forns score and APRI using receiver operating characteristic (ROC) curves. The diagnostic values of each marker panels were better than single routine laboratory markers. The S index consisting of gamma-glutamyltransferase (GGT), platelets (PLT) and albumin (ALB) (S-index: 1000 x GGT/(PLT x ALB(2))) had a higher diagnostic accuracy in predicting degree of fibrosis than any other mathematical model tested. The areas under the ROC curves (AUROC) were 0.812 and 0.890 for predicting significant fibrosis and cirrhosis in the validation cohort, respectively. The S index, a simpler mathematical model consisting of routine laboratory markers predicts significant fibrosis and cirrhosis in patients with chronic HBV infection with a high degree of accuracy, potentially decreasing the need for liver biopsy.

  9. Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients.

    PubMed

    Attallah, Abdelfattah M; Abdallah, Sanaa O; Attallah, Ahmed A; Omran, Mohamed M; Farid, Khaled; Nasif, Wesam A; Shiha, Gamal E; Abdel-Aziz, Abdel-Aziz F; Rasafy, Nancy; Shaker, Yehia M

    2013-01-01

    Several noninvasive predictive models were developed to substitute liver biopsy for fibrosis assessment. To evaluate the diagnostic value of fibronectin which reflect extracellular matrix metabolism and standard liver functions tests which reflect alterations in hepatic functions. Chronic hepatitis C (CHC) patients (n = 145) were evaluated using ROC curves and stepwise multivariate discriminant analysis (MDA) and was validated in 180 additional patients. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, albumin, complete blood count were estimated. Fibronectin concentration was determined using monoclonal antibody and ELISA. A novel index named fibronectin discriminant score (FDS) based on fibronectin, APRI and albumin was developed. FDS produced areas under ROC curves (AUC) of 0.91 for significant fibrosis and 0.81 for advanced fibrosis. The FDS correctly classified 79% of the significant liver fibrosis patients (F2-F4) with 87% sensitivity and 75% specificity. The relative risk [odds ratio (OR)] of having significant liver fibrosis using the cut-off values determined by ROC curve analyses were 6.1 for fibronectin, 4.9 for APRI, and 4.2 for albumin. FDS predicted liver fibrosis with an OR of 16.8 for significant fibrosis and 8.6 for advanced fibrosis. The FDS had similar AUC and OR in the validation group to the estimation group without statistically significant difference. FDS predicted liver fibrosis with high degree of accuracy, potentially decreasing the number of liver biopsy required.

  10. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis.

    PubMed

    Iacobellis, Angelo; Marcellini, Matilde; Andriulli, Angelo; Perri, Francesco; Leandro, Gioacchino; Devito, Rita; Nobili, Valerio

    2006-12-28

    To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). BMI helps identify children with NASH who might have fibrotic deposition in the liver.

  11. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis.

    PubMed

    Chen, Li-Zhen; Xin, Yong-Ning; Geng, Ning; Jiang, Man; Zhang, Ding-Ding; Xuan, Shi-Ying

    2015-01-21

    Patatin-like phospholipase domain-containing 3 (PNPLA3 or adiponutrin) displays anabolic and catabolic activities in lipid metabolism, and has been reported to be significantly associated with liver fat content. Various studies have established a strong link between the 148 isoleucine to methionine protein variant (I148M) of PNPLA3 and liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, detailed demographic and ethnic characteristics of the I148M variant and its role in the development of nonalcoholic fatty liver fibrosis have not been fully elucidated. The present review summarizes the current knowledge on the association between the PNPLA3 I148M variant and NAFLD, and especially its role in the development of nonalcoholic fatty liver fibrosis. First, we analyze the impact of demographic and ethnic characteristics of the PNPLA3 I148M variant and the presence of metabolic syndrome on the association between PNPLA3 I148M and NAFLD. Then, we explore the role of the PNPLA3 I148M in the development of nonalcoholic fatty liver fibrosis, and hypothesize the underlying mechanisms by speculating a pro-fibrogenic network. Finally, we briefly highlight future research that may elucidate the specific mechanisms of the PNPLA3 I148M variant in fibrogenesis, which, in turn, provides a theoretical foundation and valuable experimental data for the clinical management of nonalcoholic fatty liver fibrosis.

  12. PNPLA3 I148M variant in nonalcoholic fatty liver disease: Demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis

    PubMed Central

    Chen, Li-Zhen; Xin, Yong-Ning; Geng, Ning; Jiang, Man; Zhang, Ding-Ding; Xuan, Shi-Ying

    2015-01-01

    Patatin-like phospholipase domain-containing 3 (PNPLA3 or adiponutrin) displays anabolic and catabolic activities in lipid metabolism, and has been reported to be significantly associated with liver fat content. Various studies have established a strong link between the 148 isoleucine to methionine protein variant (I148M) of PNPLA3 and liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, detailed demographic and ethnic characteristics of the I148M variant and its role in the development of nonalcoholic fatty liver fibrosis have not been fully elucidated. The present review summarizes the current knowledge on the association between the PNPLA3 I148M variant and NAFLD, and especially its role in the development of nonalcoholic fatty liver fibrosis. First, we analyze the impact of demographic and ethnic characteristics of the PNPLA3 I148M variant and the presence of metabolic syndrome on the association between PNPLA3 I148M and NAFLD. Then, we explore the role of the PNPLA3 I148M in the development of nonalcoholic fatty liver fibrosis, and hypothesize the underlying mechanisms by speculating a pro-fibrogenic network. Finally, we briefly highlight future research that may elucidate the specific mechanisms of the PNPLA3 I148M variant in fibrogenesis, which, in turn, provides a theoretical foundation and valuable experimental data for the clinical management of nonalcoholic fatty liver fibrosis. PMID:25624712

  13. High prevalence of apolipoprotein B dyslipoproteinemias in non-alcoholic fatty liver disease: The lifelines cohort study.

    PubMed

    Nass, Karlijn J; van den Berg, Eline H; Faber, Klaas Nico; Schreuder, Tim C M A; Blokzijl, Hans; Dullaart, Robin P F

    2017-07-01

    Cardiovascular disease (CVD) is a major adverse consequence of non-alcoholic fatty liver disease (NAFLD). The association of NAFLD with various apolipoprotein B (apoB) dyslipoproteinemias is unclear. We determined the prevalence of specific apoB dyslipoproteinemias in subjects with suspected NAFLD. This study was conducted among 22,865 fasting adults living in the northern part of the Netherlands (Lifelines Cohort Study). Six apoB dyslipoproteinemias were defined using an algorithm derived from apoB, total cholesterol and triglycerides. NAFLD was defined as Fatty Liver Index (FLI) ≥60. Advanced hepatic fibrosis was defined as NAFLD fibrosis score (NFS) ≥0.676. 4790 participants (20.9%) had an FLI≥60. NAFLD subjects were older, more likely to be men, more obese and more often had diabetes and metabolic syndrome (P<0.001 for each). Among NAFLD subjects, any apoB dyslipoproteinemia was present in 61.5% vs. 16.5% in subjects without NAFLD (P<0.001). Elevated chylomicrons were not observed in NAFLD. In univariate analysis, NAFLD was associated with a higher prevalence of each apoB dyslipoproteinemia vs. subjects with an FLI<60 (P<0.001), except for low density lipoprotein (LDL) dyslipoproteinemia. Additionally, each apoB dyslipoproteinemia was independently associated with NAFLD in age- and sex-adjusted logistic regression analysis, including the apoB dyslipoproteinemias together (P<0.001). The prevalence of apoB dyslipoproteinemias was not altered in subjects with NFS ≥0.676. NAFLD rather than advanced hepatic fibrosis is independently associated with increased prevalence of chylomicrons+very low-density lipoproteins (VLDL) remnants, VLDL, LDL and VLDL+LDL dyslipoproteinemias. ApoB dyslipoproteinemias may contribute to increased CVD risk associated with NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Inhibition of EGFR attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease.

    PubMed

    Liang, Dandan; Chen, Hongjin; Zhao, Leping; Zhang, Wenxin; Hu, Jie; Liu, Zhiguo; Zhong, Peng; Wang, Wei; Wang, Jingying; Liang, Guang

    2018-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD begins with steatosis and advances to nonalcoholic steatohepatitis (NASH) and cirrhosis. The molecular mechanisms involved in NAFLD progression are not understood. Based on recent studies showing dysregulation of epidermal growth factor receptor (EGFR) in animal models of liver injury, we sought to determine if inhibition of EGFR mitigates liver fibrosis and HSC activation in NAFLD. We utilized the high fat diet (HFD)-induced murine model of liver injury to study the role of EGFR in NAFLD. The lipid accumulation, oxidative stress, hepatic stellate cell (HSC) activation and matrix deposition were examined in the liver tissues. We also evaluated the EGFR signaling pathway, ROS activation and pro-fibrogenic phenotype in oxidized low density lipoproteins (ox-LDL) challenged cultured HSCs. We demonstrate that EGFR was phosphorylated in liver tissues of HFD murine model of NAFLD. Inhibition of EGFR prevented diet-induced lipid accumulation, oxidative stress, and HSC activation and matrix deposition. In cultured HSCs, we show that ox-LDL caused rapid activation of the EGFR signaling pathway and induce the production of reactive oxygen species. EGFR also mediated HSC activation and promoted a pro-fibrogenic phenotype. In conclusion, our data demonstrate that EGFR plays an important role in NAFLD and is an attractive target for NAFLD therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis

    PubMed Central

    Iacobellis, Angelo; Marcellini, Matilde; Andriulli, Angelo; Perri, Francesco; Leandro, Gioacchino; Devito, Rita; Nobili, Valerio

    2006-01-01

    AIM: To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). METHODS: All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). RESULTS: At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). CONCLUSION: BMI helps identify children with NASH who might have fibrotic deposition in the liver. PMID:17203527

  16. Magnetic resonance imaging and transient elastography in the management of Nonalcoholic Fatty Liver Disease (NAFLD).

    PubMed

    Han, Ma Ai Thanda; Saouaf, Rola; Ayoub, Walid; Todo, Tsuyoshi; Mena, Edward; Noureddin, Mazen

    2017-04-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and cirrhosis worldwide and the second most common cause of liver transplantation in major medical centers. Because liver steatosis and fibrosis severity are related to disease morbidity and mortality, the extent of disease, and disease progression, they need to be assessed and monitored. In addition, innovation with new drug developments requires disease staging and monitoring in both phase 2 and 3 clinical trials. Currently, disease assessment in both clinical practice and research is mostly performed by liver biopsy, an invasive, procedure with risks. Noninvasive, highly accurate tests are needed that could be used in clinical trials as surrogate endpoints and in clinical practice for monitoring patients. Area Covered: We discuss noninvasive tests, transient elastography (TE) with controlled attenuation parameter (CAP), magnetic resonance imaging (MRI), and MR elastography (MRE), summarize the available evidence of their usefulness for assessing steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice. Expert Commentary: TE with CAP, MRI and MRE are highly accurate noninvasive diagnostic tools for quantifying hepatic steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice.

  17. Design and rationale of the INSYTE study: A randomised, placebo controlled study to test the efficacy of a synbiotic on liver fat, disease biomarkers and intestinal microbiota in non-alcoholic fatty liver disease.

    PubMed

    Scorletti, Eleonora; Afolabi, Paul R; Miles, Elizabeth A; Smith, Debbie E; Almehmadi, Amal; Alshathry, Albandri; Moyses, Helen E; Clough, Geraldine F; Wright, Mark; Patel, Janisha; Bindels, Laure; Delzenne, Nathalie M; Calder, Philip C; Byrne, Christopher D

    2018-05-19

    Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of fat-related conditions ranging from simple fatty liver, to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. There is growing evidence that NAFLD is a multisystem disease, affecting several extra-hepatic organs and regulatory pathways. Furthermore, since the gut and liver are linked anatomically via the portal vein, disturbances of the gut microbiota (dysbiosis) can affect the liver. In patients with NAFLD, we are testing the effects of a synbiotic which is the combination of a prebiotic (fructooligosaccharides; 4 g/day) and a probiotic (Bifidobacterium animalis subsp. lactis BB-12 at a minimum of 10 billion CFU/day) on a) liver fat percentage, b) NAFLD fibrosis algorithm scores, c) gut microbiota composition. Additionally, there will be several hypothesis-generating secondary outcomes to understand the metaorganismal pathways that influence the development and progression of NAFLD, type 2 diabetes, and cardiovascular risk. In a randomised double-blind placebo controlled trial, 104 participants were randomised to 10-14 months intervention with either synbiotic (n = 55) or placebo (n = 49). Change in gut microbiota composition will be assessed using 16S ribosomal RNA gene sequencing. Change in mean liver fat percentage will be quantified by magnetic resonance spectroscopy (MRS). In addition, change in liver fat severity will be measured using two NAFLD fibrosis algorithm scores. Recruitment was completed in April 2017 and the last study visit will be completed by April 2018. The INSYTE study was approved by the local ethics committee (REC: 12/SC/0614) and is registered at www.clinicaltrials.gov as NCT01680640. Copyright © 2017. Published by Elsevier Inc.

  18. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis.

    PubMed

    Molloy, Jeffrey W; Calcagno, Christopher J; Williams, Christopher D; Jones, Frances J; Torres, Dawn M; Harrison, Stephen A

    2012-02-01

    Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. Copyright © 2011 American Association for the Study of Liver Diseases.

  19. Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis.

    PubMed

    Traussnigg, Stefan; Kienbacher, Christian; Gajdošík, Martin; Valkovič, Ladislav; Halilbasic, Emina; Stift, Judith; Rechling, Christian; Hofer, Harald; Steindl-Munda, Petra; Ferenci, Peter; Wrba, Fritz; Trattnig, Siegfried; Krššák, Martin; Trauner, Michael

    2017-10-01

    With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD. MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton ( 1 H)-MRS. 7-Tesla phosphorus ( 31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux. Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL. Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH. © 2017 The Authors Liver International Published by John Wiley & Sons Ltd.

  20. Early Glucose Derangement Detected by Continuous Glucose Monitoring and Progression of Liver Fibrosis in Nonalcoholic Fatty Liver Disease: An Independent Predictive Factor?

    PubMed

    Schiaffini, Riccardo; Liccardo, Daniela; Alisi, Anna; Benevento, Danila; Cappa, Marco; Cianfarani, Stefano; Nobili, Valerio

    2016-01-01

    Glucose derangement has been reported to increase oxidative stress, one of the most important factors underlying the progression of hepatic fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). To date, careful evaluation of the glucose profile in pediatric NAFLD has not been performed. A total of 30 severely obese children (15 males; mean age 12.87 ± 2.19 years) with biopsy-proven NAFLD were enrolled in this study from September to December 2013. All patients underwent anthropometric and laboratory evaluation, including the oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM). Our study reveals some differences between OGTT and CGM in detecting NAFLD children with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). OGTT showed 2 (6.67%) patients with IFG and 1 (3.34%) with IGT, while CGM showed 5 (16.67%) patients with IFG and 6 (20%) with IGT. The daily blood glucose profile positively correlated with the baseline blood glucose (r = 0.39, p = 0.04) and the homeostatic model assessment (r = 0.56, p = 0.05). A positive correlation between hyperglycemia and liver fibrosis was found (r = 0.65, p < 0.05). Mean glucose values (F3-F4 group: 163.2 ± 35.92 mg/dl vs. F1 group: 136.58 ± 46.83 mg/dl and F2 group: 154.12 ± 22.51 mg/dl) and the difference between the minimum and maximum blood glucose levels (F3-F4 group: 110.21 ± 25.26 mg/dl vs. F1 group: 91.67 ± 15.97 mg/dl and F2 group: 92 ± 15.48 mg/dl) were significantly (p < 0.05) higher in the F3-F4 group compared to the F1 and F2 groups. Glucose profile derangement as detected by CGM is associated with the severity of hepatic fibrosis in children with NAFLD. © 2015 S. Karger AG, Basel.

  1. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population.

    PubMed

    Verrijken, A; Beckers, S; Francque, S; Hilden, H; Caron, S; Zegers, D; Ruppert, M; Hubens, G; Van Marck, E; Michielsen, P; Staels, B; Taskinen, M-R; Van Hul, W; Van Gaal, L

    2013-10-01

    Mechanisms explaining the relationship in non-alcoholic fatty liver disease (NAFLD), obesity, and insulin resistance are poorly understood. A genetic basis has been suggested. We studied the association between the genes patatin-like phospholipase domain-containing protein 3 (PNPLA3) and apolipoprotein C3 (APOC3) and metabolic and histological parameters of NAFLD in obese patients. Overweight and obese patients underwent a metabolic and liver assessment. If NAFLD was suspected, liver biopsy was proposed. APOC3 variant rs2854117 and PNPLA3 variant rs738409 were genotyped. Four hundred seventy patients were included (61.1% had liver biopsy). The percentage of patients with non-alcoholic steatohepatitis (NASH) was significantly different according to the PNPLA3 variant. After adjustment for age and body mass index, the PNPLA3 variant was associated with alanine aminotransferase (P < 0.001) and aspartate aminotransferase (P < 0.001). The PNPLA3 variant was associated with more severe features of steatohepatitis: steatosis (P < 0.001), lobular inflammation (P < 0.001), and ballooning (P = 0.002), but not with liver fibrosis, anthropometry, or insulin resistance. No significant difference in liver histology, anthropometric, or metabolic parameters was found between carriers and non-carriers of the APOC3 variant. PNPLA3 polymorphism rs738409 was associated with NASH and the severity of necroinflammatory changes independently of metabolic factors. No association between APOC3 gene variant rs2854117 and histological or metabolic parameters of NAFLD was found. Copyright © 2013 The Obesity Society.

  2. Noninvasive scoring algorithm to identify significant liver fibrosis among treatment-naive chronic hepatitis C patients.

    PubMed

    Koller, Tomas; Kollerova, Jana; Huorka, Martin; Meciarova, Iveta; Payer, Juraj

    2014-10-01

    Staging for liver fibrosis is recommended in the management of hepatitis C as an argument for treatment priority. Our aim was to construct a noninvasive algorithm to predict the significant liver fibrosis (SLF) using common biochemical markers and compare it with some existing models. The study group included 104 consecutive cases; SLF was defined as Ishak fibrosis stage greater than 2. The patient population was assigned randomly to the training and the validation groups of 52 cases each. The training group was used to construct the algorithm from parameters with the best predictive value. Each parameter was assigned a score that was added to the noninvasive fibrosis score (NFS). The accuracy of NFS in predicting SLF was tested in the validation group and compared with APRI, FIB4, and Forns models. Our algorithm used age, alkaline phosphatase, ferritin, APRI, α2 macroglobulin, and insulin and the NFS ranged from -4 to 5. The probability of SLF was 2.6 versus 77.1% in NFS<0 and NFS>0, leaving NFS=0 in a gray zone (29.8% of cases). The area under the receiver operating curve was 0.895 and 0.886, with a specificity, sensitivity, and diagnostic accuracy of 85.1, 92.3, and 87.5% versus 77.8, 100, and 87.9% for the training and the validation group. In comparison, the area under the receiver operating curve for APRI=0.810, FIB4=0.781, and Forns=0.703 with a diagnostic accuracy of 83.9, 72.3, and 62% and gray zone cases in 46.15, 37.5, and 44.2%. We devised an algorithm to calculate the NFS to predict SLF with good accuracy, fewer cases in the gray zone, and a straightforward clinical interpretation. NFS could be used for the initial evaluation of the treatment priority.

  3. TRUSS exacerbates NAFLD development by promoting IκBα degradation.

    PubMed

    Yu, Chang-Jiang; Wang, Qiu-Shi; Wu, Ming-Ming; Song, Bin-Lin; Liang, Chen; Lou, Jie; Tang, Liang-Liang; Yu, Xiao-Di; Niu, Na; Yang, Xu; Zhang, Bao-Long; Qu, Yao; Liu, Yang; Dong, Zhi-Chao; Zhang, Zhi-Ren

    2018-04-27

    There is no effective treatment method for non-alcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was respectively increased in the human liver specimens with NAFLD or non-alcoholic steatohepatitis (NASH), and in the livers of high-fat diet (HFD)-induced and genetically obese (ob/ob) mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance (IR), glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow (NC) feeding. All these HFD-induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with IκBα and promotes the ubiquitination and degradation of IκBα, which leading to aberrant activation of NF-κB. Overexpressing IκBα S32A/S36A , a phosphorylation-resistant mutant of IκBα, in the hepatocyte-specific TRUSS overexpressing mice almost abolished HFD-induced NAFLD and metabolic disorders. Hepatocyte TRUSS promotes pathological stimuli-induced NAFLD and metabolic disorders, via activation of NF-κB by promoting ubiquitination and degradation of IκBα. Our findings may provide a novel strategy for prevention and treatment of NAFLD by targeting TRUSS. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  4. A robust collagen scoring method for human liver fibrosis by second harmonic microscopy.

    PubMed

    Guilbert, Thomas; Odin, Christophe; Le Grand, Yann; Gailhouste, Luc; Turlin, Bruno; Ezan, Frédérick; Désille, Yoann; Baffet, Georges; Guyader, Dominique

    2010-12-06

    Second Harmonic Generation (SHG) microscopy offers the opportunity to image collagen of type I without staining. We recently showed that a simple scoring method, based on SHG images of histological human liver biopsies, correlates well with the Metavir assessment of fibrosis level (Gailhouste et al., J. Hepatol., 2010). In this article, we present a detailed study of this new scoring method with two different objective lenses. By using measurements of the objectives point spread functions and of the photomultiplier gain, and a simple model of the SHG intensity, we show that our scoring method, applied to human liver biopsies, is robust to the objective's numerical aperture (NA) for low NA, the choice of the reference sample and laser power, and the spatial sampling rate. The simplicity and robustness of our collagen scoring method may open new opportunities in the quantification of collagen content in different organs, which is of main importance in providing diagnostic information and evaluation of therapeutic efficiency.

  5. Application of the combined FibroMeter vibration-controlled transient elastography algorithm in Chinese patients with non-alcoholic fatty liver disease.

    PubMed

    Loong, Thomson Chi-Wang; Wei, Jeremy Lok; Leung, Jonathan Chung-Fai; Wong, Grace Lai-Hung; Shu, Sally She-Ting; Chim, Angel Mei-Ling; Chan, Anthony Wing-Hung; Choi, Paul Cheung-Lung; Tse, Yee-Kit; Chan, Henry Lik-Yuen; Wong, Vincent Wai-Sun

    2017-07-01

    The FibroMeter vibration-controlled transient elastography (FM VCTE) is a new formula combining the serum test FM and liver stiffness measurement (LSM) by VCTE. We tested the accuracy and utility of FM VCTE for fibrosis staging in patients with non-alcoholic fatty liver disease (NAFLD). Two hundred fifteen NAFLD patients with LSM, FM NAFLD, FM VCTE, and other serum tests (aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, BARD score, NAFLD fibrosis score, and aspartate aminotransferase-to-alanine aminotransferase ratio) performed 1 day before liver biopsy were evaluated. Sixty-nine (32.1%) and 43 (20.0%) patients had F2-4 and F3-4, respectively. LSM had higher diagnostic accuracy (area under receiver-operating characteristics curves [AUROC] 0.851 for F2-4, 0.940 for F3-4; Obuchowski index 0.937 ± 0.007) than all evaluated serum tests, while FM NAFLD was the most accurate serum test (AUROC 0.775 and 0.774; Obuchowski index 0.891 ± 0.013). FM VCTE had similar accuracy to LSM (AUROC 0.855 and 0.901; Obuchowski index 0.927 ± 0.009). LSM had excellent negative predictive values of 92.4% and 99.2% to exclude F2-4 and F3-4, but the positive predictive values (PPV) were only 71.4% and 61.0%, respectively. In patients with high LSM, the use of FM VCTE improved the PPV from 71.4% to 84.4% for F2-4 and from 61.0% to 88.9% for F3-4. Liver biopsy could be spared in around 50-65% of patients. Liver stiffness measurement alone can confidently exclude significant and advanced fibrosis in NAFLD patients. Using FM VCTE in patients with high liver stiffness can increase the positive predictive value to rule in F2-4 and F3-4. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  6. Gut Microbiota and Lifestyle Interventions in NAFLD

    PubMed Central

    Houghton, David; Stewart, Christopher J.; Day, Christopher P.; Trenell, Michael

    2016-01-01

    The human digestive system harbors a diverse and complex community of microorganisms that work in a symbiotic fashion with the host, contributing to metabolism, immune response and intestinal architecture. However, disruption of a stable and diverse community, termed “dysbiosis”, has been shown to have a profound impact upon health and disease. Emerging data demonstrate dysbiosis of the gut microbiota to be linked with non-alcoholic fatty liver disease (NAFLD). Although the exact mechanism(s) remain unknown, inflammation, damage to the intestinal membrane, and translocation of bacteria have all been suggested. Lifestyle intervention is undoubtedly effective at improving NAFLD, however, not all patients respond to these in the same manner. Furthermore, studies investigating the effects of lifestyle interventions on the gut microbiota in NAFLD patients are lacking. A deeper understanding of how different aspects of lifestyle (diet/nutrition/exercise) affect the host–microbiome interaction may allow for a more tailored approach to lifestyle intervention. With gut microbiota representing a key element of personalized medicine and nutrition, we review the effects of lifestyle interventions (diet and physical activity/exercise) on gut microbiota and how this impacts upon NAFLD prognosis. PMID:27023533

  7. A Multidisciplinary Clinical Program is Effective in Stabilizing BMI and Reducing Transaminase Levels in Pediatric Patients with NAFLD

    PubMed Central

    DeVore, Stephanie; Kohli, Rohit; Lake, Kathleen; Nicholas, Lynda; Dietrich, Kim; Balistreri, William F.; Xanthakos, Stavra A.

    2013-01-01

    Weight loss is an effective treatment for children with non-alcoholic fatty liver disease (NAFLD) but it is very difficult to achieve outside of an intensive weight management program. We hypothesized that one can achieve success in improving NAFLD and weight-related outcomes in a structured and focused multidisciplinary clinical program feasible to implement in a gastroenterology clinic. Methods We prospectively tracked the clinical status of our patients enrolled in a multidisciplinary program of dietary and exercise advice through an Institutional Review Board-approved NAFLD registry. Each patient met with a gastroenterologist and dietician every 3 months for 30 minutes to set individualized goals and monitor progress. Results 108 children have been enrolled in the registry and of the 83 that were eligible for 1 year follow-up and included in the analysis, 39 patients returned, resulting in a 47% follow-up rate. These 39 patients showed statistically significant improvements in mean BMI z-score (−0.1 units, p<0.05), total (−11 mg/dL, p<0.05) and low density lipoprotein cholesterol (−9 mg/dL, p<0.05), and serum alanine aminotransferase (ALT) levels (−36 U/L) and aspartate amino transferase (AST) levels (−22 U/L) levels. Conclusion A clinically feasible multidisciplinary program of every 3 month 30 minute visits to set and monitor nutrition and exercise goals, stabilized mean BMI z-score and significantly improved aminotransferase levels at 1 year follow-up in obese pediatric patients with NAFLD. PMID:23518484

  8. Care standards for non-alcoholic fatty liver disease in the United Kingdom 2016: a cross-sectional survey.

    PubMed

    Sheridan, David A; Aithal, Guru; Alazawi, William; Allison, Michael; Anstee, Quentin; Cobbold, Jeremy; Khan, Shahid; Fowell, Andrew; McPherson, Stuart; Newsome, Philip N; Oben, Jude; Tomlinson, Jeremy; Tsochatzis, Emmanouil

    2017-10-01

    Guidelines for the assessment of non-alcoholic fatty liver disease (NAFLD) have been published in 2016 by National Institute for Health and Care Excellence and European Associations for the study of the Liver-European Association for the study of Diabetes-European Association for the study of Obesity. Prior to publication of these guidelines, we performed a cross-sectional survey of gastroenterologists and hepatologists regarding NAFLD diagnosis and management. An online survey was circulated to members of British Association for the Study of the Liver and British Society of Gastroenterology between February 2016 and May 2016. 175 gastroenterologists/hepatologists responded, 116 completing the survey, representing 84 UK centres. 22% had local NAFLD guidelines. 45% received >300 referrals per year from primary care for investigation of abnormal liver function tests (LFTs). Clinical assessment tended to be performed in secondary rather than primary care including body mass index (82% vs 26%) and non-invasive liver screen (86% vs 32%) and ultrasound (81% vs 37%). Widely used tools for non-invasive fibrosis risk stratification were aspartate transaminase (AST)/alanine transaminase (ALT) ratio (53%), Fibroscan (50%) and NAFLD fibrosis score (41%). 78% considered liver biopsy in selected cases. 50% recommended 10% weight loss target as first-line treatment. Delivery of lifestyle interventions was mostly handed back to primary care (56%). A minority have direct access to community weight management services (22%). Follow-up was favoured by F3/4 fibrosis (72.9%), and high-risk non-invasive fibrosis tests (51%). Discharge was favoured by simple steatosis at biopsy (30%), and low-risk non-invasive scores (25%). The survey highlights areas for improvement of service provision for NAFLD assessment including improved recognition of non-alcoholic steatohepatitis in people with type 2 diabetes, streamlining abnormal LFT referral pathways, defining non-invasive liver fibrosis

  9. Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.

    PubMed

    Kobayashi, Natsuko; Kumada, Takashi; Toyoda, Hidenori; Tada, Toshifumi; Ito, Takanori; Kage, Masayoshi; Okanoue, Takeshi; Kudo, Masatoshi

    2017-01-01

    Several laboratory markers used in lieu of liver biopsy are reportedly useful in the diagnosis of nonalcoholic steatohepatitis (NASH). In the present study, we investigated the diagnostic impact of various non-invasive markers for predicting NASH. A total of 229 nonalcoholic fatty liver disease (NAFLD) patients who underwent liver biopsy were enrolled for the study. The diagnostic ability of various markers to diagnose NASH from NAFLD was investigated. A total of 140 patients were histologically diagnosed with NASH. Of these, 104 had degree 0-2 fibrosis (F0-2), and 36 had degree 3-4 fibrosis (F3-4). Multiple logistic regression analysis identified hyaluronic acid (HA) (OR 1.014; 95% CI 1.002-1.026; p = 0.024), FIB-4 index (OR 2.097; 95% CI 1.177-3.735; p = 0.012), and cytokeratin-18 fragments (CK-18F) (OR 1.002; 95% CI 1.001-1.002; p < 0.001) as factors independently associated with the diagnosis of NASH. The areas under the receiver operating characteristic curves (AUROCs) of HA, FIB-4 index, and CK-18F for the diagnosis of NASH were 0.77, 0.76, and 0.72, respectively. In addition, FIB-4 index (OR 1.907; 95% CI 1.063-3.419; p = 0.03) and CK-18F (OR 1.002; 95% CI 1.001-1.002; p < 0.001) could differentiate between NASH and NAFL, even when NASH patients with advanced fibrosis (F3-4) were excluded. AUROCs of FIB-4 index and CK-18F for the diagnosis of NASH with mild fibrosis (F0-2) from NAFLD were 0.70 and 0.70, respectively. FIB-4 index and CK-18F have good diagnostic abilities not only for NASH overall, but also for NASH with mild fibrosis. © 2017 S. Karger AG, Basel.

  10. Nutritional Management of Insulin Resistance in Nonalcoholic Fatty Liver Disease (NAFLD)

    PubMed Central

    Conlon, Beth A.; Beasley, Jeannette M.; Aebersold, Karin; Jhangiani, Sunil S.; Wylie-Rosett, Judith

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association’s (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD. PMID:24152749

  11. The characterisation of hepatic mitochondrial function in patients with non-alcoholic fatty liver disease (NAFLD) using the 13C-ketoisocaproate breath test.

    PubMed

    Afolabi, Paul R; Scorletti, Eleonora; Smith, Debbie E; Almehmadi, Amal A; Calder, Philip C; Byrne, Christopher D

    2018-06-26

    Hepatic mitochondrial function (HMF) assessed by the <sup>13</sup>C-ketoisocaproate breath test (<sup>13</sup>C-KICA BT) has been previously shown to be significantly associated with the severity of biopsy proven non-alcoholic fatty liver disease (NAFLD). However, it is uncertain whether any perturbation in HMF relates specifically to severity of liver disease or factors associated with metabolic syndrome within non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate whether there was any change in HMF assessed by <sup>13</sup>C-KICA BT in patients with NAFLD compared to control subjects, and to assess the factors that are independently associated with HMF. 77 patients with NAFLD and 11 healthy control subjects were studied. HMF was assessed using <sup>13</sup>C-KICA BT and expressed as cumulative % <sup>13</sup>C-dose recovered on breath over 1hr (cPDR over 1hr). Liver fat and fibrosis was assessed by transient elastography. Multi-variable linear regression modelling was undertaken to test the independence of associations with HMF. HMF (cPDR over 1hr) was lower in NAFLD compared to controls [13.4% (4.8) v. 21.0% (6.3); p< 0.0001)]. In NAFLD, HMF was lower in patients with diabetes versus no diabetes [12.7% (3.4) v. 14.3% (6.1); p=0.003)]. Regression modelling showed age (β= -0.08; p=0.01), waist circumference (β= -0.08; p=0.01), hip circumference (β= -0.04; p=0.01), aspartate aminotransferase (AST) (β= -0.05; p=0.01) and diabetes status (β= -1.81; p=0.01) were independently associated with HMF (R<sup>2</sup>= 41.5%; p<0.0001). In patients with NAFLD (compared to healthy subjects), there was a reduction in HMF assessed by the <sup>13</sup>C-KICA BT. Furthermore, in patients with NAFLD, HMF is independent and inversely associated with age, waist and hip circumference, AST and diabetes status. © 2018 IOP Publishing Ltd.

  12. Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases.

    PubMed

    Motamed, Nima; Rabiee, Behnam; Poustchi, Hossein; Dehestani, Babak; Hemasi, Gholam Reza; Khonsari, Mahmood Reza; Maadi, Mansooreh; Saeedian, Fatemeh Sima; Zamani, Farhad

    2017-02-01

    The association between cardiovascular diseases (CVD) and non-alcoholic fatty liver disease (NAFLD) was confirmed by a large body of evidence. This study was conducted to determine the association between NAFLD and 10-year CVD risk. This study utilized the data of 2804 subjects aged 40-74 years from a cohort study of northern Iran. Two CVD risk assessment tools, American College of Cardiology/American Heart Association and Framingham general cardiovascular risk profile for use in primary care, were utilized to determine the 10-year CVD risk in patients with NAFLD and the individuals without this condition. The mean risks were compared between these two groups. Using ACC/AHA approach, the mean risk in male participants suffering NAFLD was 14.2%, while in men without NAFLD was 11.7% (P-value < 0.0001). Using Framingham approach, the mean risks were 16.0 and 12.7% in men with and without NAFLD, respectively (P-value < 0.0001). Using ACC/AHA approach, the mean risks in female participants with and without NAFLD were 6.7 and 4.6%, respectively (P-value < 0.0001). Applying Framingham approach, the mean risk was 8.2% in women with NAFLD and 5.4% in women without NAFLD (P-value < 0.0001). The individuals with NAFLD had a higher risk of 10-year CVD events than individuals without NAFLD, according to both ACC/AHA tool and primary care version of Framingham tool. A large proportion of NAFLD patients fulfill the criteria of statin therapy recommendation, suggesting that statin therapy could reduce 10-year CVD risk in NAFLD patients. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3.

    PubMed

    Lallukka, S; Sevastianova, K; Perttilä, J; Hakkarainen, A; Orho-Melander, M; Lundbom, N; Olkkonen, V M; Yki-Järvinen, H

    2013-04-01

    The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD' = PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ((1)H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2 ± 0.7 kg/m(2); non-obese 26.0 ± 0.4 kg/m(2)) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m(2); PNPLA3-148II, 31.2 ± 0.8 kg/m(2)), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. Liver fat was similarly increased in obese NAFLD (9.5 ± 1.3% vs 5.1 ± 0.9%, obese vs non-obese, p = 0.007) and PNPLA3 NAFLD (11.4 ± 1.7% vs 5.3 ± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p < 0.001). Fasting serum insulin was higher in the obese than the non-obese group (76 ± 6 vs 47 ± 6 pmol/l, p < 0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60 ± 8 vs 62 ± 5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.

  14. Application of a computed tomography based cystic fibrosis scoring system to chest tomosynthesis

    NASA Astrophysics Data System (ADS)

    Söderman, Christina; Johnsson, Åse; Vikgren, Jenny; Rystedt, Hans; Ivarsson, Jonas; Rossi Norrlund, Rauni; Nyberg Andersson, Lena; Bâth, Magnus

    2013-03-01

    In the monitoring of progression of lung disease in patients with cystic fibrosis (CF), recurrent computed tomography (CT) examinations are often used. The relatively new imaging technique chest tomosynthesis (CTS) may be an interesting alternative in the follow-up of these patients due to its visualization of the chest in slices at radiation doses and costs significantly lower than is the case with CT. A first step towards introducing CTS imaging in the diagnostics of CF patients is to establish a scoring system appropriate for evaluating the severity of CF pulmonary disease based on findings in CTS images. Previously, several such CF scoring systems based on CT imaging have been published. The purpose of the present study was to develop a CF scoring system for CTS, by starting from an existing scoring system dedicated for CT images and making modifications regarded necessary to make it appropriate for use with CTS images. In order to determine any necessary changes, three thoracic radiologists independently used a scoring system dedicated for CT on both CT and CTS images from CF patients. The results of the scoring were jointly evaluated by all the observers, which lead to suggestions for changes to the scoring system. Suggested modifications include excluding the scoring of air trapping and doing the scoring of the findings in quadrants of the image instead of in each lung lobe.

  15. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues.

    PubMed

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health.Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper,we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameter scan provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  16. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues

    NASA Astrophysics Data System (ADS)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health. Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper, we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameters can provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  17. A new scoring system in Cystic Fibrosis: statistical tools for database analysis - a preliminary report.

    PubMed

    Hafen, G M; Hurst, C; Yearwood, J; Smith, J; Dzalilov, Z; Robinson, P J

    2008-10-05

    Cystic fibrosis is the most common fatal genetic disorder in the Caucasian population. Scoring systems for assessment of Cystic fibrosis disease severity have been used for almost 50 years, without being adapted to the milder phenotype of the disease in the 21st century. The aim of this current project is to develop a new scoring system using a database and employing various statistical tools. This study protocol reports the development of the statistical tools in order to create such a scoring system. The evaluation is based on the Cystic Fibrosis database from the cohort at the Royal Children's Hospital in Melbourne. Initially, unsupervised clustering of the all data records was performed using a range of clustering algorithms. In particular incremental clustering algorithms were used. The clusters obtained were characterised using rules from decision trees and the results examined by clinicians. In order to obtain a clearer definition of classes expert opinion of each individual's clinical severity was sought. After data preparation including expert-opinion of an individual's clinical severity on a 3 point-scale (mild, moderate and severe disease), two multivariate techniques were used throughout the analysis to establish a method that would have a better success in feature selection and model derivation: 'Canonical Analysis of Principal Coordinates' and 'Linear Discriminant Analysis'. A 3-step procedure was performed with (1) selection of features, (2) extracting 5 severity classes out of a 3 severity class as defined per expert-opinion and (3) establishment of calibration datasets. (1) Feature selection: CAP has a more effective "modelling" focus than DA.(2) Extraction of 5 severity classes: after variables were identified as important in discriminating contiguous CF severity groups on the 3-point scale as mild/moderate and moderate/severe, Discriminant Function (DF) was used to determine the new groups mild, intermediate moderate, moderate, intermediate

  18. Controversies in the Diagnosis and Management of NAFLD and NASH.

    PubMed

    Rinella, Mary E; Loomba, Rohit; Caldwell, Stephen H; Kowdley, Kris; Charlton, Michael; Tetri, Brent; Harrison, Stephen A

    2014-04-01

    Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease in the United States. Nonalcoholic steatohepatitis (NASH) occurs in a subset of patients with NAFLD and is characterized by the presence of hepa-tocellular injury, which is progressive in a substantial proportion of cases and can lead to cirrhosis and all of its complications. Although the diagnosis of NAFLD can be made through imaging studies or liver biopsy, the diagnosis of NASH still requires histologic confirmation. Liver biopsy should be performed in the presence of risk factors for advanced disease. Measures aimed at promoting weight loss, a healthier lifestyle, and optimization of metabolic risk factors remain the cornerstone of management of NAFLD. Therapeutic agents that are presently considered the most promising in NAFLD are effective in less than 50% of patients. Among patients with biopsy-proven NASH, treatment with pharmacologic agents should be considered; however, the role of specific agents in NASH still needs further study. Despite a wealth of research over the past 15 years, many controversies remain with respect to the diagnosis and management of NAFLD and NASH as well as the influence of alcohol on liver disease progression in these patients.

  19. Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis.

    PubMed

    Mohamad, Bashar; Shah, Vaishal; Onyshchenko, Mykola; Elshamy, Mohammed; Aucejo, Federico; Lopez, Rocio; Hanouneh, Ibrahim A; Alhaddad, Razan; Alkhouri, Naim

    2016-07-01

    The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggests that HCC could arise in steatotic liver without the presence of cirrhosis. The present study was conducted to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to the NAFLD- HCC patients in association with cirrhotic liver (CL). A retrospective analysis of all patients diagnosed with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012 was done. The patients were characterized based on demographic and clinical variables as well as histological and tumor features. Comparisons between the NCL and CL groups were done using analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis tests and Pearson's chi-square tests or Fisher's Exact tests as appropriate. P value of <0.05 was considered statistically significant. Thirty-six patients with NAFLD and HCC in NCL (HCC-NCL group) were identified and compared to 47 patients with NAFLD-HCC and Liver Cirrhosis (HCC-LC group). Liver fibrosis was not present in 55.9 % of patients in the HCC-NCL group (F0), stage 1 was present in 17.6 %, stage 2 in 8.8 % and stage 3 in 17.6 %. Lobular inflammation was present in 63.6 % of non-cirrhotic patients. Patients in the HCC-NCL were older (67.5 ± 12.3 vs. 62.7 ± 8.1 years), and less likely to be obese (52 % vs. 83 %) or have type 2 diabetes (38 % vs. 83 %), with p value <0.05 for all. More importantly, compared with the HCC-CL group, those in the HCC-NCL group were more likely to present with a single nodule (80.6 % vs. 52.2 %), larger nodule size (>5 cm) (77.8 % vs. 10.6 %), and receive hepatic resection as the modality of HCC treatment (66.7 % vs. 17 %); and were less likely to receive loco-regional therapy (22.3 % vs. 61.7 %) or orthotopic liver transplantation (OLT) (0 % vs. 72.3 %), with p value <0

  20. Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

    PubMed

    Patel, Y A; Gifford, E J; Glass, L M; McNeil, R; Turner, M J; Han, B; Provenzale, D; Choi, S S; Moylan, C A; Hunt, C M

    2018-01-01

    With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n = 65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n = 76), nonalcoholic steatohepatitis (NASH) without fibrosis (n = 68), NAFLD/NASH stage 1-3 fibrosis (n = 82), and NAFLD/NASH cirrhosis (n = 70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n = 38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35 kg/m 2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P < .001) and BMI (OR 1.4, P < .001) were the most significant predictors of advanced fibrosis. In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity. © 2017 John Wiley & Sons Ltd.

  1. Serum metabonomics of NAFLD plus T2DM based on liquid chromatography-mass spectrometry.

    PubMed

    Chen, Yang; Li, Chunlong; Liu, Liyan; Guo, Fuchuan; Li, Songtao; Huang, Lina; Sun, Changhao; Feng, Rennan

    2016-09-01

    Nonalcoholic fatty liver disease (NAFLD), a main liver disease around the world, is closely associated with insulin resistance, type 2 diabetes mellitus (T2DM) and other metabolic diseases. The objective of this study is to identify distinct metabolites of NAFLD patients with or without T2DM. We used a biomarker-discovery population to find distinct metabolites of NAFLD patients with or without T2DM. Then, a validation population was applied to test the model of the biomarker-discovery population. All the individuals received anthropometric and common biochemical measurements. The metabolic data were analyzed by multivariable statistical analyses using ultra-high-performance liquid chromatography/quadrupole time-of-flight-tandem mass spectrometry. There were 7, 7, 2 metabolites in the positive electrospray ionization (ESI(+)) mode, which were identified between groups from both the biomarker-discovery and validation population. The NAFLD group showed higher concentrations of oleamide, l-phenylalanine, l-proline, bilirubin, l-palmitoylcarnitine, and PC (20:5) and a lower concentration of Lyso-PAF C-18 than those of control. Compared with the control group, the NAFLD+T2DM group displayed higher oleamide, l-leucine, LysoPC (14:0), bilirubin, tetradecenoylcarnitine, linoleyl carnitine, and tetradecadiencarnitine in serum. Tetradecenoylcarnitine and tetradecadiencarnitine were more elevated in patients with NAFLD+T2DM than in the NAFLD group. Serum metabonomic analyses displayed great metabolic changes in patients with NAFLD and NAFLD plus T2DM. Our study is beneficial in providing a further view into the pathogenesis and pathophysiology of NAFLD and NAFLD plus T2DM, which might be useful for the prevention and therapy of NAFLD and NAFLD plus T2DM. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  2. Maraviroc, a CCR5 antagonist, ameliorates the development of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Pérez-Martínez, Laura; Pérez-Matute, Patricia; Aguilera-Lizarraga, Javier; Rubio-Mediavilla, Susana; Narro, Judit; Recio, Emma; Ochoa-Callejero, Laura; Oteo, José-Antonio; Blanco, José-Ramón

    2014-07-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. The NAFLD spectrum ranges from simple steatosis to cirrhosis. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. The objective of this study was to examine the effects of maraviroc, a CCR5 antagonist, on liver pathology in a NAFLD mouse model. A total of 32 male C57BL/6 mice were randomly assigned to one of four groups: (i) control group (chow diet plus tap water); (ii) maraviroc group (chow diet plus maraviroc in drinking water); (iii) high-fat diet (HFD) group (HFD plus tap water); and (iv) maraviroc/HFD group (HFD plus maraviroc). All mice were sacrificed 16 weeks after the beginning of the experiment. Biochemical analyses and liver examinations were performed. Mice in the HFD group showed a tendency towards increased body mass gain and liver damage compared with the maraviroc/HFD group. Moreover, liver weight in the HFD group was significantly higher than in the maraviroc/HFD group. Hepatic triglyceride concentration in the maraviroc/HFD group was significantly lower than in the HFD group. Interestingly, the maraviroc/HFD group exhibited a lower degree of steatosis. Furthermore, hepatic CCL5/RANTES expression was significantly lower in the maraviroc/HFD group than in the HFD group. Overall, no differences were observed between the control group and the maraviroc group. Maraviroc ameliorates hepatic steatosis in an experimental model of NAFLD. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression.

    PubMed

    Seko, Yuya; Sumida, Yoshio; Tanaka, Saiyu; Mori, Kojiroh; Taketani, Hiroyoshi; Ishiba, Hiroshi; Hara, Tasuku; Okajima, Akira; Umemura, Atsushi; Nishikawa, Taichiro; Yamaguchi, Kanji; Moriguchi, Michihisa; Kanemasa, Kazuyuki; Yasui, Kohichiroh; Imai, Shunsuke; Shimada, Keiji; Itoh, Yoshito

    2017-10-01

    Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD. In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers. Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group. In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled. © 2016 The Japan Society of Hepatology.

  4. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.

    PubMed

    Mridha, Auvro R; Wree, Alexander; Robertson, Avril A B; Yeh, Matthew M; Johnson, Casey D; Van Rooyen, Derrick M; Haczeyni, Fahrettin; Teoh, Narci C-H; Savard, Christopher; Ioannou, George N; Masters, Seth L; Schroder, Kate; Cooper, Matthew A; Feldstein, Ariel E; Farrell, Geoffrey C

    2017-05-01

    NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. We fed foz/foz and wild-type mice an atherogenic diet for 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks and determined the effects on liver fibrosis. In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation

  5. A Single Test Combining Blood Markers and Elastography is More Accurate Than Other Fibrosis Tests in the Main Causes of Chronic Liver Diseases.

    PubMed

    Ducancelle, Alexandra; Leroy, Vincent; Vergniol, Julien; Sturm, Nathalie; Le Bail, Brigitte; Zarski, Jean Pierre; Nguyen Khac, Eric; Salmon, Dominique; de Ledinghen, Victor; Calès, Paul

    2017-08-01

    International guidelines suggest combining a blood test and liver stiffness measurement (LSM) to stage liver fibrosis in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Therefore, we compared the accuracies of these tests between the main etiologies of chronic liver diseases. Overall, 1968 patients were included in 5 etiologies: CHC: 698, chronic hepatitis B: 152, human immunodeficiency virus/CHC: 628, NAFLD: 225, and alcoholic liver disease (ALD): 265. Sixteen tests [13 blood tests, LSM (Fibroscan), 2 combined: FibroMeters] were evaluated. References were Metavir staging and CHC etiology. Accuracy was evaluated mainly with the Obuchowski index (OI) and accessorily with area under the receiver operating characteristics (F≥2, F≥3, cirrhosis). OIs in CHC were: FibroMeters: 0.812, FibroMeters: 0.785 to 0.797, Fibrotest: 0.762, CirrhoMeters: 0.756 to 0.771, LSM: 0.754, Hepascore: 0.752, FibroMeter: 0.750, aspartate aminotransferase platelet ratio index: 0.742, Fib-4: 0.741. In other etiologies, most tests had nonsignificant changes in OIs. In NAFLD, CHC-specific tests were more accurate than NAFLD-specific tests. The combined FibroMeters had significantly higher accuracy than their 2 constitutive tests (FibroMeters and LSM) in at least 1 diagnostic target in all etiologies, except in ALD where LSM had the highest OI, and in 3 diagnostic targets (OIs and 2 area under the receiver operating characteristics) in CHC and NAFLD. Some tests developed in CHC outperformed other tests in their specific etiologies. Tests combining blood markers and LSM outperformed single tests, validating recent guidelines and extending them to main etiologies. Noninvasive fibrosis evaluation can thus be simplified in the main etiologies by using a unique test: either LSM alone, especially in ALD, or preferably combined to blood markers.

  6. Diet-Quality Scores and Prevalence of Nonalcoholic Fatty Liver Disease: A Population Study Using Proton-Magnetic Resonance Spectroscopy

    PubMed Central

    Chan, Ruth; Wong, Vincent Wai-Sun; Chu, Winnie Chiu-Wing; Wong, Grace Lai-Hung; Li, Liz Sin; Leung, Jason; Chim, Angel Mei-Ling; Yeung, David Ka-Wai; Sea, Mandy Man-Mei; Woo, Jean; Chan, Francis Ka-Leung; Chan, Henry Lik-Yuen

    2015-01-01

    Dietary pattern analysis is an alternative approach to examine the association between diet and nonalcoholic fatty liver disease (NAFLD). This study examined the association of two diet-quality scores, namely Diet Quality Index-International (DQI-I) and Mediterranean Diet Score (MDS) with NAFLD prevalence. Apparently healthy Chinese adults (332 male, 465 female) aged 18 years or above were recruited through a population screening between 2008 and 2010 in a cross-sectional population-based study in Hong Kong. DQI-I and MDS, as well as major food group and nutrient intakes were calculated based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at ≥5% by proton-magnetic resonance spectroscopy. Multivariate logistic regression models were used to examine the association between each diet-quality score or dietary component and prevalent NAFLD with adjustment for potential lifestyle, metabolic and genetic factors. A total of 220 subjects (27.6%) were diagnosed with NAFLD. DQI-I but not MDS was associated with the prevalence of NAFLD. A 10-unit decrease in DQI-I was associated with 24% increase in the likelihood of having NAFLD in the age and sex adjusted model (95% CI: 1.06–1.45, p = 0.009), and the association remained significant when the model was further adjusted for other lifestyle factors, metabolic and genetic factors [OR: 1.26 (95% CI: 1.03–1.54), p = 0.027]. Multivariate regression analyses showed an inverse association of the intake of vegetables and legumes, fruits and dried fruits, as well as vitamin C with the NAFLD prevalence (p<0.05). In conclusion, a better diet quality as characterized by a higher DQI-I and a higher consumption of vegetables, legumes and fruits was associated with a reduced likelihood of having NAFLD in Hong Kong Chinese. PMID:26418083

  7. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial.

    PubMed

    Loguercio, Carmela; Andreone, Pietro; Brisc, Ciprian; Brisc, Michaela Cristina; Bugianesi, Elisabetta; Chiaramonte, Maria; Cursaro, Carmela; Danila, Mirela; de Sio, Ilario; Floreani, Annarosa; Freni, Maria Antonietta; Grieco, Antonio; Groppo, Marzia; Lazzari, Roberta; Lobello, Salvatore; Lorefice, Elisabetta; Margotti, Marzia; Miele, Luca; Milani, Stefano; Okolicsanyi, Lajos; Palasciano, Giuseppe; Portincasa, Piero; Saltarelli, Patrizia; Smedile, Antonina; Somalvico, Francesco; Spadaro, Aldo; Sporea, Ioan; Sorrentino, Paolo; Vecchione, Raffaela; Tuccillo, Concetta; Del Vecchio Blanco, Camillo; Federico, Alessandro

    2012-05-01

    The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Meta-Omic Platforms to Assist in the Understanding of NAFLD Gut Microbiota Alterations: Tools and Applications

    PubMed Central

    Del Chierico, Federica; Gnani, Daniela; Vernocchi, Pamela; Petrucca, Andrea; Alisi, Anna; Dallapiccola, Bruno; Nobili, Valerio; Lorenza, Putignani

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data. PMID:24402126

  9. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

    PubMed

    Yoo, Wonbeak; Gjuka, Donjeta; Stevenson, Heather L; Song, Xiaoling; Shen, Hong; Yoo, Suk Young; Wang, Jing; Fallon, Michael; Ioannou, George N; Harrison, Stephen A; Beretta, Laura

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

  10. Combining semiquantitative measures of fibrosis and qualitative features of parenchymal remodelling to identify fibrosis regression in hepatitis C: a multiple biopsy study.

    PubMed

    Pattullo, Venessa; Thein, Hla-Hla; Heathcote, Elizabeth Jenny; Guindi, Maha

    2012-09-01

    A fall in hepatic fibrosis stage may be observed in patients with chronic hepatitis C (CHC); however, parenchymal architectural changes may also signify hepatic remodelling associated with fibrosis regression. The aim of this study was to utilize semiquantitative and qualitative methods to report the prevalence and factors associated with fibrosis regression in CHC. Paired liver biopsies were scored for fibrosis (Ishak), and for the presence of eight qualitative features of parenchymal remodelling, to derive a qualitative regression score (QR score). Combined fibrosis regression was defined as ≥2-stage fall in Ishak stage (Reg-I) or <2-stage fall in Ishak stage with a rise in QR score (Reg-Qual). Among 159 patients (biopsy interval 5.4 ± 3.1 years), Reg-I was observed in 12 (7.5%) and Reg-Qual in 26 (16.4%) patients. The combined diagnostic criteria increased the diagnosis rate for fibrosis regression (38 patients, 23.9%) compared with use of Reg-I alone (P < 0.001). Combined fibrosis regression was observed in nine patients (50%) who achieved sustained virological response (SVR), and in 29 of 141 (21%) patients despite persistent viraemia. SVR was the only clinical factor associated independently with combined fibrosis regression (odds ratio 3.05). The combination of semiquantitative measures and qualitative features aids the identification of fibrosis regression in CHC. © 2012 Blackwell Publishing Ltd.

  11. Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study.

    PubMed

    Williams, Kathryn H; Vieira De Ribeiro, Ana Júlia; Prakoso, Emilia; Veillard, Anne-Sophie; Shackel, Nicholas A; Brooks, Belinda; Bu, Yangmin; Cavanagh, Erika; Raleigh, Jim; McLennan, Susan V; McCaughan, Geoffrey W; Keane, Fiona M; Zekry, Amany; Gorrell, Mark D; Twigg, Stephen M

    2015-11-01

    Intrahepatic expression of dipeptidyl peptidase-4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non-alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity. cDPP4 was measured in 106 individuals with type 2 diabetes who had transient elastography (Cohort 1) and 145 individuals with morbid obesity who had liver biopsy (Cohort 2). Both cohorts had caspase-cleaved keratin-18 (ccK18) measured as a marker of apoptosis. Natural log increases in cDPP4 activity were associated with increasing quartiles of ccK18 (Cohorts 1 and 2) and with median liver stiffness ≥10.3 kPa (Cohort 1) and significant fibrosis (F ≥ 2) on liver biopsy (Cohort 2). In diabetes and/or obesity, cDPP4 activity is associated with current apoptosis and liver fibrosis. Given the pathogenic mechanisms by which DPP4 may progress NAFLD, measurement of cDPP4 activity may have utility to predict disease progression and DPP4 inhibition may improve liver histology over time. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  12. NAFLD prevalence differs among hispanic subgroups: the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Fleischman, Michael Wayne; Budoff, Matthew; Zeb, Ifran; Li, Dong; Foster, Temitope

    2014-05-07

    To compare prevalence rates of non-alcoholic fatty liver disease (NAFLD) between Hispanics of Mexican origin and Hispanics of Dominican and Puerto Rican origin. We evaluated prevalence rates of NAFLD between the two largest sub-populations of Hispanics in the United States; Hispanics of Mexican origin and Hispanics of Caribbean origin (Dominican and Puerto Rican), in the multi-ethnic study of atherosclerosis (MESA) cohort. MESA is a large, population based, multi-center cohort study comprised of 6814 healthy Caucasian, African-American, Hispanic, and Asian men and women aged 45-84. We utilized the baseline serum, anthropometric and radiographic measurements obtained between 2000 and 2002. NAFLD was measured via computed tomography scan and was defined as liver/spleen attenuation ratio < 1. There were 788 Hispanic participants included in the study after exclusions. The prevalence of NAFLD was 29% (n = 225). Hispanics of Mexican origin had a significantly higher prevalence of NAFLD (33%), compared to Hispanics of Dominican origin (16%), (P < 0.01) and Hispanics of Puerto Rican origin (18%), (P < 0.01). After controlling for age, sex, BMI, waist circumference, hypertension, serum HDL, triglyceride and CRP level and insulin resistance, Hispanics of Mexican origin remained significantly more likely to have NAFLD than those of Dominican and Puerto Rican origin. United States Hispanics of Mexican origin have a significantly higher prevalence of NAFLD when compared to United States Hispanics of Dominican or Puerto Rican origin after controlling for known risk factors. Care should be taken when performing risk assessment in Hispanic populations not to make assumptions of homogeneity.

  13. Association of Sleep Disorders with Nonalcoholic Fatty Liver Disease (NAFLD): A Population-based Study.

    PubMed

    Mir, Heshaam M; Stepanova, Maria; Afendy, Hena; Cable, Rebecca; Younossi, Zobair M

    2013-09-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. In smaller studies, sleep apnea has been previously associated with NAFLD. The aim of this study was to assess the prevalence and independent associations of sleep disorders in patients with NAFLD using recent population-based data. Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were used. The diagnosis of NAFLD was established as elevated liver enzymes in the absence of all other causes of chronic liver disease. Sleep disorders were diagnosed using sleep disorder questionnaires completed by NHANES participants, and included self-reported history of sleep apnea, insomnia, and restless leg syndrome. The prevalence of sleep disorders was compared between those with and without NAFLD. A total of 10,541 adult NHANES participants with complete demographic, clinical, and laboratory data were included. Of those, 15.0% had NAFLD and 7.2% reported having sleep disorders. Of those with sleep disorders, 64.7% reported history of sleep apnea, 16.0% had history of insomnia, and 4.0% had restless leg syndrome. Individuals with NAFLD were more likely to be male (53.8% vs. 45.7%, P < 0.0001), obese (50.1% vs. 33.4%, P < 0.0001) and had higher prevalence of sleep disorders (9.1% vs. 6.9%, P = 0.0118). In multivariate analysis, having any sleep disorder, sleep apnea and insomnia were all independently associated with NAFLD [OR (95% CI) = 1.40 (1.11-1.76), OR = 1.39 (0.98-1.97), and OR = 2.17 (1.19-3.95); respectively)]. This large population-based data suggests that NAFLD is associated with sleep disorders. Although the exact mechanism is unknown, this association is most likely through metabolic conditions associated with NAFLD.

  14. Association of Sleep Disorders with Nonalcoholic Fatty Liver Disease (NAFLD): A Population-based Study

    PubMed Central

    Mir, Heshaam M.; Stepanova, Maria; Afendy, Hena; Cable, Rebecca; Younossi, Zobair M.

    2013-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. In smaller studies, sleep apnea has been previously associated with NAFLD. The aim of this study was to assess the prevalence and independent associations of sleep disorders in patients with NAFLD using recent population-based data. Methods Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were used. The diagnosis of NAFLD was established as elevated liver enzymes in the absence of all other causes of chronic liver disease. Sleep disorders were diagnosed using sleep disorder questionnaires completed by NHANES participants, and included self-reported history of sleep apnea, insomnia, and restless leg syndrome. The prevalence of sleep disorders was compared between those with and without NAFLD. Results A total of 10,541 adult NHANES participants with complete demographic, clinical, and laboratory data were included. Of those, 15.0% had NAFLD and 7.2% reported having sleep disorders. Of those with sleep disorders, 64.7% reported history of sleep apnea, 16.0% had history of insomnia, and 4.0% had restless leg syndrome. Individuals with NAFLD were more likely to be male (53.8% vs. 45.7%, P < 0.0001), obese (50.1% vs. 33.4%, P < 0.0001) and had higher prevalence of sleep disorders (9.1% vs. 6.9%, P = 0.0118). In multivariate analysis, having any sleep disorder, sleep apnea and insomnia were all independently associated with NAFLD [OR (95% CI) = 1.40 (1.11–1.76), OR = 1.39 (0.98–1.97), and OR = 2.17 (1.19–3.95); respectively)]. Conclusions This large population-based data suggests that NAFLD is associated with sleep disorders. Although the exact mechanism is unknown, this association is most likely through metabolic conditions associated with NAFLD. PMID:25755498

  15. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.

    PubMed

    Gorden, D Lee; Myers, David S; Ivanova, Pavlina T; Fahy, Eoin; Maurya, Mano R; Gupta, Shakti; Min, Jun; Spann, Nathanael J; McDonald, Jeffrey G; Kelly, Samuel L; Duan, Jingjing; Sullards, M Cameron; Leiker, Thomas J; Barkley, Robert M; Quehenberger, Oswald; Armando, Aaron M; Milne, Stephen B; Mathews, Thomas P; Armstrong, Michelle D; Li, Chijun; Melvin, Willie V; Clements, Ronald H; Washington, M Kay; Mendonsa, Alisha M; Witztum, Joseph L; Guan, Ziqiang; Glass, Christopher K; Murphy, Robert C; Dennis, Edward A; Merrill, Alfred H; Russell, David W; Subramaniam, Shankar; Brown, H Alex

    2015-03-01

    The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profiling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identification of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of NAFLD. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

  16. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.

    PubMed

    Larter, Claire Z; Yeh, Matthew M; Haigh, W Geoffrey; Van Rooyen, Derrick M; Brooling, John; Heydet, Deborah; Nolan, Christopher J; Teoh, Narci C; Farrell, Geoffrey C

    2013-06-01

    Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. We sought to establish how dietary composition contributes to NASH pathogenesis. foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. Copyright © 2013 The Obesity Society.

  17. Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study.

    PubMed

    Tuttolomondo, Antonino; Petta, Salvatore; Casuccio, Alessandra; Maida, Carlo; Corte, Vittoriano Della; Daidone, Mario; Di Raimondo, Domenico; Pecoraro, Rosaria; Fonte, Roberto; Cirrincione, Anna; Zafonte, Rita; Cabibi, Daniela; Cammà, Calogero; Di Marco, Vito; Licata, Anna; Magliozzo, Franco; Marchesini, Giulio; Merlino, Giovanni; Craxì, Antonio; Pinto, Antonio

    2018-02-16

    No study evaluated vascular health markers in subjects with non-alcoholic fatty liver disease (NAFLD) through a combined analysis of reactive hyperemia peripheral arterial tonometry (RH-PAT) and arterial stiffness indexes. We aimed to assess whether NAFLD and its histological severity are associated with impairment of arterial stiffness and RH-PAT indexes in a mixed cohort of patients with biopsy-proven NAFLD. The Kleiner classification was used to grade NAFLD grade. Pulse wave velocity (PWV) and augmentation index (Aix) were used as markers of arterial stiffness, whereas endothelial function was assessed using reactive hyperemia index (RHI). The mini-mental state examination (MMSE) was administered to test cognitive performance. 80 consecutive patients with biopsy-proven NAFLD and 83 controls without fatty liver disease. NAFLD subjects showed significantly lower mean RHI, higher mean arterial stiffness indexes and lower mean MMSE score. Multivariable analysis after correction for BMI, dyslipidaemia, hypertension, sex, diabetes, age and cardiovascular disease showed that BMI, diastolic blood pressure and RHI are significantly associated to NAFLD. Simple linear regression analysis showed among non-alcoholic steatohepatitis (NASH) subjects a significant negative relationship between ballooning grade and MMSE and a significant positive association between Kleiner steatosis grade and augmentation index. Future research will be addressed to evaluate the relationship between inflammatory markers and arterial stiffness and endothelial function indexes in NAFLD subjects. These study will evaluate association between cardiovascular event incidence and arterial stiffness, endothelial and cognitive markers, and they will address the beneficial effects of cardiovascular drugs such as statins and ACE inhibitors on these surrogate markers in NAFLD subjects.

  18. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

    PubMed Central

    Henao-Mejia, Jorge; Elinav, Eran; Jin, Cheng-Cheng; Hao, Liming; Mehal, Wajahat Z.; Strowig, Till; Thaiss, Christoph A.; Kau, Andrew L.; Eisenbarth, Stephanie C.; Jurczak, Michael J.; Camporez, Joao-Paulo; Shulman, Gerald I.; Gordon, Jeffrey I.; Hoffman, Hal M.; Flavell, Richard A.

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different animal models reveal that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. PMID:22297845

  19. Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B.

    PubMed

    Pan, Qin; Zhang, Rui-Nan; Wang, Yu-Qin; Zheng, Rui-Dan; Mi, Yu-Qiang; Liu, Wen-Bin; Shen, Feng; Chen, Guang-Yu; Lu, Jia-Fa; Zhu, Chan-Yan; Zhang, Shu-Yi; Chen, Yi-Ming; Sun, Wan-Lu; Fan, Jian-Gao

    2015-07-28

    To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). Four linked

  20. Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B

    PubMed Central

    Pan, Qin; Zhang, Rui-Nan; Wang, Yu-Qin; Zheng, Rui-Dan; Mi, Yu-Qiang; Liu, Wen-Bin; Shen, Feng; Chen, Guang-Yu; Lu, Jia-Fa; Zhu, Chan-Yan; Zhang, Shu-Yi; Chen, Yi-Ming; Sun, Wan-Lu; Fan, Jian-Gao

    2015-01-01

    AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0

  1. Diet, Microbiota, Obesity, and NAFLD: A Dangerous Quartet

    PubMed Central

    Machado, Mariana Verdelho; Cortez-Pinto, Helena

    2016-01-01

    Recently, the importance of the gut-liver-adipose tissue axis has become evident. Nonalcoholic fatty liver disease (NAFLD) is the hepatic disease of a systemic metabolic disorder that radiates from energy-surplus induced adiposopathy. The gut microbiota has tremendous influences in our whole-body metabolism, and is crucial for our well-being and health. Microorganisms precede humans in more than 400 million years and our guest flora evolved with us in order to help us face aggressor microorganisms, to help us maximize the energy that can be extracted from nutrients, and to produce essential nutrients/vitamins that we are not equipped to produce. However, our gut microbiota can be disturbed, dysbiota, and become itself a source of stress and injury. Dysbiota may adversely impact metabolism and immune responses favoring obesity and obesity-related disorders such as insulin resistance/diabetes mellitus and NAFLD. In this review, we will summarize the latest evidence of the role of microbiota/dysbiota in diet-induced obesity and NAFLD, as well as the potential therapeutic role of targeting the microbiota in this set. PMID:27043550

  2. Prospective evaluation of FibroTest®, FibroMeter®, and HepaScore® for staging liver fibrosis in chronic hepatitis B: comparison with hepatitis C.

    PubMed

    Leroy, Vincent; Sturm, Nathalie; Faure, Patrice; Trocme, Candice; Marlu, Alice; Hilleret, Marie-Noëlle; Morel, Françoise; Zarski, Jean-Pierre

    2014-07-01

    Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of FibroTest®, FibroMeter®, and HepaScore® for liver fibrosis in hepatitis B compared to hepatitis C. 510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR. Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F ⩾3 were underestimated: FibroTest®: 47% vs. 26%, FibroMeter®: 24% vs. 6%, HepaScore®: 41% vs. 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, 95% CI 1.2-19.2, p<0.02) and low γGT (OR 7.3, 95% CI 2.0-27.0, p<0.003) were associated with fibrosis underestimation. Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut-offs. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  3. Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction.

    PubMed

    Yoshihisa, Akiomi; Sato, Yu; Yokokawa, Tetsuro; Sato, Takamasa; Suzuki, Satoshi; Oikawa, Masayoshi; Kobayashi, Atsushi; Yamaki, Takayoshi; Kunii, Hiroyuki; Nakazato, Kazuhiko; Saitoh, Shu-Ichi; Takeishi, Yasuchika

    2018-04-01

    Heart failure with preserved ejection fraction (HFpEF) has several pathophysiological aspects, including stiffness and/or congestion of multiple organs. Poor prognosis is expected in heart failure patients with liver stiffness, which has recently been assessed by non-alcoholic fatty liver disease fibrosis score (NFS; based on aspartate aminotransferase to alanine aminotransferase ratio, platelet counts, and albumin). We aimed to investigate the impact of NFS on prognosis of HFpEF patients, with consideration for the peripheral collagen markers such as procollagen type III peptide (PIIIP), type IV collagen 7S, and hyaluronic acid. We performed a prospective observational study. Consecutive 492 hospitalized HFpEF patients were divided into four groups based on their NFS: first-fourth quartiles (n = 123). The fourth quartile group had the highest levels of PIIIP, type IV collagen 7S, hyaluronic acid, and B-type natriuretic peptide (P<0.001 each). In addition, there were significant positive correlations between PIIIP, type IV collagen 7S, hyaluronic acid, B-type natriuretic peptide, and NFS (P < 0.001 each). In the follow-up period (mean 1107 days), 93 deaths occurred. All-cause mortality increased in all four quartiles (8.1%, 12.2%, 23.6%, and 31.7%, P < 0.001). In the multivariable Cox proportional hazard analysis, NFS was an independent predictor of all-cause mortality in the HFpEF patients. NFS, a novel indicator of liver fibrosis, correlates with circulating systemic markers of fibrosis and congestion and is associated with higher all-cause mortality in HFpEF patients. NFS can be calculated simply and may be a useful tool to assess liver stiffness and prognosis in HFpEF patients. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

  4. Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Wang, Lifeng; Chen, J; Ning, C; Lei, D; Ren, Jun

    2018-05-16

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a common public health problem and a common cause of chronic liver diseases. However, the underlying mechanisms leading to the development and progression of NAFLD remain elusive. Accumulating evidence has depicted an essential role for endoplasmic reticulum (ER) stress in the development of steatosis and later progression into nonalcoholic steatohepatitis and hepatocarcinoma. With the accumulation of unfolded and misfolded proteins in the ER lumen, ER stress is provoked to turn on the unfolded protein response (UPR). ER stress triggers a cascade reaction of transcriptional and translational events that restore ER homeostasis, promoting cell survival and adaptation. However, prolonged ER stress may be transit physiological mechanisms to pathological consequences, including insulin resistance, fat accumulation, inflammation, apoptosis, and autophagy, all of which with important roles in the development of NAFLD. Therefore, understanding the role of ER stress in the onset and pathogenesis of NAFLD is pertinent to the management of this devastating metabolic disease. Here we will summarize available information on recent findings linking ER stress to the pathogenesis of NAFLD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. The Membrane-bound O-Acyltransferase7 rs641738 Variant in Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Di Sessa, Anna; Umano, Giuseppina Rosaria; Cirillo, Grazia; Del Prete, Angela; Iacomino, Roberta; Marzuillo, Pierluigi; Giudice, Emanuele Miraglia Del

    2018-03-29

    The rs641738 polymorphism in the membrane-bound O-acyltransferase domain containing protein 7 (MBOAT7) gene has been associated with increased risk of nonalcoholic fatty liver disease (NAFLD). To investigate the association between the MBOAT7 rs641738 polymorphism and both hepatic steatosis and biochemical markers of liver damage and to evaluate the potential additive effect of this variant and the I148M patatin-like phospholipase domain-containing 3 (PNPLA3) and the rs58542926 transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms. One thousand and 2 obese children were genotyped for MBOAT7, PNPLA3, and TM6SF2 polymorphisms and underwent anthropometrical, ultrasonographic, and biochemical evaluation. Indirect measurement of liver fibrosis (Pediatric NAFLD Fibrosis Index [PNFI]) and a genetic risk score from these polymorphisms were calculated. Carriers of the MBOAT7 T allele showed both higher alanine transaminase (ALT) (P = 0.004) and PNFI values (P = 0.04) than noncarriers. These findings were confirmed also for the carriers of the MBOAT7 T allele polymorphism with hepatic steatosis compared with noncarriers. A higher genetic risk score was associated with higher ALT (P = 0.011) and with an odds ratio (OR) to show elevated ALT of 3.4 (95% CI 1.3-5.5, P = 0.003). Patients belonging to genetic risk score 3 group had an OR to present steatosis of 2.6 (95% CI 1.43-4.83, P = 0.0018) compared with those belonging to lower genetic risk score group. We first demonstrated in childhood obesity the role of the MBOAT7 rs641738 variant on serum ALT and the combined effect of the MBOAT7, PNPLA3, and TM6SF2 variants on NAFLD risk. We also provided the first pediatric association of the MBOAT7 polymorphism with indirect markers of liver fibrosis.

  6. Use of Mac‐2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis

    PubMed Central

    Kamada, Yoshihiro; Ono, Masafumi; Hyogo, Hideyuki; Fujii, Hideki; Sumida, Yoshio; Yamada, Makoto; Mori, Kojiroh; Tanaka, Saiyu; Maekawa, Tomohiro; Ebisutani, Yusuke; Yamamoto, Akiko; Takamatsu, Shinji; Yoneda, Masashi; Kawada, Norifumi; Chayama, Kazuaki; Saibara, Toshiji; Takehara, Tetsuo

    2017-01-01

    In contrast to patients with viral hepatitis, patients with nonalcoholic fatty liver disease (NAFLD) can progress to hepatocellular carcinoma during the initial stages of liver fibrosis. Development and implementation of noninvasive methods for diagnosis and progression prediction are important for effective NAFLD surveillance. Mac‐2 binding protein (Mac‐2bp) is a useful nonalcoholic steatohepatitis (NASH) diagnosis biomarker and a powerful prediction biomarker for NAFLD fibrosis stage. Wisteria floribunda agglutinin (WFA)‐positive Mac‐2bp (WFA+‐M2BP) is a novel serum fibrosis biomarker for chronic hepatitis C that has clinical validity. Mac‐2bp and WFA+‐M2BP are also clinical NAFLD biomarker candidates. We examined the efficacy of Mac‐2bp and WFA+‐M2BP for NAFLD assessment using patients with biopsy‐proven NAFLD (n = 510; NAFLD cohort) and subjects who received a health check‐up (n = 2,122; check‐up cohort). In the NAFLD cohort, we set the fibrosis predicting cutoff values as 1.80 (F1), 2.21 (F2), and 2.24 μg/mL (F3). In the subjects with fatty liver from the check‐up cohort (n = 1,291), the serum Mac‐2bp levels were >1.80 μg/mL in 38.6% of the subjects (n = 498), and >2.24 μg/mL in 24.6% of the subjects (n = 318). The NAFLD cohort results indicated that Mac‐2bp and WFA+‐M2BP were equally useful for NASH diagnosis. During the early stages of fibrosis (F1, F2), the increase in Mac‐2bp was statistically significant but WFA+‐M2BP did not increase. Logistic regression analysis revealed that Mac‐2bp was an independent determinant for the prediction of advanced fibrosis stage (≥F2), even when adjusted for WFA+‐M2BP. Immunohistochemical staining of Mac‐2bp revealed that hepatocytes strongly expressed Mac‐2bp in patients with NAFLD. Conclusion: Our results indicated that hepatocyte‐derived Mac‐2bp would be a useful single biomarker for NASH diagnosis and fibrosis stage prediction in patients with NAFLD. (Hepatology

  7. Developmental origins of NAFLD: a womb with a clue

    PubMed Central

    Wesolowski, Stephanie R.; El Kasmi, Karim C.; Jonscher, Karen R.; Friedman, Jacob E.

    2017-01-01

    Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation. PMID:27780972

  8. In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores.

    PubMed

    Schwimmer, Jeffrey B; Lavine, Joel E; Wilson, Laura A; Neuschwander-Tetri, Brent A; Xanthakos, Stavra A; Kohli, Rohit; Barlow, Sarah E; Vos, Miriam B; Karpen, Saul J; Molleston, Jean P; Whitington, Peter F; Rosenthal, Philip; Jain, Ajay K; Murray, Karen F; Brunt, Elizabeth M; Kleiner, David E; Van Natta, Mark L; Clark, Jeanne M; Tonascia, James; Doo, Edward

    2016-12-01

    No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis. There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005). In a randomized

  9. Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis123

    PubMed Central

    Depner, Christopher M.; Philbrick, Kenneth A.; Jump, Donald B.

    2013-01-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr−/− mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr−/− mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20–22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. PMID:23303872

  10. How Do Doctors Diagnose NAFLD and NASH?

    MedlinePlus

    ... NAFLD and NASH, such as overweight or obesity insulin resistance high levels of triglycerides or abnormal levels of ... NASH, such as an enlarged liver signs of insulin resistance such as darkened skin patches over your knuckles, ...

  11. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

    PubMed

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  12. The NAFLD Index: A Simple and Accurate Screening Tool for the Prediction of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Ichino, Naohiro; Osakabe, Keisuke; Sugimoto, Keiko; Suzuki, Koji; Yamada, Hiroya; Takai, Hiroji; Sugiyama, Hiroko; Yukitake, Jun; Inoue, Takashi; Ohashi, Koji; Hata, Tadayoshi; Hamajima, Nobuyuki; Nishikawa, Toru; Hashimoto, Senju; Kawabe, Naoto; Yoshioka, Kentaro

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common debilitating condition in many industrialized countries that increases the risk of cardiovascular disease. The aim of this study was to derive a simple and accurate screening tool for the prediction of NAFLD in the Japanese population. A total of 945 participants, 279 men and 666 women living in Hokkaido, Japan, were enrolled among residents who attended a health check-up program from 2010 to 2014. Participants with an alcohol consumption > 20 g/day and/or a chronic liver disease, such as chronic hepatitis B, chronic hepatitis C or autoimmune hepatitis, were excluded from this study. Clinical and laboratory data were examined to identify predictive markers of NAFLD. A new predictive index for NAFLD, the NAFLD index, was constructed for men and for women. The NAFLD index for men = -15.5693+0.3264 [BMI] +0.0134 [triglycerides (mg/dl)], and for women = -31.4686+0.3683 [BMI] +2.5699 [albumin (g/dl)] +4.6740[ALT/AST] -0.0379 [HDL cholesterol (mg/dl)]. The AUROC of the NAFLD index for men and for women was 0.87(95% CI 0.88-1.60) and 0.90 (95% CI 0.66-1.02), respectively. The cut-off point of -5.28 for men predicted NAFLD with an accuracy of 82.8%. For women, the cut-off point of -7.65 predicted NAFLD with an accuracy of 87.7%. A new index for the non-invasive prediction of NAFLD, the NAFLD index, was constructed using available clinical and laboratory data. This index is a simple screening tool to predict the presence of NAFLD.

  13. Effects of Natural Products on Fructose-Induced Nonalcoholic Fatty Liver Disease (NAFLD).

    PubMed

    Chen, Qian; Wang, Tingting; Li, Jian; Wang, Sijian; Qiu, Feng; Yu, Haiyang; Zhang, Yi; Wang, Tao

    2017-01-31

    As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (-)-epicatechin) and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

  14. Dietary Mung Bean Protein Reduces Hepatic Steatosis, Fibrosis, and Inflammation in Male Mice with Diet-Induced, Nonalcoholic Fatty Liver Disease.

    PubMed

    Watanabe, Hitoshi; Inaba, Yuka; Kimura, Kumi; Asahara, Shun-Ichiro; Kido, Yoshiaki; Matsumoto, Michihiro; Motoyama, Takayasu; Tachibana, Nobuhiko; Kaneko, Shuichi; Kohno, Mitsutaka; Inoue, Hiroshi

    2017-01-01

    As the prevalence of nonalcoholic fatty liver disease (NAFLD), including steatosis and nonalcoholic steatohepatitis, is increasing, novel dietary approaches are required for the prevention and treatment of NAFLD. We evaluated the potential of mung bean protein isolate (MuPI) to prevent NAFLD progression. In Expts. 1 and 2, the hepatic triglyceride (TG) concentration was compared between 8-wk-old male mice fed a high-fat diet (61% of energy from fat) containing casein, MuPI, and soy protein isolate and an MuPI-constituent amino acid mixture as a source of amino acids (18% of energy) for 4 wk. In Expt. 3, hepatic fatty acid synthase (Fasn) expression was evaluated in 8-wk-old male Fasn-promoter-reporter mice fed a casein- or MuPI-containing high-fat diet for 20 wk. In Expt. 4, hepatic fibrosis was examined in 8-wk-old male mice fed an atherogenic diet (61% of energy from fat, containing 1.3 g cholesterol/100 g diet) containing casein or MuPI (18% of energy) as a protein source for 20 wk. In the high fat-diet mice, the hepatic TG concentration in the MuPI group decreased by 66% and 47% in Expt. 1 compared with the casein group (P < 0.001) and the soy protein isolate group (P = 0.001), respectively, and decreased by 56% in Expt. 2 compared with the casein group (P = 0.011). However, there was no difference between the MuPI-constituent amino acid mixture and casein groups in Expt. 2. In Expt. 3, Fasn-promoter-reporter activity and hepatic TG concentration were lower in the MuPI group than in those fed casein (P < 0.05). In Expt. 4, in mice fed an atherogenic diet, hepatic fibrosis was not induced in the MuPI group, whereas it developed overtly in the casein group. MuPI potently reduced hepatic lipid accumulation in mice and may be a potential foodstuff to prevent NAFLD onset and progression. © 2017 American Society for Nutrition.

  15. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of non-alcoholic fatty-liver disease

    PubMed Central

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L.

    2015-01-01

    Nonalcoholic fatty-liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes non-alcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decrease liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w), or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high sucrose or low Cu diets had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase (Acly) and fatty-acid synthase (Fasn) gene transcription (Fold change >2, p <0.02). Low dietary Cu decreased hepatic and serum Cu (p ≤0.05), promoted lipid peroxidation, and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. PMID:26033743

  16. Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle.

    PubMed

    Dowman, Joanna K; Hopkins, Laurence J; Reynolds, Gary M; Nikolaou, Nikolaos; Armstrong, Matthew J; Shaw, Jean C; Houlihan, Diarmaid D; Lalor, Patricia F; Tomlinson, Jeremy W; Hübscher, Stefan G; Newsome, Philip N

    2014-05-01

    Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Development of Hepatocellular Carcinoma in a Murine Model of Nonalcoholic Steatohepatitis Induced by Use of a High-Fat/Fructose Diet and Sedentary Lifestyle

    PubMed Central

    Dowman, Joanna K.; Hopkins, Laurence J.; Reynolds, Gary M.; Nikolaou, Nikolaos; Armstrong, Matthew J.; Shaw, Jean C.; Houlihan, Diarmaid D.; Lalor, Patricia F.; Tomlinson, Jeremy W.; Hübscher, Stefan G.; Newsome, Philip N.

    2014-01-01

    Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice. PMID:24650559

  18. Higher mobility scores in patients with cystic fibrosis are associated with better lung function.

    PubMed

    Thobani, Aneesha; Alvarez, Jessica A; Blair, Shaina; Jackson, Kaila; Gottlieb, Eric R; Walker, Seth; Tangpricha, Vin

    2015-01-01

    The purpose of this study was to determine whether mobility and physical activity were associated with lung function in adults with cystic fibrosis (CF). This was a prospective cohort observational study in an urban, academic, specialized care center. Participants were ambulatory, nonhospitalized adults with CF. Mobility was assessed monthly by the Life-Space Assessment (LSA) questionnaire and quarterly by pedometer. Lung function was assessed by spirometry. Twenty-seven subjects participated. Subjects recorded mean pedometer steps of 20,213 ± 11,331 over three days and FEV1% predicted of 77.48% ± 22.60% over one year. The LSA score at enrollment was correlated with initial pedometer steps (r = 0.42 and P = 0.03), and mean LSA score over one year was correlated with mean number of steps (r = 0.51 and P = 0.007). LSA mobility and pedometer scores were correlated with FEV1% predicted at enrollment and throughout the study. Mobility and physical activity measured by LSA questionnaire and pedometer are positively associated with lung function in adults with CF. This study confirms the importance of mobility and physical activity and supports the utility of a simple office-based questionnaire as a measure of mobility in adults with CF.

  19. Automated CT Scan Scores of Bronchiectasis and Air Trapping in Cystic Fibrosis

    PubMed Central

    Swiercz, Waldemar; Heltshe, Sonya L.; Anthony, Margaret M.; Szefler, Paul; Klein, Rebecca; Strain, John; Brody, Alan S.; Sagel, Scott D.

    2014-01-01

    Background: Computer analysis of high-resolution CT (HRCT) scans may improve the assessment of structural lung injury in children with cystic fibrosis (CF). The goal of this cross-sectional pilot study was to validate automated, observer-independent image analysis software to establish objective, simple criteria for bronchiectasis and air trapping. Methods: HRCT scans of the chest were performed in 35 children with CF and compared with scans from 12 disease control subjects. Automated image analysis software was developed to count visible airways on inspiratory images and to measure a low attenuation density (LAD) index on expiratory images. Among the children with CF, relationships among automated measures, Brody HRCT scanning scores, lung function, and sputum markers of inflammation were assessed. Results: The number of total, central, and peripheral airways on inspiratory images and LAD (%) on expiratory images were significantly higher in children with CF compared with control subjects. Among subjects with CF, peripheral airway counts correlated strongly with Brody bronchiectasis scores by two raters (r = 0.86, P < .0001; r = 0.91, P < .0001), correlated negatively with lung function, and were positively associated with sputum free neutrophil elastase activity. LAD (%) correlated with Brody air trapping scores (r = 0.83, P < .0001; r = 0.69, P < .0001) but did not correlate with lung function or sputum inflammatory markers. Conclusions: Quantitative airway counts and LAD (%) on HRCT scans appear to be useful surrogates for bronchiectasis and air trapping in children with CF. Our automated methodology provides objective quantitative measures of bronchiectasis and air trapping that may serve as end points in CF clinical trials. PMID:24114359

  20. The hepatoprotective effect of Phyllanthus emblica L. fruit on high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in SD rats.

    PubMed

    Huang, Cheng-Ze; Tung, Yu-Tang; Hsia, Shih-Min; Wu, Chi-Hao; Yen, Gow-Chin

    2017-02-22

    Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, is closely associated with metabolic syndrome and refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. Phyllanthus emblica L. is a rich source of gallic acid and many known medicinally phytochemicals such as tannins, lignans, flavonoids, alkaloids, vitamin C, mucic acid, and ellagic acid. Our previous study has revealed that P. emblica exhibits inhibitory effects on hepatic steatosis and liver fibrosis in vitro, as well as gallic acid improves high fat diet (HFD)-induced dyslipidaemia, hepatosteatosis, and oxidative stress in vivo. Therefore, the aim of this study was to investigate the hepatoprotective effect of the water extract of P. emblica L. fruit (WEPE) on NAFLD in an animal model. The results showed that WEPE could significantly decrease body weight, peritoneal fat and epididymal fat, enhance the antioxidant enzyme activities, and improve steatosis through elevating adiponectin in adipocytes and PPAR-α in the liver as well as lowering SREBP-1c in the liver of rats fed with a high fat diet (HFD). This might be an explanation for the hepatic fat deposition-lowering effect of WEPE. These results demonstrate that WEPE could be beneficial for the amelioration of HFD-induced steatosis.

  1. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Alwahsh, Salamah Mohammad; Gebhardt, Rolf

    2017-04-01

    Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.

  2. CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor.

    PubMed

    Ronan, Nicola J; Einarsson, Gisli G; Twomey, Maria; Mooney, Denver; Mullane, David; NiChroinin, Muireann; O'Callaghan, Grace; Shanahan, Fergus; Murphy, Desmond M; O'Connor, Owen J; Shortt, Cathy A; Tunney, Michael M; Eustace, Joseph A; Maher, Michael M; Elborn, J Stuart; Plant, Barry J

    2018-02-01

    Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Significant improvements in FEV 1 , BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  3. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study.

    PubMed

    Scorletti, Eleonora; Bhatia, Lokpal; McCormick, Keith G; Clough, Geraldine F; Nash, Kathryn; Hodson, Leanne; Moyses, Helen E; Calder, Philip C; Byrne, Christopher D

    2014-10-01

    There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (β=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, β=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).

  4. Deep learning for staging liver fibrosis on CT: a pilot study.

    PubMed

    Yasaka, Koichiro; Akai, Hiroyuki; Kunimatsu, Akira; Abe, Osamu; Kiryu, Shigeru

    2018-05-14

    To investigate whether liver fibrosis can be staged by deep learning techniques based on CT images. This clinical retrospective study, approved by our institutional review board, included 496 CT examinations of 286 patients who underwent dynamic contrast-enhanced CT for evaluations of the liver and for whom histopathological information regarding liver fibrosis stage was available. The 396 portal phase images with age and sex data of patients (F0/F1/F2/F3/F4 = 113/36/56/66/125) were used for training a deep convolutional neural network (DCNN); the data for the other 100 (F0/F1/F2/F3/F4 = 29/9/14/16/32) were utilised for testing the trained network, with the histopathological fibrosis stage used as reference. To improve robustness, additional images for training data were generated by rotating or parallel shifting the images, or adding Gaussian noise. Supervised training was used to minimise the difference between the liver fibrosis stage and the fibrosis score obtained from deep learning based on CT images (F DLCT score) output by the model. Testing data were input into the trained DCNNs to evaluate their performance. The F DLCT scores showed a significant correlation with liver fibrosis stage (Spearman's correlation coefficient = 0.48, p < 0.001). The areas under the receiver operating characteristic curves (with 95% confidence intervals) for diagnosing significant fibrosis (≥ F2), advanced fibrosis (≥ F3) and cirrhosis (F4) by using F DLCT scores were 0.74 (0.64-0.85), 0.76 (0.66-0.85) and 0.73 (0.62-0.84), respectively. Liver fibrosis can be staged by using a deep learning model based on CT images, with moderate performance. • Liver fibrosis can be staged by a deep learning model based on magnified CT images including the liver surface, with moderate performance. • Scores from a trained deep learning model showed moderate correlation with histopathological liver fibrosis staging. • Further improvement are necessary before utilisation in clinical

  5. The predictive value of noninvasive serum markers of liver fibrosis in patients with chronic hepatitis C.

    PubMed

    Gökcan, Hale; Kuzu, Ufuk Barış; Öztaş, Erkin; Saygılı, Fatih; Öztuna, Derya; Suna, Nuretdin; Tenlik, İlyas; Akdoğan, Meral; Kaçar, Sabite; Kılıç, Zeki Mesut Yalın; Kayaçetin, Ertuğrul

    2016-03-01

    This study aims to show the predictive value of noninvasive serum markers on the hepatic fibrosis level. This cross sectional study involves 120 patients with chronic hepatitis C. The noninvasive markers used were as follows: age-platelet index (AP index), cirrhosis discriminant score (CDS), aspartate aminotransferase (AST)-alanine aminotransferase (ALT) ratio (AAR), fibrosis-4 (FIB-4) index, AST-platelet ratio index (APRI), Goteborg University Cirrhosis Index (GUCI), FibroQ, King's score, platelet count. Concurrent liver biopsies were evaluated using the modified Ishak and Knodell scoring systems. In accordance with the Knodell scores, F3-F4 scores were defined as "severe fibrosis," and the modified Ishak scores stage of ≥3 (F3-F6) were defined as "clinically significant fibrosis." Receiver Operating Characteristic (ROC) curve analyses were carried out to compare the noninvasive markers with hepatic fibrosis level. Mean age of the patients was 51.7±11.6. A total of 10 patients (8.3%) with Knodell scores and 24 patients (20%) with modified Ishak scores were evaluated to have ≥F3 hepatic fibrosis. ROC analyses with the Knodell and modified Ishak scores were as follows: AP index=0.61-0.57, CDS=0.66-0.55, AAR=0.60-0.49, FIB-4=0.70-0.68, APRI=0.67-0.72, GUCI=0.66-0.72, FibroQ=0.64-0.54, King's score=0.68-0.54, platelet count=0.61-0.55. We found that APRI, FIB-4, King's score, and GUCI can be used to determination patients with mild fibrosis with a high negative predictive value and in the differentiation of severe/significant fibrosis from mild to moderate fibrosis.

  6. Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.

    PubMed

    Cobbina, Enoch; Akhlaghi, Fatemeh

    2017-05-01

    Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.

  7. A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis.

    PubMed

    Calès, Paul; Boursier, Jérôme; Oberti, Frédéric; Moal, Valérie; Fouchard Hubert, Isabelle; Bertrais, Sandrine; Hunault, Gilles; Rousselet, Marie Christine

    2018-04-01

    Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis-stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi-FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeter V2G ) with those of a test targeted for cirrhosis (CirrhoMeter V2G ). In the derivation CHC population, we first compared Multi-FibroMeter V2G to FibroMeter V2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis-stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeter V2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi-FibroMeter V2G and FibroMeter V2G were the following: cirrhosis AUROC, 0.906 versus 0.878 ( P < 0.001; versus CirroMeter V2G , 0.897, P = 0.014); Obuchowski index, 0.795 versus 0.791 ( P = 0.059); classification, 86.0% versus 82.1% ( P < 0.001); significant fibrosis AUROC, 0.833 versus 0.832 ( P = 0

  8. Non-Alcoholic Fatty Liver Disease (NAFLD): new challenge for general practitioners and important burden for health authorities?

    PubMed

    Ahmed, Mohamed H; Abu, Emmanuel O; Byrne, Christopher D

    2010-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of hepatic dysfunction encountered in general practice. A large proportion of individuals with type 2 diabetes and the metabolic syndrome develop NAFLD. NAFLD is associated with severe insulin resistance and increased risk of cardiovascular disease and can progress to non-alcoholic steato-hepatitis, liver cirrhosis and cancer. Currently the only known effective treatments for NAFLD are lifestyle changes including stable weight loss and a diet low in calories. General practitioners will increasingly play a key role in dealing with this evolving but serious epidemic of NAFLD and associated metabolic complications. However, success will depend on the appropriate systems and mechanisms being in place in primary care and the proper motivation, support and education of the patient. This review provides the primary care physician with: (a) a step-by step guide of how to identify NAFLD, (b) information to exclude common other causes of liver fat accumulation and (c) additional insight into relationships between NAFLD and other conditions such as obesity, cardiovascular disease and type 2 diabetes. Copyright © 2010 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

  9. Lund-Mackay and modified Lund-Mackay score for sinus surgery in children with cystic fibrosis.

    PubMed

    Do, Bao Anh; Lands, Larry C; Mascarella, Marco A; Fanous, Amanda; Saint-Martin, Christine; Manoukian, John J; Nguyen, Lily H P

    2015-08-01

    Patients with cystic fibrosis (CF) frequently present with severe sinonasal disease often requiring radiologic imaging and surgical intervention. Few studies have focused on the relationship between radiologic scoring systems and the need for sinus surgery in this population. The objective of this study is to evaluate the Lund-Mackay (LM) and modified Lund-Mackay (m-LM) scoring systems in predicting the need for sinus surgery or revision surgery in patients with CF. We performed a retrospective chart review of CF patients undergoing computed tomography (CT) sinus imaging at a tertiary care pediatric hospital from 1995 to 2008. Patient scans were scored using both the LM and m-LM systems and compared to the rate of sinus surgery or revision surgery. Receiver-operator characteristics curves (ROC) were used to analyze the radiological scoring systems. A total of 41 children with CF were included in the study. The mean LM score for patients undergoing surgery was 17.3 (±3.1) compared to 11.5 (±6.2) for those treated medically (p<0.01). For the m-LM, the mean score of patients undergoing surgery was 20.3 (±3.5) and 13.5 (±7.3) for those medically treated (p<0.01). Using a ROC curve with a threshold score of 13 for the LM, the sensitivity was 89.3% (95% CI of 72-98) and specificity of 69.2% (95% CI of 39-91). At an optimal score of 19, the m-LM system produced a sensitivity of 67.7% (95% CI of 48-84) and specificity of 84.6% (95% CI of 55-98). The modified Lund-Mackay score provides a high specificity while the Lund-Mackay score a high sensitivity for CF patients who required sinus surgery. The combination of both radiologic scoring systems can potentially predict the need for surgery in this population. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Pharmacological and antioxidant actions of garlic and.or onion in non-alcoholic fatty liver disease (NAFLD) in rats.

    PubMed

    El-Din, Sayed H Seif; Sabra, Abdel-Nasser A; Hammam, Olfat A; Ebeid, Fatma A; El-Lakkany, Naglaa M

    2014-08-01

    Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of fat-induced liver injury, ranging from mild steatosis to cirrhosis and liver failure. This study investigates the hepatoprotective properties of garlic and onion in NAFLD rat model. Ninety male Sprague-Dawley rats were randomly divided into 9 groups; normal (I), NAFLD induced with high fat diet (HFD; II), NAFLD switched to regular diet (RD; III), NAFLD-HFD or NAFLD-RD treated with garlic (IV, V), onion (VI, VII) or the combined garlic+onion (VIII, IX) respectively. A NAFLD rat model was established by feeding the animals with a high-fat diet for 12 wk. These animals were then treated with garlic or/and onion or vehicle for 8 wk (weeks 13-20) and then killed to obtain serum samples and liver tissues. Liver histology, lipids, parameters of oxidative stress, TNF-α and TGF-β were measured. The liver in NAFLD-HFD showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration. Serum levels of ALT, AST, ALP, leptin, cholesterol, triglycerides, TNF-α, TGF-β and hepatic MDA' were significantly increased (P < 0.05) compared with normal group. This was accompanied with reduction of hepatic GSH, GR, GPx, GST, SOD and serum adiponectin. These changes were to a less degree in NAFLD-RD group. Combined administration of garlic+onion produced a better and significant decrease in liver steatosis, serum liver enzymes, oxidative markers and lipid peroxidation versus each one alone. In the same time, NAFLD-induced inflammation was also mitigated via reduction of TNF-α and TGF-β. In addition, these results were better in the group IX versus group VIII.

  11. Non-Alcoholic Fatty Liver Disease (NAFLD) - Pathogenesis, Classification, and Effect on Drug Metabolizing Enzymes and Transporters

    PubMed Central

    Cobbina, Enoch; Akhlaghi, Fatemeh

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5 % of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a ‘three-hit’ process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations. PMID:28303724

  12. Non-Alcoholic Fatty Liver Disease (NAFLD) in children and adolescents with Prader-Willi Syndrome (PWS).

    PubMed

    Fintini, D; Inzaghi, E; Colajacomo, M; Bocchini, S; Grugni, G; Brufani, C; Cappa, M; Nobili, V; Cianfarani, S; Crinò, A

    2016-06-01

    We tested the hypothesis that patients with Prader-Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P < 0.05), whereas G2 stage was significantly more frequent in control patients (P < 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children. © 2015 World Obesity.

  13. Hepatocellular carcinoma in a mouse model fed a choline-deficient, L-amino acid-defined, high-fat diet.

    PubMed

    Ikawa-Yoshida, Ayae; Matsuo, Saori; Kato, Atsuhiko; Ohmori, Yusuke; Higashida, Atsuko; Kaneko, Eiji; Matsumoto, Masahiko

    2017-08-01

    Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, details of the liver-specific molecular mechanisms responsible for the NAFLD-NASH-HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis-associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis. © 2017 The Authors. International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).

  14. Diffusing capacity and forced vital capacity in 5,003 asbestos-exposed workers: relationships to interstitial fibrosis (ILO profusion score) and pleural thickening.

    PubMed

    Miller, Albert; Warshaw, Raphael; Nezamis, James

    2013-12-01

    Asbestosis is an interstitial lung disease whose radiographic severity has long been graded by the International Labour Office (ILO) profusion score. Its effect on pulmonary function is further impacted by asbestos related pleural thickening. This report aims to describe the relationships between radiographic grading of interstitial and pleural fibrosis and a key test of pulmonary function, the diffusing capacity, which measures gas exchange and has rarely been assessed in large groups, and to confirm the relationship to an independent test of pulmonary function, the vital capacity, which measures a mechanical property of the lungs. The data were derived from a survey during the period 1997-2004 of 5,003 workers (all white males) exposed to asbestos in various trades. Tests included chest radiographs read by a certified expert ("B") reader, forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLco). Cigarette smoking was adjusted for in the predictive equation for DLCO . Workers were evaluated at a mobile facility at work sites in four southern states. Both diffusing capacity and vital capacity were negatively correlated with profusion score over the full spectrum of radiographic severity. ILO profusion scores 0/1 (conventionally classified as normal) and 1/0 (conventionally classified as abnormal) were associated with similar diffusing capacity and vital capacity values. The highest profusion scores were associated with a greater proportionate decrease in diffusing capacity than in FVC. Both tests showed an effect of pleural fibrosis. Both radiographic severity graded by the profusion score and pleural thickening are correlated with two independent measures of pulmonary function. FVC (which had been reported in smaller work forces) and DLCO (which has not been reported). Both measures show a decrease from normal to intermediate (0/1, 1/0) scores and a further decrease with greater scores, demonstrating the consistency of radiographic and functional

  15. Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism

    PubMed Central

    Jegatheesan, Prasanthi; De Bandt, Jean-Pascal

    2017-01-01

    Among various factors, such as an unhealthy diet or a sedentarity lifestyle, excessive fructose consumption is known to favor nonalcoholic fatty liver disease (NAFLD), as fructose is both a substrate and an inducer of hepatic de novo lipogenesis. The present review presents some well-established mechanisms and new clues to better understand the pathophysiology of fructose-induced NAFLD. Beyond its lipogenic effect, fructose intake is also at the onset of hepatic inflammation and cellular stress, such as oxidative and endoplasmic stress, that are key factors contributing to the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Beyond its hepatic effects, this carbohydrate may exert direct and indirect effects at the peripheral level. Excessive fructose consumption is associated, for example, with the release by the liver of several key mediators leading to alterations in the communication between the liver and the gut, muscles, and adipose tissue and to disease aggravation. These multifaceted aspects of fructose properties are in part specific to fructose, but are also shared in part with sucrose and glucose present in energy–dense beverages and foods. All these aspects must be taken into account in the development of new therapeutic strategies and thereby to better prevent NAFLD. PMID:28273805

  16. Predicting survival of patients with idiopathic pulmonary fibrosis using GAP score: a nationwide cohort study.

    PubMed

    Lee, Sang Hoon; Kim, Song Yee; Kim, Dong Soon; Kim, Young Whan; Chung, Man Pyo; Uh, Soo Taek; Park, Choon Sik; Jeong, Sung Hwan; Park, Yong Bum; Lee, Hong Lyeol; Shin, Jong Wook; Lee, Eun Joo; Lee, Jin Hwa; Jegal, Yangin; Lee, Hyun Kyung; Kim, Yong Hyun; Song, Jin Woo; Park, Sung Woo; Park, Moo Suk

    2016-10-18

    The clinical course of idiopathic pulmonary fibrosis (IPF) varies widely. Although the GAP model is useful for predicting mortality, survivals have not yet been validated for each GAP score. We aimed to elucidate how prognosis is related to GAP score and GAP stage in IPF patients. The Korean Interstitial Lung Disease Study Group conducted a national survey to evaluate various characteristics in IPF patients from 2003 to 2007. Patients were diagnosed according to the 2002 criteria of the ATS/ERS. We enrolled 1,685 patients with IPF; 1,262 had undergone DL CO measurement. Patients were stratified based on GAP score (0-7): GAP score Group 0 (n = 26), Group 1 (n = 150), Group 2 (n = 208), Group 3 (n = 376), Group 4 (n = 317), Group 5 (n = 138), Group 6 (n = 39), and Group 7 (n = 8). Higher GAP score and GAP stage were associated with a poorer prognosis (p < 0.001, respectively). Survival time in Group 3 was lower than those in Groups 1 and 2 (p = 0.043 and p = 0.039, respectively), and higher than those in groups 4, 5, and 6 (p = 0.043, p = 0.032, and p = 0.003, respectively). Gender, age, and DL CO (%) differed significantly between Groups 2 and 3. All four variables in the GAP model differed significantly between Groups 3 and 4. The GAP system showed significant predictive ability for mortality in IPF patients. However, prognosis in IPF patients with a GAP score of 3 were significantly different from those in the other stage I groups and stage II groups of Asian patients.

  17. Multi-dimensional scores to predict mortality in patients with idiopathic pulmonary fibrosis undergoing lung transplantation assessment.

    PubMed

    Fisher, Jolene H; Al-Hejaili, Faris; Kandel, Sonja; Hirji, Alim; Shapera, Shane; Mura, Marco

    2017-04-01

    The heterogeneous progression of idiopathic pulmonary fibrosis (IPF) makes prognostication difficult and contributes to high mortality on the waitlist for lung transplantation (LTx). Multi-dimensional scores (Composite Physiologic index [CPI], [Gender-Age-Physiology [GAP]; RIsk Stratification scorE [RISE]) demonstrated enhanced predictive power towards outcome in IPF. The lung allocation score (LAS) is a multi-dimensional tool commonly used to stratify patients assessed for LTx. We sought to investigate whether IPF-specific multi-dimensional scores predict mortality in patients with IPF assessed for LTx. The study included 302 patients with IPF who underwent a LTx assessment (2003-2014). Multi-dimensional scores were calculated. The primary outcome was 12-month mortality after assessment. LTx was considered as competing event in all analyses. At the end of the observation period, there were 134 transplants, 63 deaths, and 105 patients were alive without LTx. Multi-dimensional scores predicted mortality with accuracy similar to LAS, and superior to that of individual variables: area under the curve (AUC) for LAS was 0.78 (sensitivity 71%, specificity 86%); CPI 0.75 (sensitivity 67%, specificity 82%); GAP 0.67 (sensitivity 59%, specificity 74%); RISE 0.78 (sensitivity 71%, specificity 84%). A separate analysis conducted only in patients actively listed for LTx (n = 247; 50 deaths) yielded similar results. In patients with IPF assessed for LTx as well as in those actually listed, multi-dimensional scores predict mortality better than individual variables, and with accuracy similar to the LAS. If validated, multi-dimensional scores may serve as inexpensive tools to guide decisions on the timing of referral and listing for LTx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Influence of lifestyle habits, nutritional status and insulin resistance in NAFLD.

    PubMed

    Malavolti, Marcella; Battistini, Nino Carlo; Miglioli, Lucia; Bagni, Ilaria; Borelli, Luca; Marino, Mariano; Scaglioni, Federica; Bellentani, Stefano

    2012-01-01

    Non alcoholic fatty liver disease (NAFLD) is associated with obesity, diabetes and insulin resistance (IR). The aim of our study was to assess the relationship between IR, anthropometry, lifestyle habits, resting energy expenditure (REE) and degree of fatty liver at ultrasound in 48 overweight patients with NAFLD as compared to 24 controls without fatty liver, matched for age. Nutritional status, alcohol intake and physical activity were assessed by skinfold thickness measurements, a 7-day diary, and SenseWear armband (SWA). REE was assessed by both SWA (REE-SWA) and a Vmax metabolic cart (REE-Vmax). Fatty liver was measured by US and the Doppler Power Index was calculated. IR was assessed using the HOMA index. There was significant correlation between waist circumference, HOMA, Doppler power index and fatty liver grade at US. Multivariate analysis showed that alteration of waist circumference, Doppler power index, and HOMA were the major significant predictors of fatty liver. Our data demonstrated a significant association between NAFLD and central adiposity and IR.

  19. Routine blood tests to predict liver fibrosis in chronic hepatitis C.

    PubMed

    Hsieh, Yung-Yu; Tung, Shui-Yi; Lee, Kamfai; Wu, Cheng-Shyong; Wei, Kuo-Liang; Shen, Chien-Heng; Chang, Te-Sheng; Lin, Yi-Hsiung

    2012-02-28

    To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C, compared with other noninvasive tests. This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), AST to platelet ratio index, cirrhosis discriminant score, age-platelet index (API), Pohl score, FIB-4 index, and Lok's model were calculated and compared. FibroQ, FIB-4, AAR, API and Lok's model results increased significantly as fibrosis advanced (analysis of variance test: P < 0.001). FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests. FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

  20. FIB-4 and imaging for measuring fibrosis in hepatitis C virus.

    PubMed

    Turner, Barbara J; Liang, Yuanyuan; Singal, Amit G

    2017-02-01

    Noninvasive measures are widely used to assess fibrosis and may be used to prioritize hepatitis C virus (HCV) treatment. We examined risks for likely fibrosis in patients with chronic HCV infection using fibrosis-4 (FIB-4) and imaging. A HCV screening program diagnosed chronic HCV in patients born from 1945 to 1965 admitted in a safety net hospital. Likely fibrosis was based on FIB-4 (≥1.45) alone or combined with imaging interpreted as fibrosis or cirrhosis. Logistic regression was used to calculate adjusted odds ratios (AORs) for demographic, clinical, and insurance factors associated with each outcome. Using multiple linear regression among patients with likely fibrosis, we examined associations with higher Model for End-Stage Liver Disease (MELD) scores. Using FIB-4 alone, 57% (83/146) of patients had likely fibrosis versus 43% (63/148) using FIB-4 plus imaging. Obesity/overweight and Hispanic ethnicity had over three-fold to four-fold higher AORs for fibrosis, respectively, based on FIB-4 plus imaging, but both AORs were only two-fold greater with FIB-4 alone. Being uninsured was significantly associated with fibrosis based on FIB-4 alone [AOR=2.40 (95% confidence interval 1.01-5.70)] but not with imaging. Heavy alcohol use and older age were associated with higher AORs of fibrosis with both measures (all P<0.004). MELD scores were ∼3 points higher for uninsured patients, regardless of measure (both P<0.05). Using FIB-4 plus imaging to identify fibrosis in chronic HCV, higher risks are seen for Hispanics and overweight/obese individuals than using FIB-4 alone. Higher MELD scores at diagnosis for the uninsured indicate delayed access to care.

  1. Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

    PubMed Central

    Cui, Jeffrey; Chen, Chi-Hua; Lo, Min-Tzu; Schork, Nicholas; Bettencourt, Ricki; Gonzalez, Monica P; Bhatt, Archana; Hooker, Jonathan; Shaffer, Katherine; Nelson, Karen E; Long, Michelle T; Brenner, David A; Sirlin, Claude B; Loomba, Rohit

    2016-01-01

    Introduction Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic risk factors including hypertension and dyslipidemia, and may progress to liver fibrosis. Previous studies have shown that hepatic steatosis and fibrosis are heritable but whether they have a significant shared gene effect is unknown. This study aimed to examine the shared gene effects between hepatic steatosis, fibrosis, and their associations with metabolic risk factors. Methods This is a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from Southern California. Hepatic steatosis was assessed with MRI-proton density fat fraction (MRI-PDFF) and hepatic fibrosis was assessed with magnetic resonance elastography (MRE). A standard bivariate twin AE model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects (A) and individual-specific environmental effects (E). Genetic correlations (rG) estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Results The mean (±SD) age and BMI were 47.1 (±21.9) years and 26.9 (±6.5) kg/m2, respectively. 20% (26/130) of the cohort had hepatic steatosis (MRI-PDFF ≥5%) and 8.2% (10/122) had hepatic fibrosis (MRE ≥3Kpa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, hemoglobin A1c (HbA1c), and low high-density lipoprotein (HDL) had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, HOMA-IR, insulin, HbA1c, and low HDL had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% CI: 0.716–1, p<0.0001). Conclusions Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. PMID:27315352

  2. A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis

    PubMed Central

    Boursier, Jérôme; Oberti, Frédéric; Moal, Valérie; Fouchard Hubert, Isabelle; Bertrais, Sandrine; Hunault, Gilles; Rousselet, Marie Christine

    2018-01-01

    Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis‐stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi‐FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeterV2G) with those of a test targeted for cirrhosis (CirrhoMeterV2G). In the derivation CHC population, we first compared Multi‐FibroMeterV2G to FibroMeterV2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis‐stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeterV2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi‐FibroMeterV2G and FibroMeterV2G were the following: cirrhosis AUROC, 0.906 versus 0.878 (P < 0.001; versus CirroMeterV2G, 0.897, P = 0.014); Obuchowski index, 0.795 versus 0.791 (P = 0.059); classification, 86.0% versus 82.1% (P < 0.001); significant fibrosis AUROC, 0.833 versus 0.832 (P = 0

  3. [Non-alcoholic fatty liver disease (NAFLD) in patients with metabolic syndrome and type 2 diabetes mellitus. Pathomechanism, new diagnostic markers].

    PubMed

    Kieć-Wilk, Beata; Klupa, Tomasz; Dembińska-Kieć, Aldona

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a complex of a wide spectrum of liver pathology--from steatosis alone, to cirrhosis and liver cancer. The pathogenic concept of NAFLD covers overnutrition with fatty acids, underactivity. Insulin resistance is believed to play the main role in this process. NAFLD is mostly related to visceral adiposity, metabolic syndrome and type 2 diabetes melitus. The presented work is a review of in vitro and in vivo modern studies, as well as clinical observations on molecular mechanisms leading to development and progress of NAFLD. Up till today their is no treatment od NAFLD, and this pathology is not benign--it may lead to patients' death in 10 years. The clinical approach to NAFLD is prevention of it's development. The manuscript is a review of new biochemical markers allowing for early detection of metabolic disorders leading to NAFLD development, thus to sufficient prevention of this pathology in patients.

  4. Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

    PubMed

    Black, Sylvester M; Woodley, Frederick W; Tumin, Dmitry; Mumtaz, Khalid; Whitson, Bryan A; Tobias, Joseph D; Hayes, Don

    2016-04-01

    Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

  5. Molecular signature of adipose tissue in patients with both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS)

    PubMed Central

    2013-01-01

    Background Polycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only. Methods We included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann–Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed. Results The total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT). Conclusion An androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute

  6. Molecular signature of adipose tissue in patients with both non-alcoholic fatty liver disease (NAFLD) and polycystic ovarian syndrome (PCOS).

    PubMed

    Baranova, Ancha; Tran, Thuy Phuong; Afendy, Arian; Wang, Lei; Shamsaddini, Amirhossein; Mehta, Rohini; Chandhoke, Vikas; Birerdinc, Aybike; Younossi, Zobair M

    2013-05-31

    Polycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only. We included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann-Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed. The total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT). An androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute to the prothrombotic state observed

  7. Automated Quantitative Computed Tomography Versus Visual Computed Tomography Scoring in Idiopathic Pulmonary Fibrosis: Validation Against Pulmonary Function.

    PubMed

    Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Nair, Arjun; Karwoski, Ronald; Raghunath, Sushravya M; Walsh, Simon L F; Wells, Athol U; Hansell, David M

    2016-09-01

    The aim of the study was to determine whether a novel computed tomography (CT) postprocessing software technique (CALIPER) is superior to visual CT scoring as judged by functional correlations in idiopathic pulmonary fibrosis (IPF). A total of 283 consecutive patients with IPF had CT parenchymal patterns evaluated quantitatively with CALIPER and by visual scoring. These 2 techniques were evaluated against: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco), carbon monoxide transfer coefficient (Kco), and a composite physiological index (CPI), with regard to extent of interstitial lung disease (ILD), extent of emphysema, and pulmonary vascular abnormalities. CALIPER-derived estimates of ILD extent demonstrated stronger univariate correlations than visual scores for most pulmonary function tests (PFTs): (FEV1: CALIPER R=0.29, visual R=0.18; FVC: CALIPER R=0.41, visual R=0.27; DLco: CALIPER R=0.31, visual R=0.35; CPI: CALIPER R=0.48, visual R=0.44). Correlations between CT measures of emphysema extent and PFTs were weak and did not differ significantly between CALIPER and visual scoring. Intriguingly, the pulmonary vessel volume provided similar correlations to total ILD extent scored by CALIPER for FVC, DLco, and CPI (FVC: R=0.45; DLco: R=0.34; CPI: R=0.53). CALIPER was superior to visual scoring as validated by functional correlations with PFTs. The pulmonary vessel volume, a novel CALIPER CT parameter with no visual scoring equivalent, has the potential to be a CT feature in the assessment of patients with IPF and requires further exploration.

  8. Histopathological aspects of liver under variable food restriction: has the intense one-week food restriction a protective effect on non-alcoholic-fatty-liver-disease (NAFLD) development?

    PubMed

    Makovicky, Peter; Tumova, Eva; Volek, Zdenek; Makovicky, Pavol; Vodickova, Ludmila; Slyskova, Jana; Svoboda, Miroslav; Rejhova, Alexandra; Vodicka, Pavel; Samasca, Gabriel; Kralova, Alena; Nagy, Melinda; Mydlarova-Blascakova, Marta; Poracova, Jana

    2014-12-01

    Non-alcoholic-fatty-liver-disease (NAFLD) is a clinicopathologic entity characterized by a variety of hepatic injury patterns without significant alcohol use. It has a close association with obesity, so treatment includes weight loss, control of insulin sensitivity, interventions directed at inflammation and fibrosis. There is a certain relationship between the grade and duration of food restriction and hepatic function. The objective of this work was to describe the relationship between biochemistry, autoantibodies, insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and liver morphology in experimental rabbit groups with food restriction as compared to controls with ad libitum food (ADL) income. The experiment was performed on a total of 24 rabbits of a weaning age of 25-81 days. The first group (R1) was restricted between 32 and 39 days of age to 50 g of food per rabbit a day. The second group (R2) was also restricted between 32 and 39 days, but the rabbits received 65 g of food per rabbit a day. At the end of the experiment, the blood and liver samples were collected at necropsy. NAFLD has developed in all three groups. There was any autoantibody positivity in all three groups. IGF-I is moderately higher in R1 and R2 group, as compared to the control group (P > 0.05). IGFBP-3 is without statistical significance in all three groups. Alkaline phosphatase (ALP) is the only liver biochemical parameter that has significantly increased following food restriction (P > 0.039). Single one-week restriction has any protective effect on NAFLD development. Copyright © 2014 Elsevier GmbH. All rights reserved.

  9. Prevalence and Indicators of Portal Hypertension in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Mendes, Flavia D.; Suzuki, Ayako; Sanderson, Schuyler O.; Lindor, Keith D.; Angulo, Paul

    2012-01-01

    Background & Aims Little is known about the prevalence and severity of portal hypertension in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the prevalence and non-invasive predictors of portal hypertension in patients with NAFLD. Methods Signs of portal hypertension, including esophageal varices, splenomegaly, portosystemic encephalopathy, and ascites where investigated in 354 patients with NAFLD. Results One-hundred patients had portal hypertension at the time of NAFLD diagnosis (28.2%), 88 of these with septal fibrosis or cirrhosis (88%). Fibrosis stage correlated with presence (r=0.41, P<.0001) and number of findings (r=0.48, P=.006) of portal hypertension. Of the 204 patients with no or mild fibrosis (stages 0–2), 12 had portal hypertension (6%); they had a significantly higher grade of steatosis, based on biopsy analysis, compared to the 192 patients without portal hypertension (94%). Thrombocytopenia, hyperbilirubinemia, cirrhosis, and obesity were independently associated with portal hypertension. Esophageal varices were found in 57 of the 128 patients undergoing endoscopic screening (44.5%) and independently associated with thrombocytopenia, type 2 diabetes, and splenomegaly. Conclusions Signs of portal hypertension are present in 25% of patients at the time of diagnosis of NAFLD; most had advanced fibrosis or cirrhosis. Portal hypertension can occur in a small proportion of patients with mild or no fibrosis and is associated with the extent of steatosis. Features of advanced liver disease and insulin resistance might identify patients with NAFLD and portal hypertension, and those expected to derive the most benefit from endoscopic screening for esophageal varices. PMID:22610002

  10. Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis.

    PubMed

    Lee, Hyo Young; Jun, Dae Won; Kim, Hyun Jung; Oh, Hyunwoo; Saeed, Waqar Khalid; Ahn, Hyeongsik; Cheung, Ramsey C; Nguyen, Mindie H

    2018-03-20

    A number of clinical trials reported varying effects of cholesterol lowering agents in nonalcoholic fatty liver disease (NAFLD) patients. We, therefore, assessed the changes in hepatic steatosis and NAFLD activity score (NAS) after treatment with cholesterol lowering agents in NAFLD patients by metaanalysis. The Cochrane Library, the MEDLINE, and the Embase databases were searched until May 2015, without any language restrictions, for randomized controlled trials (RCTs) and nonrandomized studies (NRSs). Additional references were obtained from review of bibliography of relevant articles. The quality of evidence was assessed using the grading of recommendations assessment, development and evaluation guidelines. Three RCTs (n = 98) and two NRSs (n = 101) met our study inclusion criteria (adult, NAFLD, liver biopsy). Liver biopsy was performed in all five studies, but only the three studies reported NAS. Ezetimibe significantly decreased NAS (standardized mean difference [SMD], -0.30; 95% confidence interval [CI], -0.57 to -0.03) but not hepatic steatosis in RCT (SMD, -0.1; 95% CI, -0.53 to 0.32), while the effect was significant for both NAS and intrahepatic content in NRSs (SMD, -3.0; 95% CI, -6.9 to 0.91). Ezetimibe decreased NAS without improving hepatic steatosis.

  11. Automated morphometry provides accurate and reproducible virtual staging of liver fibrosis in chronic hepatitis C

    PubMed Central

    Calès, Paul; Chaigneau, Julien; Hunault, Gilles; Michalak, Sophie; Cavaro-Menard, Christine; Fasquel, Jean-Baptiste; Bertrais, Sandrine; Rousselet, Marie-Christine

    2015-01-01

    Background: Liver fibrosis staging provides prognostic value, although hampered by observer variability. We used digital analysis to develop diagnostic morphometric scores for significant fibrosis, cirrhosis and fibrosis staging in chronic hepatitis C. Materials and Methods: We automated the measurement of 44 classical and new morphometric descriptors. The reference was histological METAVIR fibrosis (F) staging (F0 to F4) on liver biopsies. The derivation population included 416 patients and liver biopsies ≥20 mm-length. Two validation population included 438 patients. Results: In the derivation population, the area under the receiver operating characteristic (AUROC) for clinically significant fibrosis (F stage ≥2) of a logistic score combining 5 new descriptors (stellar fibrosis area, edge linearity, bridge thickness, bridge number, nodularity) was 0.957. The AUROC for cirrhosis of 6 new descriptors (edge linearity, nodularity, portal stellar fibrosis area, portal distance, granularity, fragmentation) was 0.994. Predicted METAVIR F staging combining 8 morphometric descriptors agreed well with METAVIR F staging by pathologists: κ = 0.868. Morphometric score of clinically significant fibrosis had a higher correlation with porto-septal fibrosis area (rs = 0.835) than METAVIR F staging (rs = 0.756, P < 0.001) and the same correlations with fibrosis biomarkers, e.g., serum hyaluronate: rs = 0.484 versus rs = 0.476 for METAVIR F (P = 0.862). In the validation population, the AUROCs of clinically significant fibrosis and cirrhosis scores were, respectively: 0.893 and 0.993 in 153 patients (biopsy < 20 mm); 0.955 and 0.994 in 285 patients (biopsy ≥ 20 mm). The three morphometric diagnoses agreed with consensus expert reference as well as or better than diagnoses by first-line pathologists in 285 patients, respectively: significant fibrosis: 0.733 versus 0.733 (κ), cirrhosis: 0.900 versus 0.827, METAVIR F: 0.881 versus 0.865. Conclusion: The new automated

  12. Reduced circulating levels of sTWEAK are associated with NAFLD and may affect hepatocyte triglyceride accumulation.

    PubMed

    Lozano-Bartolomé, J; Llauradó, G; Rodriguez, M M; Fernandez-Real, J M; Garcia-Fontgivell, J F; Puig, J; Maymó-Masip, E; Vendrell, J; Chacón, M R

    2016-09-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD. We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case-control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation. We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001-0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes. Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human

  13. Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD.

    PubMed

    Pierantonelli, Irene; Rychlicki, Chiara; Agostinelli, Laura; Giordano, Debora Maria; Gaggini, Melania; Fraumene, Cristina; Saponaro, Chiara; Manghina, Valeria; Sartini, Loris; Mingarelli, Eleonora; Pinto, Claudio; Buzzigoli, Emma; Trozzi, Luciano; Giordano, Antonio; Marzioni, Marco; Minicis, Samuele De; Uzzau, Sergio; Cinti, Saverio; Gastaldelli, Amalia; Svegliati-Baroni, Gianluca

    2017-09-22

    Non-Alcoholic Fatty Liver Disease (NAFLD) represents the most common form of chronic liver injury and can progress to cirrhosis and hepatocellular carcinoma. A "multi-hit" theory, involving high fat diet and signals from the gut-liver axis, has been hypothesized. The role of the NLRP3-inflammasome, which senses dangerous signals, is controversial. Nlrp3 -/- and wild-type mice were fed a Western-lifestyle diet with fructose in drinking water (HFHC) or a chow diet. Nlrp3 -/- -HFHC showed higher hepatic expression of PPAR γ2 (that regulates lipid uptake and storage) and triglyceride content, histological score of liver injury and greater adipose tissue inflammation. In Nlrp3 -/- -HFHC, dysregulation of gut immune response with impaired antimicrobial peptides expression, increased intestinal permeability and the occurrence of a dysbiotic microbiota led to bacterial translocation, associated with higher hepatic expression of TLR4 (an LPS receptor) and TLR9 (a receptor for double-stranded bacterial DNA). After antibiotic treatment, gram-negative species and bacterial translocation were reduced, and adverse effects restored both in liver and adipose tissue. In conclusion, the combination of a Western-lifestyle diet with innate immune dysfunction leads to NAFLD progression, mediated at least in part by dysbiosis and bacterial translocation, thus identifying new specific targets for NAFLD therapy.

  14. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease

    PubMed Central

    Perumpail, Brandon J; Khan, Muhammad Ali; Yoo, Eric R; Cholankeril, George; Kim, Donghee; Ahmed, Aijaz

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis. PMID:29307986

  15. Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.

    PubMed

    Farrell, Geoffrey C; Mridha, Auvro R; Yeh, Matthew M; Arsov, Todor; Van Rooyen, Derrick M; Brooling, John; Nguyen, Tori; Heydet, Deborah; Delghingaro-Augusto, Viviane; Nolan, Christopher J; Shackel, Nicholas A; McLennan, Susan V; Teoh, Narci C; Larter, Claire Z

    2014-08-01

    Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways. All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF-fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF-α, IL-12, IL-4, IL-10 was increased (but not IFN-γ, IL-1β, IL-17A), and IL-4:IFN-γ ratio (indicating Th-2 predominance) was higher in HF-fed foz/foz C57BL6/J than BALB/c mice. In livers of HF-fed foz/foz C57BL6/J mice, TGF-β was unaltered but PDGFα and CTGF were increased in association with enhanced α-SMA, CD147and MMP activity. In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Assessment of Portal Venous and Hepatic Artery Haemodynamic Variation in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

    PubMed

    Balasubramanian, Padhmini; Boopathy, Vinoth; Govindasamy, Ezhumalai; Venkatesh, Basavaiya Prabhu

    2016-08-01

    Non-Alcoholic Fatty Liver Disease (NAFLD) has various spectrums of liver diseases like isolated fatty liver, steatohepatitis and cirrhosis usually progressing in a linear fashion. In this process they are known to cause certain haemodynamic changes in the portal flow and hepatic artery flow. The aim of the study was to study these haemodynamic changes in patients with NAFLD and to correlate it with the disease severity. Ninety patients diagnosed to have NAFLD based on ultrasound abdomen (30 each in grade1, grade2 and grade3 NAFLD) and 30 controls (Normal liver on ultrasound abdomen) were subjected to portal vein and hepatic artery Doppler study. Peak maximum velocity (Vmax), Peak minimum velocity (Vmin), Mean flow velocity (MFV), and Vein pulsality index (VPI) of the portal vein and hepatic artery resistivity index (HARI) of the hepatic artery were the doppler parameters which were assessed. Liver span was also assessed both for the fatty liver and controls. The mean Vmax, Vmin, MFV and VPI of the portal vein in patients with NAFLD was 12.23±1.74cm/sec, 9.31±1.45cm/sec, 10.76±1.48cm/sec, and 0.24±0.04 as compared to 14.05±2.43cm/sec, 10.01±2.27cm/sec, 12.23±2.47cm/sec, 0.3±0.08 in controls respectively. All these differences were statistically significant except for Vmin. The Mean HARI in patients with fatty liver was 0.65±0.06 when compared to controls of 0.75±0.06 (p=0.001). HARI (r-value of -0.517) had a better negative correlation followed by VPI (r-value of -0.44) and Vmax (r-value of -0.293) with the severity of NAFLD. MFV had a very weak negative correlation (r-value of -0.182) with the severity of NAFLD. The Vmax, MFV, VPI and HARI were significantly less when compared to controls suggesting a reduced portal flow and an increased hepatic arterial flow in patients with NAFLD. Among the parameters, HARI correlated better with the severity of NAFLD followed by VPI.

  17. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update

    PubMed Central

    Athyros, Vasilios G; Tziomalos, Konstantinos; Katsiki, Niki; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is considered to be an independent cardiovascular disease (CVD) risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis (NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease (CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness (AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis (mainly by simple non-invasive tests), CKD, and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above. PMID:26078558

  18. Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis

    PubMed Central

    Jolley, Caroline J.; Elston, Caroline; Moxham, John; Rafferty, Gerrard F.

    2016-01-01

    The electromyogram recorded from the diaphragm (EMGdi) and parasternal intercostal muscle using surface electrodes (sEMGpara) provides a measure of neural respiratory drive (NRD), the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max) obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline) corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02) and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04) were lower in the healthy individuals compared to the cystic fibrosis

  19. Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis.

    PubMed

    Reilly, Charles C; Jolley, Caroline J; Elston, Caroline; Moxham, John; Rafferty, Gerrard F

    2016-01-01

    The electromyogram recorded from the diaphragm (EMG di ) and parasternal intercostal muscle using surface electrodes (sEMG para ) provides a measure of neural respiratory drive (NRD), the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV 1 ) 53.5% predicted) and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMG di and sEMG para were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max) obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMG di % max and sEMG para % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMG di % max and sEMG para % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMG di % max and sEMG para % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline) corresponding levels of EMG di % max (20.2±12% versus 32.15±15%, p=0.02) and sEMG para % max (18.9±8% versus 29.2±15%, p=0.04) were lower in the healthy individuals compared to the cystic

  20. Screening for Nonalcoholic Fatty Liver Disease in Inflammatory Bowel Diseases: A Cohort Study Using Transient Elastography.

    PubMed

    Saroli Palumbo, Chiara; Restellini, Sophie; Chao, Che-Yung; Aruljothy, Achuthan; Lemieux, Carolyne; Wild, Gary; Afif, Waqqas; Lakatos, Peter L; Bitton, Alain; Cocciolillo, Sila; Ghali, Peter; Bessissow, Talat; Sebastiani, Giada

    2018-06-07

    Inflammatory bowel disease (IBD) patients may be at risk for nonalcoholic fatty liver disease (NAFLD) due to chronic inflammation, hepatotoxic drugs, and alteration of the gut microbiota. Prospective data using accurate diagnostic methods are lacking. We prospectively investigated prevalence and predictors of NAFLD and liver fibrosis by transient elastography (TE) with associated controlled attenuation parameter (CAP) in IBD patients as part of a routine screening program. NAFLD was defined as CAP ≥248 dB/m. Significant liver fibrosis (stage 2 or higher out of 4) was defined as TE measurement ≥7.0 kPa. Predictors of NAFLD and significant liver fibrosis were determined by logistic regression analysis. A total of 384 patients (mean age 42.4 years, 45.0% male, 64.6% with Crohn's disease) with no significant alcohol intake were included. Prevalence of NAFLD and significant liver fibrosis was 32.8% and 12.2%, respectively. Independent predictors of NAFLD were older age (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.15-1.82), higher body mass index (BMI; aOR, 1.31; 95% CI, 1.20-1.42) and higher triglycerides (aOR, 1.45; 95% CI, 1.01-2.09). Significant liver fibrosis was independently predicted by older age (aOR, 1.38; 95% CI, 1.12-1.64) and higher BMI (aOR, 1.14; 95% CI, 1.07-1.23). Extrahepatic diseases were more common in IBD patients with NAFLD compared with those without, namely chronic kidney disease (10.3 vs 2.3%; P < 0.001) and cardiovascular diseases (11.3 vs 4.7%; P = 0.02). NAFLD diagnosed by TE with CAP is a frequent comorbidity in IBD patients and is associated with extrahepatic diseases. Noninvasive screening strategies could help early diagnosis and initiation of interventions, including weight loss, correction of dyslipidemia, and linkage to care. 10.1093/ibd/izy200_video1izy200.video15794817619001.

  1. An inexpensive and worldwide available digital image analysis technique for histological fibrosis quantification in chronic hepatitis C.

    PubMed

    Campos, C F F; Paiva, D D; Perazzo, H; Moreira, P S; Areco, L F F; Terra, C; Perez, R; Figueiredo, F A F

    2014-03-01

    Hepatic fibrosis staging is based on semiquantitative scores. Digital imaging analysis (DIA) appears more accurate because fibrosis is quantified in a continuous scale. However, high cost, lack of standardization and worldwide unavailability restrict its use in clinical practice. We developed an inexpensive and widely available DIA technique for fibrosis quantification in hepatitis C, and here, we evaluate its reproducibility and correlation with semiquantitative scores, and determine the fibrosis percentage associated with septal fibrosis and cirrhosis. 282 needle biopsies staged by Ishak and METAVIR scores were included. Images of trichrome-stained sections were captured and processed using Adobe(®) Photoshop(®) CS3 and Adobe(®) Bridge(®) softwares. The percentage of fibrosis (fibrosis index) was determined by the ratio between the fibrosis area and the total sample area, expressed in pixels calculated in an automated way. An excellent correlation between DIA fibrosis index and Ishak and METAVIR scores was observed (Spearman's r = 0.95 and 0.92; P < 0.001, respectively). Excellent intra-observer reproducibility was observed in a randomly chosen subset of 39 biopsies with an intraclass correlation index of 0.99 (95% CI, 0.95-0.99). The best cut-offs associated with septal fibrosis and cirrhosis were 6% (AUROC 0.97, 95% CI, 0.95-0.99) and 27% (AUROC 1.0, 95% CI, 0.99-1), respectively. This new DIA technique had high correlation with semiquantitative scores in hepatitis C. This method is reproducible, inexpensive and available worldwide allowing its use in clinical practice. The incorporation of DIA technique provides a more complete evaluation of fibrosis adding the quantification to architectural patterns. © 2013 John Wiley & Sons Ltd.

  2. A cystic fibrosis handbook for teachers.

    PubMed

    Ryan, L L; Williams, J K

    1996-01-01

    The purposes of this project were to (1) develop a handbook on cystic fibrosis for elementary school teachers and to (2) pilot this handbook with a group of teachers and school nurses. The project used a descriptive survey design in which parents, teachers, and school nurses of 14 elementary-age children with cystic fibrosis were recruited from one cystic fibrosis clinic. Interest in using the handbook with their child's teachers was elicited from parents; also, interest in using the handbook was obtained by open-ended questions in a mailed survey sent to teachers and school nurses. Levels of teacher and school nurse knowledge were measured with a true/false pretest and posttest instrument. All parents expressed a desire to use the handbook with their child's teachers. Sixty-seven percent of the teachers and 89% of the school nurses returned the survey, and all endorsed the use of the handbook in their classrooms or schools. Comparison of the pretest and posttest scores from the teachers revealed an increase in teachers' knowledge. Scores on pretest and posttest measures from school nurses were high at each testing time. Results support the use of a printed handbook to promote knowledge of cystic fibrosis in teachers and to support communication among nurses, parents, and teachers.

  3. Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis.

    PubMed

    Zou, An; Magee, Nancy; Deng, Fengyan; Lehn, Sarah; Zhong, Cuncong; Zhang, Yuxia

    2018-06-01

    Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP ) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro , we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun-mediated transcriptional repression of Shp Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C-C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

    PubMed

    Takyar, Varun; Nath, Anand; Beri, Andrea; Gharib, Ahmed M; Rotman, Yaron

    2017-09-01

    Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with nonalcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. We conducted a cross-sectional study of subjects who were classified as healthy volunteers between 2011 and 2015 and had no known liver disease. Subjects were classified as presumed NAFLD (pNF; alanine aminotransferase [ALT] level ≥ 20 for women or ≥ 31 for men and body mass index [BMI] > 25 kg/m 2 ), healthy non-NAFLD controls (normal ALT and BMI), or indeterminate. A total of 3160 subjects participated as healthy volunteers in 149 clinical trials (1-29 trials per subject); 1732 of these subjects (55%) had a BMI > 25 kg/m 2 and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%), and these subjects were older than healthy control subjects and had higher triglycerides, low-density lipoprotein cholesterol, and HbA1c and lower high-density lipoprotein cholesterol (P < 0.001 for all). The 149 trials included 101 non-interventional, 33 interventional, and 15 vaccine trials. The impact on study validity of recruiting NAFLD subjects as controls was estimated as likely, probable, and unlikely in 10, 41, and 98 trials, respectively. The proportion of pNF subjects (28%-29%) did not differ by impact. Only 14% of trials used both BMI and ALT for screening. ALT cutoffs for screening were based on local reference values. Grade 3-4 ALT elevations during the study period were rare but more common in pNF subjects than in healthy control subjects (4 versus 1). NAFLD is common and often overlooked in volunteers for clinical trials, despite its potential impact on subject safety and validity of study findings. Increased awareness of NAFLD prevalence and stricter ALT cutoffs may ameliorate

  5. Coffee consumption and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis.

    PubMed

    Wijarnpreecha, Karn; Thongprayoon, Charat; Ungprasert, Patompong

    2017-02-01

    Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health concern. Coffee might have a protective effect against NAFLD. However, the results of previous reports are conflicting. Therefore, we carried out this meta-analysis to summarize all available data. This study consisted of two meta-analyses. The first meta-analysis included observational studies comparing the risk of NAFLD in patients who did and did not drink coffee. The second analysis included studies comparing the risk of liver fibrosis between NAFLD patients who did and did not drink coffee. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated. Out of 355 articles, five studies fulfilled our eligibility criteria and were included in the analysis. The risk of NAFLD in patients who drank coffee was significantly lower than that in patients who did not pooled RR 0.71 (95% CI, 0.60-0.85). We also found a significantly decreased risk of liver fibrosis among NAFLD patients who drank coffee compared with those who did not, with a pooled RR of 0.70 (95% CI, 0.60-0.82). However, it should be noted that the definition of regular coffee consumption varied between studies, which is the main limitation of this meta-analysis. Our study found a significantly decreased risk of NAFLD among coffee drinkers and significantly decreased risk of liver fibrosis among patients with NAFLD who drank coffee on a regular basis. Whether consumption of coffee could be considered a preventative measure against NAFLD needs further investigations.

  6. Halofuginone can worsen liver fibrosis in bile duct obstructed rats.

    PubMed

    Van de Casteele, Marc; Roskams, Tania; Van der Elst, Ingrid; van Pelt, Jos F; Fevery, Johan; Nevens, Frederik

    2004-10-01

    Halofuginone (HF) is an antifibrotic agent in rat models of liver fibrosis caused by repetitive intoxications. A beneficial effect of HF on a biliary type of liver fibrosis has not been proven yet. Bile duct-obstructed rats were given HF from the moment of obstruction onwards and compared with no treatment. After 3 weeks, respectively, 6 weeks, aminopyrine breath test (ABT) and haemodynamic measurements including of portal pressure were carried out. Liver pieces were taken for Sirius red quantitative scoring, as well as for semiquantitative determinations of collagen type I and III RNA levels. ABT was significantly worse in HF-treated rats as compared with no treatment (P=0.02). Haemodynamic data and collagen type I and III determinations were not significantly different between groups. Biliary fibrosis scores were significantly higher in HF-treated rats as compared with no treatment (P=0.03). More Sirius red staining was associated with more proliferation of bile ductules. HF may worsen biliary fibrosis. This contrasts sharply with antifibrotic effects in other models of liver fibrosis. Distinctive cellular mechanisms in biliary fibrosis may explain this discrepancy. One should be cautious for chronic application of HF in man with cholestasis.

  7. Non-alcoholic fatty liver disease (Nafld) in obese children- effect of refined carbohydrates in diet.

    PubMed

    Félix, Deise Rosa; Costenaro, Fabiola; Gottschall, Catarina Bertaso Andreatta; Coral, Gabriela Perdomo

    2016-11-15

    The incidence of childhood obesity has increased progressively and, associated with this, nonalcoholic fatty liver disease (NAFLD) has often been diagnosed in this age group. To determine the risk factors associated with NAFLD in obese children, with special emphasis on diet. A prospective cross-sectional study was conducted with obese children referred to the endocrinology outpatient clinic. Questions about dietary habits and physical activity were applied. In addition, two 24 h food recalls were collected. Anthropometric measurements, biochemical tests and abdominal ultrasound were obtained. The study was approved by the institutional review board of Irmandade Santa Casa de Misericórdia de Porto Alegre Hospital (ISCMPA). A 5% statistical significance level was considered statistically significant. Of 55 patients initially allocated, 39 were evaluated and 8 (20.5%) had a diagnosis of NAFLD, which was more prevalent among boys (87.5%). Logistic regression analysis showed that the predictive factors independently associated with the presence of NAFLD were male gender (OR: 1.62; 95% CI: 1.08- 2.44; p = 0.038); high amount of refined carbohydrates in the diet (OR: 2.17; 95% CI: 1.05 - 6.82; p = 0.038) and absence of routine physical activity (OR: 3.35; 95% CI:1.97 - 0.006; p = 0.006). The prevalence of NAFLD in obese children in our series was high. Furthermore, the high amount of refined carbohydrates in the diet, male gender and sedentary lifestyle were significant risk factors for its occurrence.

  8. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease123

    PubMed Central

    Guerrerio, Anthony L; Colvin, Ryan M; Schwartz, Amy K; Molleston, Jean P; Murray, Karen F; Diehl, AnnaMae; Mohan, Parvathi; Schwimmer, Jeffrey B; Lavine, Joel E; Torbenson, Michael S

    2012-01-01

    Background: There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency. Objective: We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features. Design: We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN–developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9–13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicine's definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI. Results: Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women. Conclusion: Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT

  9. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease.

    PubMed

    Guerrerio, Anthony L; Colvin, Ryan M; Schwartz, Amy K; Molleston, Jean P; Murray, Karen F; Diehl, AnnaMae; Mohan, Parvathi; Schwimmer, Jeffrey B; Lavine, Joel E; Torbenson, Michael S; Scheimann, Ann O

    2012-04-01

    There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency. We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features. We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicine's definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI. Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women. Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635.

  10. Association between obstructive sleep apnea and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

    PubMed

    Jin, Shanshan; Jiang, Suwen; Hu, Airong

    2018-01-15

    The relationship between obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) has been an issue of great concern. The primary purpose of this study was to determine the influence of OSA on the levels of liver enzymes including alanine transaminase (ALT) and aspartate transaminase (AST). The secondary purpose was to estimate the effect of OSA on the histological lesions of NAFLD, such as steatosis, lobular inflammation, ballooning degeneration, fibrosis, as well as NAFLD activity score (NAS). A systematic literature review using PubMed, Cochrane Library, Embase, and Ovid technologies from January 2007 to April 2017 was performed, and 9 studies (2272 participants) that met the selection criteria were evaluated. The present study demonstrated that OSA was related to ALT levels, but no significant correlation was found with AST levels. The subgroup analysis showed that the severity of OSA was associated with ALT levels, not with AST levels. The meta-regression analysis showed that age, sex, homeostasis model assessment, diabetes mellitus, body mass index, and waist circumference did not have a significant effect on the levels of ALT and AST. OSA was also found to be significantly correlated with steatosis, lobular inflammation, ballooning degeneration, and fibrosis, but was not correlated with NAS. OSA was independently related to the development and progression of NAFLD in terms of liver enzyme level and histological alterations. Future studies should investigate the possible relevant mechanisms, thereby guiding the exploration of potential therapeutic implications to prevent the progression of disease.

  11. Nonalcoholic Fatty Liver Disease and Fibrosis in Youth Taking Psychotropic Medications: Literature Review, Case Reports, and Management.

    PubMed

    Gracious, Barbara L; Bhatt, Ramona; Potter, Carol

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic because of the greater prevalence of obesity. Despite implications for youth with severe mental disorders, little has been published in the psychiatric literature about this increasingly common medical comorbidity. The goals of this article are to: 1) provide an overview of the epidemiology and pathophysiology of NAFLD, including progression to nonalcoholic steatohepatitis (NASH); 2) describe two clinical cases illustrating difficulties faced in management; and 3) review screening recommendations, differential diagnosis, and monitoring and intervention approaches. A literature review was conducted, including guidelines and recommendations, with case presentations including case and control liver histology biopsy photographs. NAFLD in childhood and adolescence, as a precursor to NASH, progresses to fibrosis in a small percentage of youth, leading to risk for early onset cirrhosis and the need for transplantation. The cases presented raise concern that youth with severe mental health disorders, already at greater risk for obesity and its sequelae, may be at higher risk for progression to NASH, potentially because of greater rates of weight gain on top of overweight or obese status, and to liver metabolism changes from psychotropic medications favoring fat deposition. Patients with rapid weight gain into the overweight or obese categories, or who develop elevated liver transaminases that persist across 3-6 months, should be screened or referred for screening by their psychotropic-providing clinicians for early detection, diagnosis, and co-management by a pediatric gastroenterologist, to decrease risk of progression to NASH, which is reversible if early and sufficient lifestyle change results in significant weight loss. There is urgent need for controlled research on the relationships among weight gain, psychotropic medications, ultrasound and biopsy findings, and rates of progression to NAFLD and

  12. Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

    PubMed

    Boursier, J; Anty, R; Vonghia, L; Moal, V; Vanwolleghem, T; Canivet, C M; Michalak, S; Bonnafous, S; Michielsen, P; Oberti, F; Iannelli, A; Van Gaal, L; Patouraux, S; Blanchet, O; Verrijken, A; Gual, P; Rousselet, M-C; Driessen, A; Hunault, G; Bertrais, S; Tran, A; Calès, P; Francque, S

    2018-05-01

    The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. To develop a new blood test specifically dedicated for this new diagnostic target of interest. Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved. © 2018 John Wiley & Sons Ltd.

  13. Coffee and tea consumption in relation with non-alcoholic fatty liver and metabolic syndrome: A systematic review and meta-analysis of observational studies.

    PubMed

    Marventano, Stefano; Salomone, Federico; Godos, Justyna; Pluchinotta, Francesca; Del Rio, Daniele; Mistretta, Antonio; Grosso, Giuseppe

    2016-12-01

    Diet plays a role in the onset and progression of metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS). We aimed to systematically review and perform quantitative analyses of results from observational studies on coffee/tea consumption and NAFLD or MetS. A Medline and Embase search was performed to retrieve articles published up to March 2015. We used a combination of the keywords "coffee", "caffeine", "tea", "non-alcoholic fatty liver disease", "non-alcoholic steatohepatitis", "metabolic syndrome". Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by random-effects model. Seven studies assessed coffee consumption in NAFLD patients. Fibrosis scores were reported in four out of seven; all four studies revealed an inverse association of coffee intake with fibrosis severity, although the lack of comparable exposure and outcomes did not allow to perform pooled analysis. Seven studies met the inclusion criteria to be included in the meta-analysis on coffee consumption and MetS. Individuals consuming higher quantities of coffee were less like to have MetS (RR = 0.87, 95% CI: 0.79-0.96). However, the association of coffee and individual components of MetS was not consistent across the studies. Pooled analysis of six studies exploring the association between tea consumption and MetS resulted in decreased odds of MetS for individuals consuming more tea (RR = 0.83, 95% CI: 0.73-0.95). Studies on coffee and NAFLD suggest that coffee consumption could have a protective role on fibrosis. Both coffee and tea consumption are associated with less likelihood of having MetS but further research with better designed studies is needed. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  14. Non-alcoholic fatty liver disease–From the cardiologist perspective

    PubMed Central

    Sîrbu, Oana; Floria, Mariana; Dăscălița, Petru; Şorodoc, Victorița; Şorodoc, Laurențiu

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes a range of disorders characterized by excess accumulation of triglycerides within the liver. While simple steatosis may be clinically stable, non-alcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. NAFLD is globally considered a significant health concern not only because of its incidence but also because of its economic impact. The fact that NAFLD is associated with cardiovascular disease is widely recognized, as well as the fact that NAFLD patient mortality rises when such an association is present. In particular, NAFLD is associated with coronary and carotid atherosclerosis, endothelial dysfunction and arterial rigidity, ventricles function, valves morphology, congestive heart failure, and arrhythmias (especially atrial fibrillation). Additionally, the hypercoagulability status in NAFLD patient may be suggested by the presence of inflammatory and coagulation markers. In order to differentiate between milder forms and the more severe ones that necessitate aggressive therapy, individualized risk scores may be used. This narrative review will analyze and interpret the papers published in PubMed in the last 16 years, in an attempt to expand our understanding of the NASH as a possible cardiovascular risk factor. PMID:27389154

  15. Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans

    PubMed Central

    Wang, Xiaoliang; Gawrieh, Samer; Gamazon, Eric R.; Athinarayanan, Shaminie; Liu, Yang-Lin; Darlay, Rebecca; Cordell, Heather J; Daly, Ann K

    2017-01-01

    The increased expression of PNPLA3148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10−8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers. PMID:27744419

  16. Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans.

    PubMed

    Liu, Wanqing; Anstee, Quentin M; Wang, Xiaoliang; Gawrieh, Samer; Gamazon, Eric R; Athinarayanan, Shaminie; Liu, Yang-Lin; Darlay, Rebecca; Cordell, Heather J; Daly, Ann K; Day, Chris P; Chalasani, Naga

    2016-10-13

    The increased expression of PNPLA3 148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL ( p = 6.6×10 -8 ) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3 148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers.

  17. Correlation of blood glucose, serum chemerin and insulin resistance with NAFLD in patients with type 2 diabetes mellitus.

    PubMed

    Zhang, Zhengjun; Wang, Jijun; Wang, Hongmei

    2018-03-01

    Non-alcoholic fatty liver disease (NAFLD) is a form of clinical syndrome characterized by the fatty degeneration in liver histology and should be further investigated. The aim of the study was to investigate the effects of blood glucose, serum chemerin and insulin resistance on non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus to provide a basis for the prevention and treatment thereof. In total, 300 patients with type 2 diabetes mellitus treated and admitted into the Endocrinology Department of our hospital from June 2015 to June 2017 were enrolled and divided into the simple type 2 diabetes mellitus (group A) and concurrent NAFLD (group B) groups. The sex, age, body mass index (BMI), blood pressure, blood biochemical indexes and chemerin level were compared between the two groups. The patients in group B were further divided into the mild fatty liver (group B1), moderate fatty liver (group B2) and severe fatty liver (group B3) groups. The sex, age, BMI blood pressure, blood biochemical indexes and chemerin level were also compared among the three groups. Finally, the risk factors of type 2 diabetes mellitus complicated by NAFLD were analyzed via logistic regression. The BMI, fasting plasma glucose (FPG), 2 h post-prandial plasma glucose (2hPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-β indexes and serum chemerin level in group B were significantly higher than those in group A (P<0.05 or P<0.01). Notably, the aggravation of NAFLD, the aforementioned indexes were obviously increased (P<0.05 or P<0.01). The regression analysis revealed that BMI, FPG, TC, LDL-c, FINS, HOMA-IR and chemerin were risk factors of concurrent NAFLD. Thus, type 2 diabetes mellitus complicated by NAFLD is closely associated with severe glucose-lipid metabolism disorder and insulin

  18. Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models.

    PubMed

    Yu, Wencheng; Guo, Fang; Song, Xiaoxia

    2017-12-01

    Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown. This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay. After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p < 0.05) significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-β1, TNF-α and PDGF, but the expression of Cav-1 was higher (p < 0.05). Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p < 0.05). Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores (r = -0.506, p < 0.01; r = -0.676, p < 0.01) as well as expression of TGF-β1, TNF-α and PDGF (r = -0.590, p < 0.01; r = -0.530, p < 0.01; r = -0.553, p < 0.01). Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and

  19. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms.

    PubMed

    Iacono, Anna; Raso, Giuseppina Mattace; Canani, Roberto Berni; Calignano, Antonio; Meli, Rosaria

    2011-08-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and in children. NAFLD is characterized by aberrant lipid storage in hepatocytes (hepatic steatosis) and inflammatory progression to nonalcoholic steatohepatitis. Evidences so far suggest that intrahepatic lipid accumulation does not always derive from obesity. Gut microbiota has been considered as a regulator of energy homeostasis and ectopic fat deposition, suggesting its implications in metabolic diseases. Probiotics are live microbial that alter the enteric microflora and have beneficial effects on human health. Although the molecular mechanisms of probiotics have not been completely elucidated yet, many of their effects have proved to be beneficial in NAFLD, including the modulation of the intestinal microbiota, an antibacterial substance production, an improved epithelial barrier function and a reduced intestinal inflammation. Given the close anatomical and functional correlation between the bowel and the liver, and the immunoregulatory effects elicited by probiotics, the aim of this review is to summarize today's knowledge about probiotics in NAFLD, focusing in particular on their molecular and biochemical mechanisms, as well as highlighting their efficacy as an emerging therapeutic strategy to treat this condition. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Liver enzymes and histology in obese patients with obstructive sleep apnea.

    PubMed

    Kallwitz, Eric R; Herdegen, James; Madura, James; Jakate, Shriram; Cotler, Scott J

    2007-01-01

    Recent studies have shown an association between obstructive sleep apnea (OSA) and elevated liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the current study was to compare biochemical and histologic findings in patients with NAFLD as a function of OSA status. Subjects consisted of 85 patients who had a sleep study followed by a liver biopsy performed at the time of obesity surgery. The diagnosis of OSA was based on an apnea hypopnea index of >/=15. Demographic and laboratory data were collected retrospectively. Liver biopsies were systematically evaluated for features of NAFLD including degree of steatosis, inflammation, and fibrosis. All but one patient had histologic evidence of NAFLD and 51% of the study population had OSA. A higher proportion of patients with OSA had elevated alanine aminotransferase levels (13/39) compared with those without OSA (3/34) (P=0.01). Only 19% of subjects had fibrosis on liver biopsy and still fewer (5%) had bridging fibrosis or cirrhosis. There was a trend toward a higher prevalence of OSA in patients with evidence of progressive liver disease, as indicated by inflammation plus fibrosis (11/15), compared with those with inflammation alone (22/48) (P=0.06). In obese patients with NAFLD, OSA was associated with elevated alanine aminotransferase levels and a trend toward histologic evidence of progressive liver disease.

  1. PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress.

    PubMed

    Carpino, Guido; Pastori, Daniele; Baratta, Francesco; Overi, Diletta; Labbadia, Giancarlo; Polimeni, Licia; Di Costanzo, Alessia; Pannitteri, Gaetano; Carnevale, Roberto; Del Ben, Maria; Arca, Marcello; Violi, Francesco; Angelico, Francesco; Gaudio, Eugenio

    2017-11-17

    Pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by predisposing genetic variations, dysmetabolism, systemic oxidative stress, and local cellular and molecular cross-talks. Patatin-like phospholipase domain containing 3 (PNPLA3) gene I148M variant is a known determinant of NAFLD. Aims were to evaluate whether PNPLA3 I148M variant was associated with a specific histological pattern, hepatic stem/progenitor cell (HpSC) niche activation and serum oxidative stress markers. Liver biopsies were obtained from 54 NAFLD patients. The activation of HpSC compartment was evaluated by the extension of ductular reaction (DR); hepatic stellate cells, myofibroblasts (MFs), and macrophages were evaluated by immunohistochemistry. Systemic oxidative stress was assessed measuring serum levels of soluble NOX2-derived peptide (sNOX2-dp) and 8-isoprostaglandin F 2α (8-iso-PGF 2α ). PNPLA3 carriers showed higher steatosis, portal inflammation and HpSC niche activation compared to wild-type patients. DR was correlated with NAFLD activity score (NAS) and fibrosis score. Serum 8-iso-PGF 2α were significantly higher in I148M carriers compared to non-carriers and were correlated with DR and portal inflammation. sNox2-dp was correlated with NAS and with HpSC niche activation. In conclusion, NAFLD patients carrying PNPLA3 I148M are characterized by a prominent activation of HpSC niche which is associated with a more aggressive histological pattern (portal fibrogenesis) and increased oxidative stress.

  2. Enhanced liver fibrosis test using ELISA assay accurately discriminates advanced stage of liver fibrosis as determined by transient elastography fibroscan in treatment naïve chronic HCV patients.

    PubMed

    Omran, Dalia; Yosry, Ayman; Darweesh, Samar K; Nabeel, Mohammed M; El-Beshlawey, Mohammed; Saif, Sameh; Fared, Azza; Hassany, Mohamed; Zayed, Rania A

    2018-02-01

    Evaluation of liver fibrosis stage is crucial in the assessment of chronic HCV patients, regarding decision to start treatment and during follow-up. Our aim was to assess the validity of the enhanced liver fibrosis (ELF) score in discrimination of advanced stage of liver fibrosis in naïve chronic HCV patients. We prospectively evaluated liver fibrosis stage in one hundred eighty-one naïve chronic HCV Egyptian patients by transient elastography (TE)-FibroScan. Patients were categorized into mild to moderate fibrosis (≤F2) group and advanced fibrosis (≥F3) group. The ELF score components, hyaluronic acid (HA), amino-terminal propeptide of type-III-procollagen (PIIINP) and tissue inhibitor of metalloproteinase type-1 (TIMP-1), were done using ELISA test. The mean values of ELF and its individual components significantly correlated with the hepatic fibrosis stage as measured by TE-FibroScan (P value 0.001). ELF cutoff value of 9.8 generated a sensitivity of 77.8%, specificity of 67.1%, area under the receiver operator characteristic curve (AUROC) of 0.76 with 95% confidence interval [CI] (0.68-0.83) for detecting advanced fibrosis (F ≥ 3). ELF panel is a good, reliable noninvasive test and showed comparable results to TE-FibroScan in detecting liver fibrosis stage in treatment naïve chronic HCV patients.

  3. Chest computed tomography scores are predictive of survival in patients with cystic fibrosis awaiting lung transplantation.

    PubMed

    Loeve, Martine; Hop, Wim C J; de Bruijne, Marleen; van Hal, Peter T W; Robinson, Phil; Aitken, Moira L; Dodd, Jonathan D; Tiddens, Harm A W M

    2012-05-15

    Up to one-third of patients with cystic fibrosis (CF) awaiting lung transplantation (LTX) die while waiting. Inclusion of computed tomography (CT) scores may improve survival prediction models such as the lung allocation score (LAS). This study investigated the association between CT and survival in patients with CF screened for LTX. Clinical data and chest CTs of 411 patients with CF screened for LTX between 1990 and 2005 were collected from 17 centers. CTs were scored with the Severe Advanced Lung Disease (SALD) four-category scoring system, including the components infection/inflammation (INF), air trapping/hypoperfusion (AT), normal/hyperperfusion (NOR), and bulla/cysts (BUL). The volume of each component was computed using semiautomated software. Survival analysis included Kaplan-Meier curves and Cox regression models. Three hundred and sixty-six (186 males) of 411 patients entered the waiting list (median age, 23 yr; range, 5-58 yr). Subsequently, 67 of 366 (18%) died while waiting, 263 of 366 (72%) underwent LTX, and 36 of 366 (10%) were awaiting LTX at the census date. INF and LAS were significantly associated with waiting list mortality in univariate analyses. The multivariate Cox model including INF and LAS grouped in tertiles, and comparing tertiles 2 and 3 with tertile 1, showed waiting list mortality hazard ratios of 1.62 (95% confidence interval [95% CI], 0.78-3.36; P = 0.19) and 2.65 (95% CI, 1.35-5.20; P = 0.005) for INF, and 1.42 (95% CI, 0.63-3.24; P = 0.40), and 2.32 (95% CI, 1.17-4.60; P = 0.016) for LAS, respectively. These results indicated that INF and LAS had significant, independent predictive value for survival. CT score INF correlates with survival, and adds to the predictive value of LAS.

  4. Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.

    PubMed

    Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

    2015-08-01

    Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH.

  5. Obstructive Sleep Apnea is associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology

    PubMed Central

    Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y.; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

    2015-01-01

    Background and Aims Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the United States. Existing data on the relationship between OSA and NAFLD is conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Methods Two hundred thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5% macrovesicular steatosis, lobular inflammation and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Results Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 U/L vs. 37.7 U/L, P=0.0007; AST 31.7 U/L vs. 20.5 U/L, P=0.0007). OSA was associated with the presence of NASH and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P =0.03 OR, 2.01; 95%, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. Conclusions OSA is associated with elevated aminotransferase levels, the presence of NASH and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH. PMID:25840922

  6. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease.

    PubMed

    Pais, Raluca; Rusu, Elena; Zilisteanu, Diana; Circiumaru, Alexandra; Micu, Laurentiu; Voiculescu, Mihai; Poynard, Thierry; Ratziu, Vlad

    2015-01-01

    The association of NAFLD with chronic hepatitis C (CHC) has been extensively studied but little is known about its coexistence with chronic hepatitis B (CHB). To investigate the prevalence and determinants of steatosis and insulin resistance (IR) in CHB and its consequences on liver injury compared with CHC and NAFLD. Patients with CHB (N=110), CHC (N=111) and NAFLD (N=136) were evaluated by biomarkers of steatosis (SteatoTest>0.38 as a surrogate for steatosis >5%), IR (HOMA-IR>2.7 as a surrogate for IR) and fibrosis (FibroTest>0.48 as a surrogate for significant fibrosis, ≥F2). HOMA-IR gradually increased in CHB, CHC and NAFLD: 2.3±1.8; 3±2.6 and 3.8±2.7 (p<0.001). The prevalence of steatosis >5% was 21% (CHB), 43% (CHC) and 82% (NAFLD), (p<0.001). The prevalence of fibrosis≥F2 was 10% (CHB), 42% (CHC) and 21% (NAFLD), p<0.001. In CHB, IR was related to host and not viral factors. CHB patients with steatosis had higher BMI (29±5.7kg/m(2) vs. 24±4kg/m(2), p<0.001), waist circumference (96±14cm vs. 84±11cm, p=0.001) and HOMA-IR (3.9±2.6 vs. 1.8±1.2, p<0.001) than those without steatosis. HOMA-IR independently predicted steatosis in CHB (OR=1.9, 95% CI, 1.09-3.27, p<0.05) and CHC (OR=1.38; 95% CI, 1.07-1.78, p<0.02). In CHB, metabolic risk factors and HOMA-IR were not associated with significant fibrosis. HOMA-IR was an independent predictor of fibrosis in CHC. Steatosis may co-exist in CHB patients but with a lower prevalence than in CHC and NAFLD. In CHB steatosis is related to host and not viral factors, and is not associated with the severity of fibrosis. Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  7. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study.

    PubMed

    Hagström, Hannes; Nasr, Patrik; Ekstedt, Mattias; Hammar, Ulf; Stål, Per; Hultcrantz, Rolf; Kechagias, Stergios

    2018-01-01

    Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion : Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. ( Hepatology Communications 2018;2:48-57).

  8. Simple score to predict risk of hepatocellular carcinoma in chronic hepatitis C patients with advanced fibrosis after pegylated interferon and ribavirin therapy.

    PubMed

    Hu, Ching-Chih; Weng, Cheng-Hao; Chang, Liang-Che; Lin, Chih-Lang; Chen, Yen-Ting; Hu, Ching-Fang; Hua, Man-Chin; Chen, Li-Wei; Chien, Rong-Nan

    2018-01-01

    Eradication of chronic hepatitis C virus (HCV) after interferon-based therapy and its association with the reduction of risk of hepatocellular carcinoma (HCC) in HCV-infected patients with advanced fibrosis is controversial. The study is aimed to develop a simple scoring model for HCC prediction among advanced fibrotic chronic hepatitis C (CHC) patients after pegylated interferon (pegIFN) and ribavirin (RBV) therapy. We enrolled 271 biopsy-proven CHC patients with advanced fibrosis between 2003 and 2016, and divided them into non-HCC (n=211) and HCC (n=60) groups. The median observation duration was 6.0 years (range: 0.9-12.6 years). The HCC prevalence after pegIFN and RBV therapy in CHC patients with sustained virologic response (SVR) and without SVR was 14.7% and 32.2%, respectively. Multivariate Cox regression showed age ≥59.5 years old at initiation of therapy (HR: 2.542, 95% CI: 1.390-4.650, P =0.002), pretreatment total bilirubin ≥1.1 mg/dL (HR: 2.630, 95% CI: 1.420-4.871, P =0.002), pretreatment platelet counts <146.5 × 10 3 /μL (HR: 2.751, 95% CI: 1.373-5.511, P =0.004), no achievement of SVR (HR: 2.331, 95% CI: 1.277-4.253, P =0.006), and no diabetes at treatment initiation (HR: 3.085, 95% CI: 1.283-7.418, P =0.012) were significant predictors of HCC development. The scoring model consisted of the five categorical predictors and had an optimal cutoff point of 2.5. The area under receiver operating characteristic (AUROC) of the scoring model was 0.774±0.035 ( P <0.001). The sensitivity and specificity of the cutoff value to detect HCC were 81.3% and 57.5%. The 5-year and 10-year cumulative incidence of HCC was 4.9% and 10.0% in patients with simple score ≤2; and 25.9% and 44.6% in patients with simple score ≥3 ( P <0.001). The simple clinical-guided score has high discriminatory power for HCC prediction in advanced fibrotic CHC patients after pegIFN and RBV therapy.

  9. Primary biliary cirrhosis degree assessment by acoustic radiation force impulse imaging and hepatic fibrosis indicators

    PubMed Central

    Zhang, Hai-Chun; Hu, Rong-Fei; Zhu, Ting; Tong, Ling; Zhang, Qiu-Qin

    2016-01-01

    AIM: To evaluate the assessment of primary biliary cirrhosis degree by acoustic radiation force impulse imaging (ARFI) and hepatic fibrosis indicators. METHODS: One hundred and twenty patients who developed liver cirrhosis secondary to primary biliary cirrhosis were selected as the observation group, with the degree of patient liver cirrhosis graded by Child-Pugh (CP) score. Sixty healthy individuals were selected as the control group. The four indicators of hepatic fibrosis were detected in all research objects, including hyaluronic acid (HA), laminin (LN), type III collagen (PC III), and type IV collagen (IV-C). The liver parenchyma hardness value (LS) was then measured by ARFI technique. LS and the four indicators of liver fibrosis (HA, LN, PC III, and IV-C) were observed in different grade CP scores. The diagnostic value of LS and the four indicators of liver fibrosis in determining liver cirrhosis degree with PBC, whether used alone or in combination, were analyzed by receiver operating characteristic (ROC) curve. RESULTS: LS and the four indicators of liver fibrosis within the three classes (A, B, and C) of CP scores in the observation group were higher than in the control group, with C class > B class > A class; the differences were statistically significant (P < 0.01). Although AUC values of LS within the three classes of CP scores were higher than in the four indicators of liver fibrosis, sensitivity and specificity were unstable. The ROC curves of LS combined with the four indicators of liver fibrosis revealed that: AUC and sensitivity in all indicators combined in the A class of CP score were higher than in LS alone, albeit with slightly decreased specificity; AUC and specificity in all indicators combined in the B class of CP score were higher than in LS alone, with unchanged sensitivity; AUC values (0.967), sensitivity (97.4%), and specificity (90%) of all indicators combined in the C class of CP score were higher than in LS alone (0.936, 92.1%, 83

  10. Primary biliary cirrhosis degree assessment by acoustic radiation force impulse imaging and hepatic fibrosis indicators.

    PubMed

    Zhang, Hai-Chun; Hu, Rong-Fei; Zhu, Ting; Tong, Ling; Zhang, Qiu-Qin

    2016-06-14

    To evaluate the assessment of primary biliary cirrhosis degree by acoustic radiation force impulse imaging (ARFI) and hepatic fibrosis indicators. One hundred and twenty patients who developed liver cirrhosis secondary to primary biliary cirrhosis were selected as the observation group, with the degree of patient liver cirrhosis graded by Child-Pugh (CP) score. Sixty healthy individuals were selected as the control group. The four indicators of hepatic fibrosis were detected in all research objects, including hyaluronic acid (HA), laminin (LN), type III collagen (PC III), and type IV collagen (IV-C). The liver parenchyma hardness value (LS) was then measured by ARFI technique. LS and the four indicators of liver fibrosis (HA, LN, PC III, and IV-C) were observed in different grade CP scores. The diagnostic value of LS and the four indicators of liver fibrosis in determining liver cirrhosis degree with PBC, whether used alone or in combination, were analyzed by receiver operating characteristic (ROC) curve. LS and the four indicators of liver fibrosis within the three classes (A, B, and C) of CP scores in the observation group were higher than in the control group, with C class > B class > A class; the differences were statistically significant (P < 0.01). Although AUC values of LS within the three classes of CP scores were higher than in the four indicators of liver fibrosis, sensitivity and specificity were unstable. The ROC curves of LS combined with the four indicators of liver fibrosis revealed that: AUC and sensitivity in all indicators combined in the A class of CP score were higher than in LS alone, albeit with slightly decreased specificity; AUC and specificity in all indicators combined in the B class of CP score were higher than in LS alone, with unchanged sensitivity; AUC values (0.967), sensitivity (97.4%), and specificity (90%) of all indicators combined in the C class of CP score were higher than in LS alone (0.936, 92.1%, 83.3%). The diagnostic value

  11. Targeted delivery of microRNA 146b mimic to hepatocytes by lactosylated PDMAEMA nanoparticles for the treatment of NAFLD.

    PubMed

    He, Shuying; Guo, Weihong; Deng, Feihong; Chen, Kequan; Jiang, Yonghong; Dong, Minyu; Peng, Liang; Chen, Xueqing

    2018-03-21

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and precision therapeutic will be a benefit for the NAFLD regression. In this study, we observed low microRNA 146 b (miR-146 b) expression in NAFLD mice model induced by methionine-choline-deficient diet (MCD) compared with control group. Furthermore, miR-146b -/- mice induced MCD exhibited severe liver steatosis and hepatitis. A bio-distribution study showed that novel Lactosylated PDMAEMA nanoparticles effectively targeted hepatocytes Lac-PDMAEMA. We coupled miR-146b mimic with Lac-PDMAEMA and then were administrated to NAFLD mice model, which could obviously alleviate the hepatic steatosis. Lac-PDMAEMA effectively delivered miR-146b mimic to hepatocytes with a ∼8-fold upregulation of miR-146b mimic targeting MyD88 and IRAK1, and in turn suppressed the expression of PPARγ. Meanwhile, TNF-α and IL-6 mRNA levels were decreased after administration of Lac-PDMAEMA/miR-146b mimic. So, we made a conclusion that targeted delivering miR-146b mimic to the hepatocytes by, coupling Lac-PDMAEMA nanoparticles could effectively alleviate the hepatic steatosis in NAFLD mice, which maybe bring a new and effective way to intervene and therapy the NAFLD.

  12. Quantification of myocardial fibrosis by digital image analysis and interactive stereology.

    PubMed

    Daunoravicius, Dainius; Besusparis, Justinas; Zurauskas, Edvardas; Laurinaviciene, Aida; Bironaite, Daiva; Pankuweit, Sabine; Plancoulaine, Benoit; Herlin, Paulette; Bogomolovas, Julius; Grabauskiene, Virginija; Laurinavicius, Arvydas

    2014-06-09

    Cardiac fibrosis disrupts the normal myocardial structure and has a direct impact on heart function and survival. Despite already available digital methods, the pathologist's visual score is still widely considered as ground truth and used as a primary method in histomorphometric evaluations. The aim of this study was to compare the accuracy of digital image analysis tools and the pathologist's visual scoring for evaluating fibrosis in human myocardial biopsies, based on reference data obtained by point counting performed on the same images. Endomyocardial biopsy material from 38 patients diagnosed with inflammatory dilated cardiomyopathy was used. The extent of total cardiac fibrosis was assessed by image analysis on Masson's trichrome-stained tissue specimens using automated Colocalization and Genie software, by Stereology grid count and manually by Pathologist's visual score. A total of 116 slides were analyzed. The mean results obtained by the Colocalization software (13.72 ± 12.24%) were closest to the reference value of stereology (RVS), while the Genie software and Pathologist score gave a slight underestimation. RVS values correlated strongly with values obtained using the Colocalization and Genie (r>0.9, p<0.001) software as well as the pathologist visual score. Differences in fibrosis quantification by Colocalization and RVS were statistically insignificant. However, significant bias was found in the results obtained by using Genie versus RVS and pathologist score versus RVS with mean difference values of: -1.61% and 2.24%. Bland-Altman plots showed a bidirectional bias dependent on the magnitude of the measurement: Colocalization software overestimated the area fraction of fibrosis in the lower end, and underestimated in the higher end of the RVS values. Meanwhile, Genie software as well as the pathologist score showed more uniform results throughout the values, with a slight underestimation in the mid-range for both. Both applied digital image analysis

  13. Utility of the ELF Test for Detecting Steatohepatitis in Morbid Obese Patients with Suspicion of Nonalcoholic Fatty Liver Disease.

    PubMed

    López, Iria Cebreiros; Aroca, Florentina Guzmán; Bernal, Maria Dolores Frutos; Mompeán, Juan Antonio Luján; Bernal, Águeda Bas; Martínez, Antonio Miguel Hernández; Barba, Enrique Martínez; Velasco, Jose Antonio Noguera; Paricio, Pascual Parilla

    2017-09-01

    Morbid obese patients have a high rate of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NASH is related to the progression and poor evolution of chronic hepatopathy in NAFLD, so that its detection makes it possible to identify the subjects who are most at risk in order to prioritize treatment. The ELF test (Enhanced Liver Fibrosis test; Siemens Diagnostics, NY, USA) has been assessed for its capacity to detect fibrosis in patients with NAFLD, but its capacity for diagnosing NASH has not been checked. Our objective is to determine the utility of the ELF test for detecting NASH in morbid obese patients with suspected NAFLD. ELF values were determined in a cohort of obese patients who underwent bariatric surgery with suspected NAFLD. Liver biopsy was used as the reference standard. The values of ELF were significantly higher in patients with NASH (p = 0.002) and in those who presented with metabolic syndrome (p = 0.047). An ELF cut-off point of 8.72 allows the detection of patients with NASH with a sensitivity of 71.4% and a specificity of 74.1% (AUC = 0.742, p = 0.002). The ELF test is efficient for the identification of obese patients with NAFLD and early signs of steatohepatitis and fibrosis.

  14. Combined Adiponectin Deficiency and Resistance in Obese Patients: Can It Solve Part of the Puzzle in Nonalcoholic Steatohepatitis.

    PubMed

    Salman, Ahmed; Hegazy, Mona; AbdElfadl, Soheir

    2015-06-15

    Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, nonalcoholic steatohepatitis (NASH) and fibrosis in obese patients identifies the risk group with increased incidence of liver-related deaths. To clarify the role of serum adiponectin and its receptor liver gene expression in the progression of liver damage in NAFLD. Fifty four (54) obese patients with NAFLD preliminary diagnosed by liver ultra-sound were recruited. Full medical history, anthropometric measurement, biochemical studies, serum adiponectin level, liver biopsy for histological examination and NAS score to identify NASH patients, and assessment of adiponectin receptor gene expression by RT-PCR, were conducted for each patients. Fifteen ages matched average weight healthy adult had been chosen as a control for serum adiponectin level. According to NAS score, patients were divided into non- NASH (8 patients), and NASH (46 patients). Serum adiponectin level was significantly lower in NAFLD patients compared to normal participants (p < 0.004). Serum adiponectin level was lower in NASH patients (4.437 ± 2.569 ng/dl in NASH vs. 5.138 ± 2.841 ng/dl in non-NASH). Adiponectin receptor liver gene expression was lower in NASH patients (0.8459 ± 0.4671 vs. 1.0688 ± 0.3965 in non-NASH). Both adiponectin deficiency and resistance had a role in progression of simple liver steatosis to severe injury in obese patients.

  15. Evaluation of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis.

    PubMed

    Xu, Qinyu; Sheng, Li; Bao, Han; Chen, Xiaoyu; Guo, Canjie; Li, Hai; Ma, Xiong; Qiu, Dekai; Hua, Jing

    2017-03-01

    Transient elastography (TE) can reliably stage liver fibrosis via liver stiffness measurement (LSM) in chronic liver disease. However, the accuracy of TE for assessment of liver fibrosis in patients with autoimmune hepatitis (AIH) is still limited. We evaluate TE in staging liver fibrosis in AIH patients and compare with other noninvasive diagnostic tools. A total of 100 patients with biopsy-proven AIH were included. The correlation between LSM and fibrosis stage was analyzed using Spearman correlation test. The optimal cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. The diagnostic accuracy of LSM for severe fibrosis was compared with those of serum biochemical scores. Median LSM in AIH patients was higher than that of healthy controls (11.2 ± 8.2 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM had significant correlation with fibrosis (r = 0.752, P < 0.01) and increased progressively with increasing fibrosis stages in AIH patients. AUROC values of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.878 (95%CI: 0.789-0.967), 0.883 (0.820-0.946), and 0.914 (0.852-0.976), respectively. The optimal cut-off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.45, 8.75, and 12.50 kPa, respectively. LSM was superior to APRI score and FIB-4 score in detecting severe fibrosis (F ≥ 3). Serum ALT levels had minor effect on LSM values. Transient elastography is an accurate and reliable noninvasive tool in assessing liver fibrosis in AIH. Hepatic inflammatory activity had no significant effect on LSM determination. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  16. Low Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients with Type 2 Diabetes Mellitus and NAFLD.

    PubMed

    Bruinstroop, Eveline; Dalan, Rinkoo; Yang, Cao; Bee, Yong Mong; Chandran, Kurumbian; Cho, Li Wei; Soh, Shui Boon; Teo, Eng Kiong; Toh, Sue-Anne; Leow, Melvin Khee Shing; Sinha, Rohit A; Sadananthan, Suresh Anand; Michael, Navin; Stapleton, Heather; Leung, Christopher; Angus, Peter W; Patel, Sheila K; Burrell, Louise M; Chi, Lim Su; Fang, Sum Chee; Velan, S Sendhil; Yen, Paul M

    2018-04-27

    Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus and associated with significant morbidity and mortality. Thyroid hormone (TH) increases β-oxidation of fatty acids and decreases intrahepatic lipid content (IHLC) in rodents with NAFLD. In this study we investigated the possibility of low intrahepatic TH concentration in NAFLD and studied the effect of TH treatment in humans. We performed a phase 2b single arm study in six hospitals in Singapore to study whether TH reduced IHLC. Rats fed a MCD diet to induce NAFLD were used to show intrahepatic thyroid hormone concentrations. Euthyroid patients with type 2 diabetes mellitus and steatosis measured by ultrasonograpy. Levothyroxine was titrated at TSH 0.34-1.70 mIU/L before a 16-week maintenance phase. The primary outcome measure was change in IHLC measured by 1H-MRS after treatment. 20 male patients were included in the per protocol analysis (mean age 47.8±7.8 years, BMI 30.9±4.4 kg/m2, baseline IHLC 13±4 %). After treatment IHLC was decreased by 12 % ± 26 % relative to baseline (absolute change -2 %; 95% CI -3 to 0, p=0.046). Small decreases in BMI (p=0.044), VAT volume (p=0.047), and SAT volume (p=0.045) were observed. No significant changes in glucose regulation or lipid profile occurred. This is the first study demonstrating the efficacy and safety of low dose TH therapy for NAFLD in man, and suggests that TH or TH analogs may be beneficial for this condition.

  17. Identification and Fibrosis Staging of Hepatitis C Patients Using the Electronic Medical Record System.

    PubMed

    Anand, Vijay; Hyun, Christian; Khan, Qasim M; Hall, Curtis; Hessefort, Norbert; Sonnenberg, Amnon; Fimmel, Claus J

    2016-09-01

    The aim of this study was to noninvasively assess the severity of chronic hepatitis C virus (HCV) in large patient populations. It would be helpful if fibrosis scores could be calculated solely on the basis of data contained in the patients' electronic medical records (EMR). We performed a pilot study to identify all HCV-infected patients in a large health care system, and predict their fibrosis stage on the basis of demographic and laboratory data using common data from their EMR. HCV-infected patients were identified using the EMR. The liver biopsies of 191 HCV patients were graded using the Ishak and Metavir scoring systems. Demographic and laboratory data were extracted from the EMR and used to calculate the aminotransferase to platelet ratio index, Fib-4, Fibrosis Index, Forns, Göteborg University Cirrhosis Index, Lok Index, and Vira-HepC. In total, 869 HCV-infected patients were identified from a population of over 1 million. In the subgroup of patients with liver biopsies, all 7 algorithms were significantly correlated with the fibrosis stage. The degree of correlation was moderate, with correlation coefficients ranging from 0.22 to 0.60. For the detection of advanced fibrosis (Metavir 3 or 4), the areas under the receiver operating characteristic curve ranged from 0.71 to 0.84, with no significant differences between the individual scores. Sensitivities, specificities, and positive and negative predictive values were within the previously reported range. All scores tended to perform better for higher fibrosis stages. Our study demonstrates that HCV-infected patients can be identified and their fibrosis staged using commonly available EMR-based algorithms.

  18. Is the neutrophil to lymphocyte ratio associated with liver fibrosis in patients with chronic hepatitis B?

    PubMed

    Kekilli, Murat; Tanoglu, Alpaslan; Sakin, Yusuf Serdar; Kurt, Mevlut; Ocal, Serkan; Bagci, Sait

    2015-05-14

    To determine the association between the neutrophil to lymphocyte (N/L) ratio and the degree of liver fibrosis in patients with chronic hepatitis B (CHB) infection. Between December 2011 and February 2013, 129 consecutive CHB patients who were admitted to the study hospitals for histological evaluation of chronic hepatitis B-related liver fibrosis were included in this retrospective study. The patients were divided into two groups based on the fibrosis score: individuals with a fibrosis score of F0 or F1 were included in the "no/minimal liver fibrosis" group, whereas patients with a fibrosis score of F2, F3, or F4 were included in the "advanced liver fibrosis" group. The Statistical Package for Social Sciences 18.0 for Windows was used to analyze the data. A P value of < 0.05 was accepted as statistically significant. Three experienced and blinded pathologists evaluated the fibrotic status and inflammatory activity of 129 liver biopsy samples from the CHB patients. Following histopathological examination, the "no/minimal fibrosis" group included 79 individuals, while the "advanced fibrosis" group included 50 individuals. Mean (N/L) ratio levels were notably lower in patients with advanced fibrosis when compared with patients with no/minimal fibrosis. The mean value of the aspartate aminotransferase-platelet ratio index was markedly higher in cases with advanced fibrosis compared to those with no/minimal fibrosis. Reduced levels of the peripheral blood N/L ratio were found to give high sensitivity, specificity and predictive values in CHB patients with significant fibrosis. The prominent finding of our research suggests that the N/L ratio can be used as a novel noninvasive marker of fibrosis in patients with CHB.

  19. Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries

    PubMed Central

    Lückhoff, Hilmar K; Kruger, Frederik C; Kotze, Maritha J

    2015-01-01

    Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption. PMID:26019735

  20. Phyllanthus Niruri Standardized Extract Alleviates the Progression of Non-Alcoholic Fatty Liver Disease and Decreases Atherosclerotic Risk in Sprague-Dawley Rats.

    PubMed

    Al Zarzour, Raghdaa Hamdan; Ahmad, Mariam; Asmawi, Mohd Zaini; Kaur, Gurjeet; Saeed, Mohammed Ali Ahmed; Al-Mansoub, Majed Ahmed; Saghir, Sultan Ayesh Mohammed; Usman, Nasiba Salisu; Al-Dulaimi, Dhamraa W; Yam, Mun Fei

    2017-07-18

    Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri ( P. niruri ) . NAFLD was induced in male Sprague-Dawley rats using a special high-fat diet (HFD). A 50% methanolic extract (50% ME) exhibited the highest inhibitory effect against NAFLD progression. It significantly reduced hepatomegaly (16%) and visceral fat weight (22%), decreased NAFLD score, prevented fibrosis, and reduced serum total cholesterol (TC) (48%), low-density lipoprotein (LDL) (65%), free fatty acids (FFAs) (25%), alanine aminotransferase (ALT) (45%), alkaline phosphatase (ALP) (38%), insulin concentration (67%), homeostatic model assessment of insulin resistance (HOMA-IR) (73%), serum atherogenic ratios TC/high-density lipoprotein (HDL) (29%), LDL/HDL (66%) and (TC-HDL)/HDL (64%), hepatic content of cholesterol (43%), triglyceride (29%) and malondialdehyde (MDA) (40%) compared to a non-treated HFD group. In vitro, 50% ME of P. niruri inhibited α-glucosidase, pancreatic lipase enzymes and cholesterol micellization. It also had higher total phenolic and total flavonoid contents compared to other extracts. Ellagic acid and phyllanthin were identified as major compounds. These results suggest that P. niruri could be further developed as a novel natural hepatoprotective agent against NAFLD and atherosclerosis.

  1. Phyllanthus Niruri Standardized Extract Alleviates the Progression of Non-Alcoholic Fatty Liver Disease and Decreases Atherosclerotic Risk in Sprague–Dawley Rats

    PubMed Central

    Al Zarzour, Raghdaa Hamdan; Ahmad, Mariam; Asmawi, Mohd. Zaini; Kaur, Gurjeet; Al-Mansoub, Majed Ahmed; Saghir, Sultan Ayesh Mohammed; Usman, Nasiba Salisu; Al-Dulaimi, Dhamraa W.; Yam, Mun Fei

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri (P. niruri). NAFLD was induced in male Sprague–Dawley rats using a special high-fat diet (HFD). A 50% methanolic extract (50% ME) exhibited the highest inhibitory effect against NAFLD progression. It significantly reduced hepatomegaly (16%) and visceral fat weight (22%), decreased NAFLD score, prevented fibrosis, and reduced serum total cholesterol (TC) (48%), low-density lipoprotein (LDL) (65%), free fatty acids (FFAs) (25%), alanine aminotransferase (ALT) (45%), alkaline phosphatase (ALP) (38%), insulin concentration (67%), homeostatic model assessment of insulin resistance (HOMA-IR) (73%), serum atherogenic ratios TC/high-density lipoprotein (HDL) (29%), LDL/HDL (66%) and (TC–HDL)/HDL (64%), hepatic content of cholesterol (43%), triglyceride (29%) and malondialdehyde (MDA) (40%) compared to a non-treated HFD group. In vitro, 50% ME of P. niruri inhibited α-glucosidase, pancreatic lipase enzymes and cholesterol micellization. It also had higher total phenolic and total flavonoid contents compared to other extracts. Ellagic acid and phyllanthin were identified as major compounds. These results suggest that P. niruri could be further developed as a novel natural hepatoprotective agent against NAFLD and atherosclerosis. PMID:28718838

  2. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease.

    PubMed

    Haas, Joel T; Francque, Sven; Staels, Bart

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation, and hepatocyte dysfunction. Importantly, it is also closely linked to obesity and the metabolic syndrome. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma, and cardiovascular disease. Although the precise signals remain poorly understood, NAFLD pathogenesis likely involves actions of the different hepatic cell types and multiple extrahepatic signals. The complexity of this disease has been a major impediment to the development of appropriate metrics of its progression and effective therapies. Recent clinical data place increasing importance on identifying fibrosis, as it is a strong indicator of hepatic disease-related mortality. Preclinical modeling of the fibrotic process remains challenging, particularly in the contexts of obesity and the metabolic syndrome. Future studies are needed to define the molecular pathways determining the natural progression of NAFLD, including key determinants of fibrosis and disease-related outcomes. This review covers the evolving concepts of NAFLD from both human and animal studies. We discuss recent clinical and diagnostic methods assessing NAFLD diagnosis, progression, and outcomes; compare the features of genetic and dietary animal models of NAFLD; and highlight pharmacological approaches for disease treatment.

  3. Additive Effects of the Risk Alleles of PNPLA3 and TM6SF2 on Non-alcoholic Fatty Liver Disease (NAFLD) in a Chinese Population.

    PubMed

    Wang, Xiaoliang; Liu, Zhipeng; Wang, Kai; Wang, Zhaowen; Sun, Xing; Zhong, Lin; Deng, Guilong; Song, Guohe; Sun, Baining; Peng, Zhihai; Liu, Wanqing

    2016-01-01

    Recent genome-wide association studies have identified that variants in or near PNPLA3, NCAN, GCKR, LYPLAL1, and TM6SF2 are significantly associated with non-alcoholic fatty liver disease (NAFLD) in multiple ethnic groups. Studies on their impact on NAFLD in Han Chinese are still limited. In this study, we examined the relevance of these variants to NAFLD in a community-based Han Chinese population and further explored their potential joint effect on NAFLD. Six single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, rs2294918, NCAN rs2228603, GCKR rs780094, LYPLAL1 rs12137855, and TM6SF2 rs58542926) previously identified in genome-wide analyses, to be associated with NAFLD were genotyped in 384 NAFLD patients and 384 age- and gender-matched healthy controls. We found two out of the six polymorphisms, PNPLA3 rs738409 (OR = 1.52, 95%CI: 1.19-1.96; P = 0.00087) and TM6SF2 rs58542926 (OR = 2.11, 95%CI: 1.34-3.39; P = 0.0016) are independently associated with NAFLD after adjustment for the effects of age, gender, and BMI. Our analysis further demonstrated the strong additive effects of the risk alleles of PNPLA3 and TM6SF2 with an overall significance between the number of risk alleles and NAFLD (OR = 1.64, 95%CI: 1.34-2.01; P = 1.4 × 10(-6)). The OR for NAFLD increased in an additive manner, with an average increase in OR of 1.52 per additional risk allele. Our results confirmed that the PNPLA3 and TM6SF2 variants were the most significant risk alleles for NAFLD in Chinese population. Therefore, genotyping these two genetic risk factors may help identify individuals with the highest risk of NAFLD.

  4. Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease.

    PubMed

    Hannah, William N; Harrison, Stephen A

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD is the most common liver disease in developed countries. Weight reduction of 3% to 5% is associated with improved steatosis; reductions of 5% to 7% are necessary for decreased inflammation; with 7% to 10%, individuals may experience NAFLD/NASH remission and regression of fibrosis. No specific dietary intervention has proven beneficial beyond calorie restriction. Physical activity without weight loss seems to decrease hepatic steatosis. Bariatric surgery is associated with decreased cardiovascular risk and improved overall mortality in addition to reduction in hepatic steatosis, inflammation, and fibrosis. Published by Elsevier Inc.

  5. Nonlinear microscopy of lipid storage and fibrosis in muscle and liver tissues of mice fed high-fat diets

    NASA Astrophysics Data System (ADS)

    Brackmann, Christian; Gabrielsson, Britt; Svedberg, Fredrik; Holmäng, Agneta; Sandberg, Ann-Sofie; Enejder, Annika

    2010-11-01

    Hallmarks of high-fat Western diet intake, such as excessive lipid accumulation in skeletal muscle and liver as well as liver fibrosis, are investigated in tissues from mice using nonlinear microscopy, second harmonic generation (SHG), and coherent anti-Stokes Raman scattering (CARS), supported by conventional analysis methods. Two aspects are presented; intake of standard chow versus Western diet, and a comparison between two high-fat Western diets of different polyunsaturated lipid content. CARS microscopy images of intramyocellular lipid droplets in muscle tissue show an increased amount for Western diet compared to standard diet samples. Even stronger diet impact is found for liver samples, where combined CARS and SHG microscopy visualize clear differences in lipid content and collagen fiber development, the latter indicating nonalcoholic fatty liver disease (NAFLD) and steatohepatitis induced at a relatively early stage for Western diet. Characteristic for NAFLD, the fibrous tissue-containing lipids accumulate in larger structures. This is also observed in CARS images of liver samples from two Western-type diets of different polyunsaturated lipid contents. In summary, nonlinear microscopy has strong potential (further promoted by technical advances toward clinical use) for detection and characterization of steatohepatitis already in its early stages.

  6. Nonlinear microscopy of lipid storage and fibrosis in muscle and liver tissues of mice fed high-fat diets.

    PubMed

    Brackmann, Christian; Gabrielsson, Britt; Svedberg, Fredrik; Holmaang, Agneta; Sandberg, Ann-Sofie; Enejder, Annika

    2010-01-01

    Hallmarks of high-fat Western diet intake, such as excessive lipid accumulation in skeletal muscle and liver as well as liver fibrosis, are investigated in tissues from mice using nonlinear microscopy, second harmonic generation (SHG), and coherent anti-Stokes Raman scattering (CARS), supported by conventional analysis methods. Two aspects are presented; intake of standard chow versus Western diet, and a comparison between two high-fat Western diets of different polyunsaturated lipid content. CARS microscopy images of intramyocellular lipid droplets in muscle tissue show an increased amount for Western diet compared to standard diet samples. Even stronger diet impact is found for liver samples, where combined CARS and SHG microscopy visualize clear differences in lipid content and collagen fiber development, the latter indicating nonalcoholic fatty liver disease (NAFLD) and steatohepatitis induced at a relatively early stage for Western diet. Characteristic for NAFLD, the fibrous tissue-containing lipids accumulate in larger structures. This is also observed in CARS images of liver samples from two Western-type diets of different polyunsaturated lipid contents. In summary, nonlinear microscopy has strong potential (further promoted by technical advances toward clinical use) for detection and characterization of steatohepatitis already in its early stages.

  7. Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights

    PubMed Central

    Stephenson, Kristen; Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer; Thomson, Joanne; Alpini, Gianfranco; Francis, Heather

    2018-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a disease of increasing interest, as its prevalence is on the rise. NAFLD has been linked to metabolic syndrome, which is becoming more common due to the Western diet. Because NAFLD can lead to cirrhosis and related complications including hepatocellular carcinoma, the increasing prevalence is concerning, and medical therapy aimed at treating NAFLD is of great interest. Researchers studying the effects of medical therapy on NAFLD use dietary mouse models. The two main types of mouse model diets are the methionine- and choline-deficient (MCD) diet and the Western-like diet (WD). Although both induce NAFLD, the mechanisms are very different. We reviewed several studies conducted within the last 5 years that used MCD diet or WD mouse models in order to mimic this disease in a way most similar to humans. The MCD diet inconsistently induces NAFLD and fibrosis and does not completely induce metabolic syndrome. Thus, the clinical significance of the MCD diet is questionable. In contrast, WD mouse models consisting of high fat, cholesterol, and a combination of high-fructose corn syrup, sucrose, fructose, or glucose not only lead to metabolic syndrome but also induce NAFLD with fibrosis, making these choices most suitable for research. PMID:29096730

  8. Inflammatory Mediators of Hepatic Steatosis

    PubMed Central

    Hijona, Elizabeth; Hijona, Lander; Arenas, Juan I.; Bujanda, Luis

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications. PMID:20300479

  9. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats.

    PubMed

    Wengrower, Dov; Zanninelli, Giuliana; Latella, Giovanni; Necozione, Stefano; Metanes, Issa; Israeli, Eran; Lysy, Joseph; Pines, Mark; Papo, Orit; Goldin, Eran

    2012-01-01

    Intestinal fibrosis is a challenging clinical condition in several fibrostenosing enteropathies, particularly Crohn's disease. Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis. Fibrosis, due to an abnormal accumulation of extracellular matrix proteins, is a chronic and progressive process mediated by cell⁄matrix⁄cytokine and growth factor interactions, but may be a reversible phenomenon. Of the several molecules regulating fibrogenesis, transforming growth factor-beta 1 (TGF-b1) appears to play a pivotal role; it is strongly induced by the local activation of angiotensin II. The levels of both TGF-b1 and angiotensin II are elevated in fibrostenosing Crohn's disease. To evaluate the in vivo effect of losartan - an angiotensin II receptor antagonist - on the course of chronic colitis-associated fibrosis and on TGF-b1 expression. Colitis was induced by intrarectal instillation of trinitrobenzene sulphonic acid (TNBS) (15 mg⁄mL) while losartan was administered orally daily by gavage (7 mg⁄kg⁄day) for 21 days. Three groups of rats were evaluated: control (n=10); TNBS treated (n=10); and TNBS + losartan treated (n=10). Inflammation and fibrosis of the colon were evaluated by macro- and microscopic score analysis. Colonic TGF-b1 levels was measured using ELISA. Twenty-one days after induction, losartan significantly improved the macro- and microscopic scores of fibrosis in the colonic wall and reduced TGF-b1 concentration. Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-b1 expression.

  10. A vegetarian diet does not protect against nonalcoholic fatty liver disease (NAFLD): A cross-sectional study between Buddhist priests and the general population.

    PubMed

    Choi, Sung Hun; Oh, Dong Jun; Kwon, Ki Hwan; Lee, Jun Kyu; Koh, Moon Soo; Lee, Jin Ho; Kang, Hyoun Woo

    2015-07-01

    There is limited data that supports a role for a vegetarian diet in nonalcoholic fatty liver disease (NAFLD). The aim of this study is to evaluate the relationship between vegetarian diets and NAFLD, considering metabolic syndrome and obesity. This is a cross-sectional, retrospective study comparing the prevalence of NAFLD of 615 Buddhist priests and age-, sex-, Body mass index (BMI)-and presence/absence of metabolic syndrome-matched controls who underwent routine health checkups in a health promotion center. Diagnosis and severity of NAFLD was determined based on ultrasonographic findings. The prevalence of NAFLD was not statistically significantly different between the Buddhist priests and the general population (29.9% vs. 25.05%, p=0.055). The Buddhist priest group had higher serum albumin, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and serum triglyceride levels and lower serum total bilirubin, serum fasting glucose, and serum high density lipoprotein (HDL) levels than the general population group. In univariate analysis and multivariate analysis, NAFLD was associated with old age, male gender, increased BMI, increased waist circumference, metabolic syndrome, high albumin, high glucose, high AST, high ALT, high gamma glutamyl transpeptidase (GGT), high triglycerides, low HDL, high low density lipoprotein (LDL), and high total cholesterol. The vegetarian diet does not protect against NAFLD.

  11. Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis

    PubMed Central

    Ramos, Fernando; Robledo, Cristina; Izquierdo-García, Francisco Miguel; Suárez-Vilela, Dimas; Benito, Rocío; Fuertes, Marta; Insunza, Andrés; Barragán, Eva; del Rey, Mónica; de Morales, José María García-Ruiz; Tormo, Mar; Salido, Eduardo; Zamora, Lurdes; Pedro, Carmen; Sánchez-del-Real, Javier; Díez-Campelo, María; del Cañizo, Consuelo; Sanz, Guillermo F.; Hernández-Rivas, Jesús María

    2016-01-01

    The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB, and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis. PMID:27127180

  12. Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.

    PubMed

    Nozaki, Yuichi; Fujita, Koji; Wada, Koichiro; Yoneda, Masato; Shinohara, Yoshiyasu; Imajo, Kento; Ogawa, Yuji; Kessoku, Takaomi; Nakamuta, Makoto; Saito, Satoru; Masaki, Naohiko; Nagashima, Yoji; Terauchi, Yasuo; Nakajima, Atsushi

    2015-12-17

    Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

  13. Voice Disorder in Cystic Fibrosis Patients

    PubMed Central

    Lourenço, Bruna Mendes; Costa, Kauê Machado; da Silva Filho, Manoel

    2014-01-01

    Cystic fibrosis is a common autosomal recessive disorder with drastic respiratory symptoms, including shortness of breath and chronic cough. While most of cystic fibrosis treatment is dedicated to mitigating the effects of respiratory dysfunction, the potential effects of this disease on vocal parameters have not been systematically studied. We hypothesized that cystic fibrosis patients, given their characteristic respiratory disorders, would also present dysphonic symptoms. Given that voice disorders can severely impair quality of life, the identification of a potential cystic fibrosis-related dysphonia could be of great value for the clinical evaluation and treatment of this disease. We tested our hypothesis by measuring vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. We found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When we segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men. Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. Our results show that CF patients exhibit significant dysphonia and suggest they may

  14. Correlation of endothelin-1 concentration and angiotensin-converting enzyme activity with the staging of liver fibrosis.

    PubMed

    Kardum, Dusko; Fabijanić, Damir; Lukić, Anita; Romić, Zeljko; Petrovecki, Mladen; Bogdanović, Zoran; Jurić, Klara; Urek-Crncević, Marija; Banić, Marko

    2012-06-01

    Increased serum angiotensin-converting enzyme (SACE) activity and serum concentration of endothelin-1 (ET-1) were found in liver cirrhosis. We investigated a correlation between the different stages of liver fibrosis and SACE activity and serum ET-1 concentration. Seventy patients with pathohistologically established chronic liver disease were divided in three groups according to Ishak criteria for liver fibrosis: minimal fibrosis (Ishak score 0-1, n =20), medium fibrosis (Ishak score 2-5, n=20) and cirrhosis (Ishak score 6, n=30). SACE activity and ET-1 concentration were determined using commercial ELISA kits. SACE activity and ET-1 concentrations were proportional to the severity of disease, the highest being in patients with liver cirrhosis. Maximal increase in SACE activity was found between minimal and medium fibrosis while maximal increase in ET-1 concentration was revealed between medium fibrosis and cirrhosis. The analysis of the Receiver Operating Characteristic (ROC) curve for SACE activity suggested a cut-off value to separate minimal from medium fibrosis at 59.00 U/L (sensitivity 100%, specificity 64.7%). The cut-off value for serum ET-1 concentration to separate medium fibrosis from cirrhosis was 12.4 pg/mL (sensitivity 96.8%, specificity 94.4%). A positive correlation between SACE activity and ET-1 concentration was registered (Spearman's ñ = 0.438, p = 0.004). Both SACE activity and ET-1 concentration were increased in all stages of liver fibrosis. Cut-off points for SACE activity and ET-1 concentration could be a biochemical marker for the progression of fibrosis. Positive correlation between SACE activity and ET-1 concentration might indicate their interaction in the development of liver cirrhosis.

  15. n-3 Fatty acids combined with flavan-3-ols prevent steatosis and liver injury in a murine model of NAFLD.

    PubMed

    Vauzour, David; Rodriguez-Ramiro, Ildefonso; Rushbrook, Simon; Ipharraguerre, Ignacio R; Bevan, Damon; Davies, Susan; Tejera, Noemi; Mena, Pedro; de Pascual-Teresa, Sonia; Del Rio, Daniele; Gavrilovic, Jelena; Minihane, Anne Marie

    2018-01-01

    Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Hypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Bezerra Duarte, Sebastião Mauro; Faintuch, Joel; Stefano, José Tadeu; Sobral de Oliveira, Maria Beatriz; de Campos Mazo, Daniel Ferraz; Rabelo, Fabiola; Vanni, Denise; Nogueira, Monize Aydar; Carrilho, Flair José; Marques Souza de Oliveira, Claudia Pinto

    2014-01-01

    To investigate the role of hypocaloric highprotein diet, a prospective clinical study was conducted in NAFLD patients. Pre-versus post-interventional data were analyzed in 48 stable NAFLD patients (submitted to a hypocaloric high-protein diet during 75 days. Variables included anthropometrics (body mass index/ BMI and waist circumference/WC), whole-body and segmental bioimpedance analysis and biochemical tests. Diet compliance was assessed by interviews every two weeks. BMI, WC and body fat mass remained relatively stable (-1.3%, -1.8% and -2.5% respectively, no significance). HDL- cholesterol increased (P < 0.05) whereas total, LDL and VLDL cholesterol, triglycerides, aspartate aminotransferase/ AST, gamma glutamyltransferase/GGT, alkaline phosphatase/ AP, fasting blood glucose and glycated hemoglobin/ HbA1c decreased (P < 0.05). When patients were stratified according to increase (22/48, 45.8%) and decrease (21/48, 43.8%) of BMI, association between weight decrease and liver benefit could be elicited in such circumstances for ALT, AP and AST/ALT ratio. No change could be demonstrated in patients who gained weight. Multivariate assessment confirmed that waist circumference, ferritin, triacylglycerol, and markers of glucose homeostasis were the most relevant associated with liver enzymes. Ours results are consistent with the literature of calorie restriction in the management of NAFLD. Changes in lifestyle and weight loss are recommended for NAFLD patients. European guidelines also support this recommendation. This is the first study that demonstrated that a high protein, hypocaloric diet were associated with improvement of lipid profile, glucose homeostasis and liver enzymes in NAFLD independent on BMI decrease or body fat mass reduction.

  17. Quantification of myocardial fibrosis by digital image analysis and interactive stereology

    PubMed Central

    2014-01-01

    Background Cardiac fibrosis disrupts the normal myocardial structure and has a direct impact on heart function and survival. Despite already available digital methods, the pathologist’s visual score is still widely considered as ground truth and used as a primary method in histomorphometric evaluations. The aim of this study was to compare the accuracy of digital image analysis tools and the pathologist’s visual scoring for evaluating fibrosis in human myocardial biopsies, based on reference data obtained by point counting performed on the same images. Methods Endomyocardial biopsy material from 38 patients diagnosed with inflammatory dilated cardiomyopathy was used. The extent of total cardiac fibrosis was assessed by image analysis on Masson’s trichrome-stained tissue specimens using automated Colocalization and Genie software, by Stereology grid count and manually by Pathologist’s visual score. Results A total of 116 slides were analyzed. The mean results obtained by the Colocalization software (13.72 ± 12.24%) were closest to the reference value of stereology (RVS), while the Genie software and Pathologist score gave a slight underestimation. RVS values correlated strongly with values obtained using the Colocalization and Genie (r > 0.9, p < 0.001) software as well as the pathologist visual score. Differences in fibrosis quantification by Colocalization and RVS were statistically insignificant. However, significant bias was found in the results obtained by using Genie versus RVS and pathologist score versus RVS with mean difference values of: -1.61% and 2.24%. Bland-Altman plots showed a bidirectional bias dependent on the magnitude of the measurement: Colocalization software overestimated the area fraction of fibrosis in the lower end, and underestimated in the higher end of the RVS values. Meanwhile, Genie software as well as the pathologist score showed more uniform results throughout the values, with a slight underestimation in the mid

  18. Protein S is protective in pulmonary fibrosis.

    PubMed

    Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

    2016-08-01

    Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

  19. Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease.

    PubMed

    Baffy, Gyorgy

    2018-03-01

    Nonalcoholic fatty liver disease (NAFLD) advanced to cirrhosis is often complicated by clinically significant portal hypertension, which is primarily caused by increased intrahepatic vascular resistance. Liver fibrosis has been identified as a critical determinant of this process. However, there is evidence that portal venous pressure may begin to rise in the earliest stages of NAFLD when fibrosis is far less advanced or absent. The biological and clinical significance of these early changes in sinusoidal homeostasis remains unclear. Experimental and human observations indicate that sinusoidal space restriction due to hepatocellular lipid accumulation and ballooning may impair sinusoidal flow and generate shear stress, increasingly disrupting sinusoidal microcirculation. Sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells are key partners of hepatocytes affected by NAFLD in promoting endothelial dysfunction through enhanced contractility, capillarization, adhesion and entrapment of blood cells, extracellular matrix deposition, and neovascularization. These biomechanical and rheological changes are aggravated by a dysfunctional gut-liver axis and splanchnic vasoregulation, culminating in fibrosis and clinically significant portal hypertension. We may speculate that increased portal venous pressure is an essential element of the pathogenesis across the entire spectrum of NAFLD. Improved methods of noninvasive portal venous pressure monitoring will hopefully give new insights into the pathobiology of NAFLD and help efforts to identify patients at increased risk for adverse outcomes. In addition, novel drug candidates targeting reversible components of aberrant sinusoidal circulation may prevent progression in NAFLD.

  20. Associations between Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Non-Alcoholic Fatty Liver Disease (NAFLD) Risk: A Meta-Analysis

    PubMed Central

    Sun, Man-Yi; Zhang, Li; Shi, Song-Li; Lin, Jing-Na

    2016-01-01

    Background C677T and A1298C are the most common allelic variants of Methylenetetrahydrofolate Reductase (MTHFR) gene. The association between MTHFR polymorphisms and the occurrence of non-alcoholic fatty liver disease (NAFLD) remains controversial. This study was thus performed to examine whether MTHFR mutations are associated with the susceptibility to NAFLD. Methods A first meta-analysis on the association between the MTHFR polymorphisms and NAFLD risks was carried out via Review Manager 5.0 and Stata/SE 12.0 software. The on-line databases, such as PubMed, EMBASE, CENTRAL, WOS, Scopus and EBSCOhost (updated to April 1st, 2016), were searched for eligible case-control studies. The odd radio (OR), 95% confidence interval (CI) and P value were calculated through Mantel-Haenszel statistics under random- or fixed-effect model. Results Eight articles (785 cases and 1188 controls) contributed data to the current meta-analysis. For C677T, increased NAFLD risks were observed in case group under homozygote model (T/T vs C/C, OR = 1.49, 95% CI = 1.03~2.15, P = 0.04) and recessive model (T/T vs C/C+C/T, OR = 1.42, 95% CI = 1.07~1.88, P = 0.02), but not the other genetics models, compared with control group. For A1298C, significantly increased NAFLD risks were detected in allele model (C vs A, OR = 1.53, 95% CI = 1.13~2.07, P = 0.006), homozygote model (C/C vs A/A, OR = 2.81, 95% CI = 1.63~4.85, P = 0.0002), dominant model (A/C+C/C vs A/A, OR = 1.60, 95% CI = 1.06~2.41, P = 0.03) and recessive model (C/C vs A/A+A/C, OR = 2.08, 95% CI = 1.45~3.00, P<0.0001), but not heterozygote model. Conclusion T/T genotype of MTHFR C677T polymorphism and C/C genotype of MTHFR A1298C are more likely to be associated with the susceptibility to NAFLD. PMID:27128842

  1. The 'donations for decreased ALT (D4D)' prosocial behavior incentive scheme for NAFLD patients.

    PubMed

    Sumida, Yoshio; Yoshikawa, Toshikazu; Tanaka, Saiyu; Taketani, Hiroyoshi; Kanemasa, Kazuyuki; Nishimura, Tekeshi; Yamaguchi, Kanji; Mitsuyoshi, Hironori; Yasui, Kohichiroh; Minami, Masahito; Naito, Yuji; Itoh, Yoshito

    2014-12-01

    Physicians often experience difficulties in motivating patients with non-alcoholic fatty liver disease (NAFLD) to undergo lifestyle changes. The aim of this study is to examine whether 'Donations for Decreased alanine aminotransferase (ALT)' (D4D) prosocial behavior incentive can serve as an effective intrinsic motivational factor in comparison with conventional dietary and exercise intervention alone for NAFLD patients. Twenty-five NAFLD patients with elevated ALT were randomly assigned to a control group that received conventional dietary and exercise intervention alone, or a donation group whereby, as an incentive, we would make a monetary donation to the United Nations World Food Programme (WFP) based on the decrease in their ALT levels achieved over 12 weeks, in addition to receiving control intervention. In a donation group, we would donate US$1 to the WFP for every 1 IU/l of decrease in their ALT levels. There were no differences of pre-treatment clinical characteristics between the two groups. Significant reductions of ALT levels were achieved only in a donation group, although post-treatment ALT levels were not different between the two groups. These patients raised a total of $316 for the WFP. Promoting patients' intrinsic motivation by incorporating 'D4D' prosocial behavior incentive into conventional dietary and exercise intervention may provide a means to improve NAFLD. © The Author 2013. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

    PubMed Central

    Leite, Nathalie C; Villela-Nogueira, Cristiane A; Cardoso, Claudia R L; Salles, Gil F

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus. PMID:25024596

  3. Higher Estimated Net Endogenous Acid Production May Be Associated with Increased Prevalence of Nonalcoholic Fatty Liver Disease in Chinese Adults in Hong Kong

    PubMed Central

    Chan, Ruth; Wong, Vincent Wai-Sun; Chu, Winnie Chiu-Wing; Wong, Grace Lai-Hung; Li, Liz Sin; Leung, Jason; Chim, Angel Mei-Ling; Yeung, David Ka-Wai; Sea, Mandy Man-Mei; Woo, Jean; Chan, Francis Ka-Leung; Chan, Henry Lik-Yuen

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been associated with reduced growth hormone levels and signaling. Such hormonal changes also occur in metabolic acidosis. Since mild metabolic acidosis can be diet induced, diet-induced acid load may constitute a nutritional factor with possible influence on NAFLD development. This study explored whether a higher diet-induced acid load is associated with an increased likelihood of NAFLD. Apparently healthy Chinese adults (330 male, 463 female) aged 19-72 years were recruited through population screening between 2008 and 2010 in a cross-sectional population-based study in Hong Kong. Estimated net endogenous acid production (NEAP) was calculated using Frassetto’s method and potential renal acid load (PRAL) was calculated using Remer’s method based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at >5% by proton-magnetic resonance spectroscopy. Possible advanced fibrosis was defined as liver stiffness at >7.9 kPa by transient elastography. Multivariate logistic regression models were used to examine the association between each measure of dietary acid load and prevalent NAFLD or possible advanced fibrosis with adjustment for potential anthropometric and lifestyle factors. 220 subjects (27.7%) were diagnosed with NAFLD. Estimated NEAP was positively associated with the likelihood of having NAFLD after adjustment for age, sex, body mass index, current drinker status and the presence of metabolic syndrome [OR (95% CI) = 1.25 (1.02-1.52), p = 0.022]. The association was slightly attenuated but remained significant when the model was further adjusted for other dietary variables. No association between PRAL and NAFLD prevalence was observed. Both estimated NEAP and PRAL were not associated with the presence of possible advance fibrosis. Our findings suggest that there may be a modest association between diet-induced acid load and NAFLD. More studies are needed to

  4. Vitamin K1 attenuates bile duct ligation-induced liver fibrosis in rats.

    PubMed

    Jiao, Kun; Sun, Quan; Chen, Baian; Li, Shengli; Lu, Jing

    2014-06-01

    Vitamin K1 is used as a liver protection drug for cholestasis-induced liver fibrosis in China, but the mechanism of vitamin K1's action in liver fibrosis is unclear. In this study, a model of liver fibrosis was achieved via bile duct ligation in rats. The rats were then injected with vitamin K1, and the levels of serum aspartate aminotransferase, alanine transaminase, total bilirubin and the fibrotic grade score, collagen content, the expressions of α-smooth muscle actin (SMA) and cytokeratin 19 (CK19) were measured on day 28 after ligation. The levels of the biochemical parameters, fibrotic score and collagen content were significantly reduced by treatment with vitamin K1 in bile duct-ligated rats. In addition, α-SMA and CK19 expression was significantly reduced by vitamin K1 treatment in bile duct-ligated rats. These results suggested that vitamin K1 may attenuate liver fibrosis by inhibiting hepatic stellate cell activation in bile duct-ligated rats.

  5. Performance of real-time strain elastography, transient elastography, and aspartate-to-platelet ratio index in the assessment of fibrosis in chronic hepatitis C.

    PubMed

    Ferraioli, Giovanna; Tinelli, Carmine; Malfitano, Antonello; Dal Bello, Barbara; Filice, Gaetano; Filice, Carlo; Above, Elisabetta; Barbarini, Giorgio; Brunetti, Enrico; Calderon, Willy; Di Gregorio, Marta; Lissandrin, Raffaella; Ludovisi, Serena; Maiocchi, Laura; Michelone, Giuseppe; Mondelli, Mario; Patruno, Savino F A; Perretti, Alessandro; Poma, Gianluigi; Sacchi, Paolo; Zaramella, Marco; Zicchetti, Mabel

    2012-07-01

    The purpose of this article is to evaluate the diagnostic performance of transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index in assessing fibrosis in patients with chronic hepatitis C by using histologic Metavir scores as reference standard. Consecutive patients with chronic hepatitis C scheduled for liver biopsy were enrolled. Liver biopsy was performed on the same day as transient elastography and real-time strain elastography. Transient elastography and real-time strain elastography were performed in the same patient encounter by a single investigator using a medical device based on elastometry and an ultrasound machine, respectively. Diagnostic performance was assessed by using receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) analysis. One hundred thirty patients (91 men and 39 women) were analyzed. The cutoff values for transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index were 6.9 kPa, 1.82, and 0.37, respectively, for fibrosis score of 2 or higher; 7.3 kPa, 1.86, and 0.70, respectively, for fibrosis score of 3 or higher; and 9.3 kPa, 2.33, and 0.70, respectively, for fibrosis score of 4. AUC values of transient elastography, real-time strain elastography, aspartate-to-platelet ratio index were 0.88, 0.74, and 0.86, respectively, for fibrosis score of 2 or higher; 0.95, 0.80, and 0.89, respectively, for fibrosis score of 3 or higher; and 0.97, 0.80, and 0.84, respectively, for fibrosis score of 4. A combination of the three methods, when two of three were in agreement, showed AUC curves of 0.93, 0.95, and 0.95 for fibrosis scores of 2 or higher, 3 or higher, and 4, respectively. Transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index values were correlated with histologic stages of fibrosis. Transient elastography offered excellent diagnostic performance in assessing severe fibrosis and

  6. Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.

    PubMed

    Estes, Chris; Anstee, Quentin M; Arias-Loste, Maria Teresa; Bantel, Heike; Bellentani, Stefeno; Caballeria, Joan; Colombo, Massimo; Craxi, Antonio; Crespo, Javier; Day, Christopher P; Geier, Andreas; Kondili, Loreta A; Lazarus, Jeffrey V; Loomba, Rohit; Manns, Michael P; Marchesini, Giulio; Negro, Francesco; Petta, Salvatore; Ratziu, Vlad; Romero-Gomez, Manuel; Sanyal, Arun; Schattenberg, Jörn M; Tacke, Frank; Trautwein, Christian; Wei, Lai; Zeuzem, Stefan; Razavi, Homie

    2018-06-07

    Nonalcoholic fatty liver disease (NAFLD) with resulting nonalcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma (HCC) globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. A model was used to estimate NAFLD and NASH disease progression in 8 countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as result of urbanization and the lowest growth in Japan as result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as result of an aging/increasing population. NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can lead to advanced liver disease, and are occurring in increasing numbers in tandem with epidemics of obesity and diabetes. A mathematical model was built to understand how the disease burden associated with NAFLD and NASH will change over time. Results suggest increasing numbers of cases of advanced liver disease and liver-related mortality in the coming years

  7. Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population

    PubMed Central

    Liu, Xiao-Lin; Pan, Qin; Zhang, Rui-Nan; Shen, Feng; Yan, Shi-Yan; Sun, Chao; Xu, Zheng-Jie; Chen, Yuan-Wen; Fan, Jian-Gao

    2016-01-01

    AIM To assess disease-specific circulating microRNAs (miRNAs) in non-alcoholic steatohepatitis (NASH) patients. METHODS A total of 111 biopsy-proven non-alcoholic fatty liver disease (NAFLD) or chronic hepatitis B (CHB) patients and healthy controls from mainland China were enrolled to measure their serum levels of miR-122, -125b, -146b, -16, -21, -192, -27b and -34a. The correlations between serum miRNAs and histological features of NAFLD were determined. The diagnostic value of miRNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI), respectively. RESULTS Circulating miR-122, -16, -192 and -34a showed differential expression levels between NAFLD and CHB patients, and miR-34a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples (P < 0.01). Serum miR-122, -192 and -34a levels were correlated with steatosis (R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity (R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum miR-16 levels were associated with fibrosis (R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of miR-34a for NASH (area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but miR-16 showed a limited performance in the diagnosis of significant fibrosis in NASH. CONCLUSION Circulating miR-34a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH. PMID:27956809

  8. Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.

    PubMed

    Bhat, Mamatha; Tazari, Mahmood; Sebastiani, Giada

    2017-01-01

    Recurrent fibrosis after liver transplantation (LT) impacts on long-term graft and patient survival. We performed a meta-analysis to compare the accuracy of non-invasive methods to diagnose significant recurrent fibrosis (stage F2-F4) following LT. Studies comparing serum fibrosis biomarkers, namely AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), or transient elastography (TE) with liver biopsy in LT recipients were systematically identified through electronic databases. In the meta-analysis, we calculated the weighted pooled odds ratio and used a fixed effect model, as there was no significant heterogeneity between studies. Eight studies were included for APRI, four for FIB-4, and twelve for TE. The mean prevalence of significant liver fibrosis was 37.4%. The summary odds ratio was significantly higher for TE (21.17, 95% CI confidence interval 14.10-31.77, p = 1X10-30) as compared to APRI (9.02, 95% CI 5.79-14.07; p = 1X10-30) and FIB-4 (7.08, 95% CI 4.00-12.55; p = 1.93X10-11). In conclusion, TE performs best to diagnose recurrent fibrosis in LT recipients. APRI and FIB-4 can be used as an estimate of significant fibrosis at centres where TE is not available. Longitudinal assessment of fibrosis by means of these non-invasive tests may reduce the need for liver biopsy.

  9. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats

    PubMed Central

    Wengrower, Dov; Zanninelli, Giuliana; Latella, Giovanni; Necozione, Stefano; Metanes, Issa; Israeli, Eran; Lysy, Joseph; Pines, Mark; Papo, Orit; Goldin, Eran

    2012-01-01

    BACKGROUND: Intestinal fibrosis is a challenging clinical condition in several fibrostenosing enteropathies, particularly Crohn’s disease. Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis. Fibrosis, due to an abnormal accumulation of extracellular matrix proteins, is a chronic and progressive process mediated by cell/matrix/cytokine and growth factor interactions, but may be a reversible phenomenon. Of the several molecules regulating fibrogenesis, transforming growth factor-beta 1 (TGF-β1) appears to play a pivotal role; it is strongly induced by the local activation of angiotensin II. The levels of both TGF-β1 and angiotensin II are elevated in fibrostenosing Crohn’s disease. AIMS: To evaluate the in vivo effect of losartan – an angiotensin II receptor antagonist – on the course of chronic colitis-associated fibrosis and on TGF-β1 expression. METHODS: Colitis was induced by intrarectal instillation of trinitrobenzene sulphonic acid (TNBS) (15 mg/mL) while losartan was administered orally daily by gavage (7 mg/kg/day) for 21 days. Three groups of rats were evaluated: control (n=10); TNBS treated (n=10); and TNBS + losartan treated (n=10). Inflammation and fibrosis of the colon were evaluated by macro- and microscopic score analysis. Colonic TGF-β1 levels was measured using ELISA. RESULTS: Twenty-one days after induction, losartan significantly improved the macro- and microscopic scores of fibrosis in the colonic wall and reduced TGF-β1 concentration. CONCLUSIONS: Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-β1 expression. PMID:22288068

  10. Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis.

    PubMed

    Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Maher, Toby M; Nair, Arjun; Karwoski, Ronald; Renzoni, Elisabetta; Walsh, Simon L F; Hansell, David M; Wells, Athol U

    2017-07-01

    This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D LCO ), transfer coefficient of the lung for carbon monoxide ( K CO ), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer ( D LCO ).There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema. Copyright ©ERS 2017.

  11. Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase[S

    PubMed Central

    van der Veen, Jelske N.; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E.; Jacobs, René L.

    2017-01-01

    Mice lacking phosphatidylethanolamine N-methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt−/− mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt−/− livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt−/− mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt−/− mice were similar to those in Pemt+/+ mice. Importantly, Pemt−/− mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt−/− mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. PMID:28159867

  12. The Natural Course of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. PMID:27213358

  13. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV.

    PubMed

    Rockstroh, Jürgen Kurt

    2017-04-01

    Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.

  14. Idiopathic Pulmonary Fibrosis: Data-driven Textural Analysis of Extent of Fibrosis at Baseline and 15-Month Follow-up.

    PubMed

    Humphries, Stephen M; Yagihashi, Kunihiro; Huckleberry, Jason; Rho, Byung-Hak; Schroeder, Joyce D; Strand, Matthew; Schwarz, Marvin I; Flaherty, Kevin R; Kazerooni, Ella A; van Beek, Edwin J R; Lynch, David A

    2017-10-01

    Purpose To evaluate associations between pulmonary function and both quantitative analysis and visual assessment of thin-section computed tomography (CT) images at baseline and at 15-month follow-up in subjects with idiopathic pulmonary fibrosis (IPF). Materials and Methods This retrospective analysis of preexisting anonymized data, collected prospectively between 2007 and 2013 in a HIPAA-compliant study, was exempt from additional institutional review board approval. The extent of lung fibrosis at baseline inspiratory chest CT in 280 subjects enrolled in the IPF Network was evaluated. Visual analysis was performed by using a semiquantitative scoring system. Computer-based quantitative analysis included CT histogram-based measurements and a data-driven textural analysis (DTA). Follow-up CT images in 72 of these subjects were also analyzed. Univariate comparisons were performed by using Spearman rank correlation. Multivariate and longitudinal analyses were performed by using a linear mixed model approach, in which models were compared by using asymptotic χ 2 tests. Results At baseline, all CT-derived measures showed moderate significant correlation (P < .001) with pulmonary function. At follow-up CT, changes in DTA scores showed significant correlation with changes in both forced vital capacity percentage predicted (ρ = -0.41, P < .001) and diffusing capacity for carbon monoxide percentage predicted (ρ = -0.40, P < .001). Asymptotic χ 2 tests showed that inclusion of DTA score significantly improved fit of both baseline and longitudinal linear mixed models in the prediction of pulmonary function (P < .001 for both). Conclusion When compared with semiquantitative visual assessment and CT histogram-based measurements, DTA score provides additional information that can be used to predict diminished function. Automatic quantification of lung fibrosis at CT yields an index of severity that correlates with visual assessment and functional change in subjects with IPF

  15. Similarities and differences between pediatric and adult nonalcoholic fatty liver disease.

    PubMed

    Crespo, Maricruz; Lappe, Sara; Feldstein, Ariel E; Alkhouri, Naim

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is highly common and potentially serious in children and adolescents. The term NAFLD refers to a spectrum of diseases ranging from accumulation of fat in the liver (simple steatosis or nonalcoholic fatty liver "NAFL") to the potentially progressive form of nonalcoholic steatohepatitis (NASH) characterized by hepatocyte ballooning, inflammation, and often associated with fibrosis. While large prospective longitudinal studies in pediatric NAFLD are still lacking, growing evidence suggests that children with NAFL are at increased risk for cardiometabolic complications, while those with NASH and advance fibrosis are also at risk for significant liver-related morbidity including cirrhosis and its complications. Pediatric NAFLD shares features of adult NAFLD but also shows many different characteristics in terms of prevalence, histology, diagnosis and management. Translational studies suggest that NAFLD is a highly heritable disease in which genetic variations and environment closely interact to determine the disease phenotype and the progression to the more advanced forms of the disease. Changes in lifestyle, targeting gradual weight reduction, and physical exercise continue to be the mainstay of treatment for NAFLD in children. Recent advances in development of noninvasive diagnostic modalities and the potential for identifying effective pharmacological interventions may result in significant progress in the management of NAFLD in the pediatric population. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis.

    PubMed

    Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

    2016-07-01

    Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR(-/)(-) mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the (2)H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P<0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P<0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the (2)H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance.

    PubMed

    Toonen, Erik J M; Mirea, Andreea-Manuela; Tack, Cees J; Stienstra, Rinke; Ballak, Dov B; van Diepen, Janna A; Hijmans, Anneke; Chavakis, Triantafyllos; Dokter, Wim H; Pham, Christine T N; Netea, Mihai G; Dinarello, Charles A; Joosten, Leo A B

    2016-05-24

    Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive pro-inflammatory mediators IL-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human alpha-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3 deficient mice showed strongly reduced levels of lipids in the liver after fed a high fat diet. Moreover, these mice were resistant to high fat diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1(-/-) mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with alpha-1 antitrypsin during the last 10 days of a 16 week high fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

  18. The ZJU index is a powerful index for identifying NAFLD in the general Chinese population.

    PubMed

    Li, Linman; You, Wenyi; Ren, Wei

    2017-10-01

    The ZJU index is a novel model for detecting non-alcoholic fatty liver disease (NAFLD) that it is calculated based on combination of the body mass index, fasting plasma glucose, triglycerides, and the serum alanine aminotransferase-to-aspartate transaminase ratio. We aimed to evaluate the diagnostic accuracy of the ZJU index in detecting NAFLD in the Chinese population. This was a cross-sectional study. Anthropometric measurements, laboratory data, and ultrasonography features were collected through a standard protocol. The ZJU index, fatty liver index, hepatic steatosis index, lipid accumulation product, and visceral adiposity index were calculated. Then the predictive values of the five indices were compared according to the area under receiver-operating characteristic curve (AUROC) values. A total of 19,804 participants were recruited, of whom 7324 participants were diagnosed with NFALD and 12,480 subjects were regarded as controls. The AUROC value for NAFLD identification by the ZJU index was 0.925 (95% confidence interval [CI]: 0.919-0.931), which was significantly higher than the values for the other four models (P < 0.001). Furthermore, from age 31 years to >60 years, the AUROC for the ZJU increased from 87.1 to 95.4%, values which were also greater than those for the other four indices. Analysis by sex also showed that the performance of the ZJU index in males and females was better than that of the other four indices. The ZJU index is an accurate and easy to employ tool for identifying NAFLD in the general Chinese population.

  19. Targeting Lifestyle Behavior Change in Adults with NAFLD During a 20-min Consultation: Summary of the Dietary and Exercise Literature.

    PubMed

    Hallsworth, Kate; Avery, Leah; Trenell, Michael I

    2016-03-01

    Non-alcoholic fatty liver disease (NAFLD) is largely linked to poor diet, lack of physical activity/exercise, and being overweight. In the absence of approved pharmaceutical agents, lifestyle modification, encompassing dietary change and increased physical activity/exercise to initiate weight loss, is the recommended therapy for NAFLD. Despite this, the use of lifestyle therapy within clinical settings is lacking with limited guidance available about what it should involve, how it should be delivered, and whether it can be feasibly delivered as part of standard care. This paper highlights the evidence for the use of lifestyle modification in NAFLD. While there is evidence to support use of behavioral strategies to support lifestyle behavior change in other clinical populations, these are yet to be assessed in people with NAFLD. However, there is sufficient evidence to suggest that behavioral intervention targeting diet and physical activity to promote weight loss in general is effective and a number of practical strategies are presented on how this could be achieved.

  20. The Effects of Ramadan Fasting on Body Composition, Blood Pressure, Glucose Metabolism, and Markers of Inflammation in NAFLD Patients: An Observational Trial.

    PubMed

    Aliasghari, Fereshteh; Izadi, Azimeh; Gargari, Bahram Pourghassem; Ebrahimi, Sara

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and is a serious global health problem. Regarding the increasing prevalence of NAFLD, finding various strategies to prevent and manage the disease is of great importance. The aim of this study was to determine the effects of caloric restriction during Ramadan fasting on anthropometric indices, fasting glucose, plasma insulin, insulin resistance, and inflammatory cytokines (C-reactive protein and interleukin 6) in patients with NAFLD. We conducted this study with 83 patients with NAFLD, 42 of whom decided to fast and 41 controls who decided not to fast for Ramadan, between June 18 and July 17, 2015. Anthropometric parameters were measured and a sample of venous blood was obtained for biochemical assays before and after Ramadan. There was a significant decrease in all anthropometric parameters as well as fasting glucose, plasma insulin, and insulin resistance. Relative to the nonfasting group, fasting significantly reduced circulating inflammatory, but changes in blood pressure after Ramadan were not significant. This study shows significant effects on parameters during Ramadan fasting such as anthropometric indices, fasting glucose, plasma insulin, and inflammatory cytokines in patients with NAFLD. The results of this study suggest that Ramadan fasting may be useful to improve NAFLD, so further studies are needed in this area.

  1. Thrombin and factor Xa link the coagulation system with liver fibrosis.

    PubMed

    Dhar, Ameet; Sadiq, Fouzia; Anstee, Quentin M; Levene, Adam P; Goldin, Robert D; Thursz, Mark R

    2018-05-08

    Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis. HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated. Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/- 4.12) compared to culturing with FXa or thrombin alone (26.90%+/- 8.90, p = 0.02; 13.1%+/- 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001). FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.

  2. [Effect of Shugan Jianpi Recipe on LXRα/FAS signaling pathway mediated hepatocyte fatty deposits in NAFLD rats].

    PubMed

    Gong, Xiang-Wen; Yang-Qin-He; Yan, Hai-Zhen; Zhang, Yu-Pei; Huang, Jin; Xu, Yong-Jian; Zhang, Jin-Wen; Lin, Chun-Mei

    2014-12-01

    To explore the effect of Shugan Jianpi Recipe (SJR) on LXRα/FAS signaling pathway mediated hepatocyte fatty deposits in nonalcoholic fatty liver disease (NAFLD) rats. Totally 75 SPF grade male SD rats were randomly divided into 5 groups, i.e., the normal control group, the model group, the Shugan Recipe (SR) treatment groups, the Jianpi Recipe (JR) treatment group, and the SJR group. Except rats in the normal control group, the NAFLD rat model was duplicated using high fat diet (HFD). SR (Chaihu Shugan Powder) was administered to rats in the SR group. JR (Shenlin Baizhu Powder) was administered to rats in the JR group. SJR (Chaihu Shugan Powder plus Shenlin Baizhu Powder) was administered to rats in the SJR group. Changes of liver fat were analyzed using automatic biochemical analyzer. Liver cells were separated by low-speed centrifugation. Their activities and purities were identify using Typan blue and flow cytometry (FCM). Expression levels of LXRα and FAS mRNA in hepatocytes detected by Real-time quantitative PCR. Expression levels of LXRα and FAS protein were detected by Western blot. (1) Pathological results showed in the model group, hepatocytes were swollen with nucleus locating at the cell edge after oil red O staining; unequal sized small vacuoles could be seen inside cytoplasm. Some small vacuoles merged big vacuoles. All these indi- cated a NAFLD rat model was successfully established by high fat diet. Pathological structural changes could be impaired to some degree in all medicated groups, especially in the SR group. (2) Compared with the normal control group, expression levels of LXRα and FAS genes and proteins obviously increased in the model group (P < 0.01). Compared with the model group, their expression levels were obviously down-regulated in the JR group and the SR group (P < 0.01, P < 0.05). LXRα/FAS signaling pathway was an important signaling pathway for mediating lipid metabolism disorders of NAFLD rats. SJR could make hepatocyte fatty

  3. Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease.

    PubMed

    De Vito, Rita; Alisi, Anna; Masotti, Andrea; Ceccarelli, Sara; Panera, Nadia; Citti, Arianna; Salata, Michele; Valenti, Luca; Feldstein, Ariel E; Nobili, Valerio

    2012-07-01

    Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45+ (P<0.0001) and CD163+ (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3+ cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45+, CD3+ and CD163+ cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3+ cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.

  4. MR enterography-histology comparison in resected pediatric small bowel Crohn disease strictures: can imaging predict fibrosis?

    PubMed

    Barkmeier, Daniel T; Dillman, Jonathan R; Al-Hawary, Mahmoud; Heider, Amer; Davenport, Matthew S; Smith, Ethan A; Adler, Jeremy

    2016-04-01

    Crohn disease is a chronic inflammatory condition that can lead to intestinal strictures. The presence of fibrosis within strictures alters optimal management but is not reliably detected by current imaging methods. To correlate the MRI features of surgically resected small-bowel strictures in pediatric Crohn disease with histological inflammation and fibrosis scoring. We included children with Crohn disease who had symptomatic small-bowel strictures requiring surgical resection and had preoperative MR enterography (MRE) within 3 months of surgery (n = 20). Two blinded radiologists reviewed MRE examinations to document stricture-related findings. A pediatric pathologist scored stricture histological specimens for fibrosis (0-4) and inflammation (0-4). MRE findings were correlated with histological data using Spearman correlation (ρ) and exact logistic regression analysis. There was significant positive correlation between histological bowel wall fibrosis and inflammation in resected strictures (ρ = 0.55; P = 0.01). Confluent transmural histological fibrosis was associated with pre-stricture upstream small-bowel dilatation >3 cm at univariate (odds ratio [OR] = 51.7; 95% confidence interval [CI]: 7.6- > 999.9; P = 0.0002) and multivariate (OR = 43.4; 95% CI: 6.1- > 999.9; P = 0.0006, adjusted for age) analysis. The degree of bowel wall T2-weighted signal intensity failed to correlate with histological bowel wall fibrosis or inflammation (P-values >0.05). There were significant negative correlations between histological fibrosis score and patient age at resection (ρ = -0.48, P = 0.03), and time from diagnosis to surgery (ρ = -0.73, P = 0.0002). Histological fibrosis and inflammation co-exist in symptomatic pediatric Crohn disease small-bowel strictures and are positively correlated. Pre-stenotic upstream small-bowel dilatation greater than 3 cm is significantly associated with confluent transmural fibrosis.

  5. Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS.

    PubMed

    Petta, Salvatore; Ciresi, Alessandro; Bianco, Jessica; Geraci, Vincenzo; Boemi, Roberta; Galvano, Luigi; Magliozzo, Franco; Merlino, Giovanni; Craxì, Antonio; Giordano, Carla

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) recognize obesity and insulin resistance (IR) as common pathogenic background. We assessed 1) whether PCOS is a risk factor for steatosis, and 2) the impact, in PCOS patients, of IR and hyperandrogenism on steatosis and fibrosis. We considered 202 consecutive Italian PCOS nondiabetic patients and 101 age-matched controls. PCOS was diagnosed applying the Rotterdam diagnostic criteria. Steatosis was diagnosed if hepatic steatosis index (HSI) >36, while fibrosis by using the FIB-4 score. As surrogate estimate of insulin sensitivity we considered the insulin sensitivity index (ISI). Free androgen index (FAI) was calculated as estimate of biochemical hyperandrogenism. In the entire population, steatosis was observed in 68.8% of patients with PCOS, compared to 33.3 of controls (p<0.001), this association being maintained after adjusting for metabolic confounders (OR 3.73, 95% CI 1.74-8.02; P = 0.001). In PCOS patients, steatosis was independently linked to WC (OR 1.04, 95% CI 1.01-1.08; P = 0.006) and ISI Matsuda (OR 0.69, 95% CI 0.53-0.88; P = 0.004), not to free androgen index (OR 1.10, 95% CI 0.96-1.26; P = 0.14). Notably, ISI Matsuda was confirmed as independently associated with steatosis in both obese (OR 0.42, 95% CI 0.23-0.77, P = 0.005) and nonobese (OR 0.69, 95% CI 0.53-0.91, P = 0.009), patients, while FAI (OR 1.45, 95% CI 1.12-1.87; P = 0.004) emerged as an independent risk factor only in nonobese PCOS. Similarly, higher FIB-4 was independently associated with higher FAI (p = 0.02) in nonobese and with lower ISI Matsuda (p = 0.04) in obese patients. We found that PCOS is an independent risk factor for steatosis, and that, IR and hyperandrogenism, this last especially in nonobese patients, are the key players of liver damage in PCOS.

  6. Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Siddiqui, Mohammad S; Patidar, Kavish R; Boyett, Sherry; Luketic, Velimir A; Puri, Puneet; Sanyal, Arun J

    2016-04-01

    In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a

  7. Quantification of Fibrosis and Osteosclerosis in Myeloproliferative Neoplasms: A Computer-Assisted Image Study

    PubMed Central

    Teman, Carolin J.; Wilson, Andrew R.; Perkins, Sherrie L.; Hickman, Kimberly; Prchal, Josef T.; Salama, Mohamed E.

    2010-01-01

    Evaluation of bone marrow fibrosis and osteosclerosis in myeloproliferative neoplasms (MPN) is subject to interobserver inconsistency. Performance data for currently utilized fibrosis grading systems are lacking, and classification scales for osteosclerosis do not exist. Digital imaging can serve as a quantification method for fibrosis and osteosclerosis. We used digital imaging techniques for trabecular area assessment and reticulin-fiber quantification. Patients with all Philadelphia negative MPN subtypes had higher trabecular volume than controls (p ≤0.0015). Results suggest that the degree of osteosclerosis helps differentiate primary myelofibrosis from other MPN. Numerical quantification of fibrosis highly correlated with subjective scores, and interobserver correlation was satisfactory. Digital imaging provides accurate quantification for osteosclerosis and fibrosis. PMID:20122729

  8. Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.

    PubMed

    Martini, K; Gygax, C M; Benden, C; Morgan, A R; Parker, G J M; Frauenfelder, T

    2018-04-13

    To demonstrate, in patients with cystic fibrosis (CF), the correlation between three-dimensional dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements and computed tomography Brody score (CF-CT) and lung function testing (LFT). Twenty-one patients (median age, 25 years; female, n = 8) with a range of CF lung disease and five healthy volunteers (median age, 31 years; female, n = 2) underwent OE-MRI performed on a 1.5-T MRI scanner. Coronal volumes were acquired while patients alternately breathed room air and 100% oxygen. Pre-oxygen T 1 was measured. Dynamic series of T 1 -weighted volumes were then obtained while breathing oxygen. T 1 -parameter maps were generated and the following OE-MRI parameters were measured: oxygen uptake (ΔPO 2max ), wash-in time and wash-out time. High-resolution CT and LFT were performed. The relationship between CF-CT, LFT and OE-MRI parameters were evaluated using Pearson correlation for the whole lung and regionally. Mean CF-CT was 24.1±17.1. Mean ΔPO 2max and mean wash-in as well as skewness of wash-out showed significant correlation with CF-CT (ΔPO 2max : r = -0.741, p < 0.001; mean wash-in: r = 0.501, p = 0.017; skewness of wash-out: r = 0.597, p = 0.001). There was significant correlation for the whole lung and regionally between LFT parameters and OE-MR (ΔPO 2max : r = 0.718, p < 0.001; wash-in: r = -0.576, p = 0.003; wash-out skewness: r = -0.552, p = 0.004). Functional lung imaging using OE-MRI has the capability to assess the severity of CF lung disease and shows a significant correlation with LFT and CF-CT. • Oxygen-enhanced MRI might play a future role in evaluation and follow-up of cystic fibrosis. • Heterogeneity of parameter maps reflects localised functional impairment in cystic fibrosis. • Avoidance of cumulative radiation burden in CF is feasible using OE-MRI.

  9. Topical superoxide dismutase in posttreatment fibrosis in patients with head and neck cancer.

    PubMed

    Landeen, Kelly C; Spanos, William C; Gromer, Laurie

    2018-05-13

    Topical superoxide dismutase (SOD) has been shown to decrease postradiation fibrosis in some cancers but has not demonstrated an effect in patients with head and neck cancer. The purpose of this study was to determine if topical SOD is an effective treatment for postradiation neck fibrosis. This was a randomized prospective blinded clinical study of topical SOD versus placebo for the treatment of neck fibrosis. Measures of fibrosis grade and quality of life were obtained at baseline and after 3 months of treatment. Improvement in fibrosis score was comparable between the 2 study arms at 3 months. Both study groups showed improvement but the differences between groups was not statistically significant. Topical SOD likely has limited benefit for posttreatment neck fibrosis but this study confirms other published evidence of benefit from active physical therapy of posttreatment fibrosis in patients with head and neck cancer. © 2018 Wiley Periodicals, Inc.

  10. Gd-EOB-DTPA-enhanced T1ρ imaging vs diffusion metrics for assessment liver inflammation and early stage fibrosis of nonalcoholic steatohepatitis in rabbits.

    PubMed

    Xie, Yuanliang; Zhang, Hongfeng; Jin, Chaoling; Wang, Xiang; Wang, Xiaoqi; Chen, Jingting; Xu, Yikai

    2018-05-01

    To assess the value of T1ρ,T1ρ on hepatobiliary phase (HBP) and diffusion metrics in staging of Non-alcoholic fatty liver disease (NAFLD) activity scores, inflammation, fibrosis in NASH rabbits model. Non-alcoholic steatohepatitis (NASH) rabbits model was induced by feeding a varied duration of high-fat, high-cholesterol diet. T1ρ,T1ρ (HBP) 20min after administration of Gd-EOB-DTPA, and Intravoxel incoherent motion imaging (IVIM) diffusion-weighted imaging were performed on a 3.0T magnetic resonance (MR) imaging unit. The diagnostic value of each parameter for NAS, inflammation and fibrosis severity were determined. T1ρ (r=0.658) and T1ρ (HBP) (r=0.750) have strong association with NASH overall activity, T1ρ (HBP) is strongly relevant to inflammation stage (r=0.812). There was negative association between f and inflammation (r=-0.480), whilst no significant relation between other three parameters (apparent diffusion coefficient (ADC), pseudo-diffusion coefficient (D*) and true diffusion coefficient (D)) and inflammation or overall activity. The areas under the receiver operating characteristic curves (AUCs) of f, ADC, T1ρ and T1ρ-HBP were 0.871, 0.728, 0.849 and 0.949 for differentiating NASH; 0.731, 0.552, 0.925 and 0.922 for G2-3 inflammation; and 0.767, 0.625, 0.816, and 0.882 for S1-2 fibrosis. Comparison of ROC curve showed T1ρ (HBP) had an optimal diagnostic performance for NASH [T1ρ (HBP) vs ADC, AUC:0.949 vs 0.728, P=0.043], inflammation [T1ρ (HBP) vs ADC, AUC:0.922 vs 0.552, P=0.003], fibrosis [T1ρ (HBP) vs ADC, AUC:0.882 vs 0.625, P=0.046]. The combination of T1ρ (HBP)+perfusion fraction (f) showed highest diagnostic value for NASH (AUC:0.971), inflammation (AUC:0.935). Among T1ρ imaging and IVIM diffusion metrics, combination of T1rho (HBP)+f was found to be superior noninvasive imaging biomarker for NASH activity assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Fast macromolecular proton fraction mapping of the human liver in vivo for quantitative assessment of hepatic fibrosis

    PubMed Central

    Yarnykh, Vasily L.; Tartaglione, Erica V.; Ioannou, George N.

    2015-01-01

    Macromolecular proton fraction (MPF) is a quantitative MRI parameter determining the magnetization transfer (MT) effect in tissues and defined as a relative amount of immobile macromolecular protons involved into magnetization exchange with mobile water protons. MPF has a potential for quantitative assessment of fibrous tissue due to intrinsically high MPF specific for collagen. The goal of this study was to investigate a relationship between histologically determined fibrosis stage and MPF in the liver parenchyma measured using a recently developed fast single-point clinically-targeted MPF mapping method. Optimal saturation parameters for single-point liver MPF measurements were determined from the analysis of liver Z-spectra in vivo based on the error propagation model. Sixteen patients with chronic hepatitis C viral infection underwent 3T MRI using an optimized liver MPF mapping protocol. Fourteen patients had prior liver biopsy with histologically staged fibrosis (METAVIR scores F0-F3), and two patients had clinically diagnosed cirrhosis (score F4 was assigned). The protocol included four breath-hold three-dimensional scans with 2×3×6 mm3 resolution and 10 transverse sections: 1) dynamic acquisition of MT-weighted and reference images; 2) dynamic acquisition of three images for variable flip angle T1 mapping; 3) dual-echo B0 map; and 4) actual flip-angle imaging B1 map. Average liver MPF was determined as the mode of MPF histograms. MPF was significantly increased in patients with clinically significant fibrosis (scores F2-F4, n=6) compared to patients with no or mild fibrosis (scores F0-F1, n=10): 6.49±0.36% vs. 5.94±0.26%, P<0.01 (Mann-Whitney test). MPF and fibrosis score were strongly positively correlated with the Spearman's rank correlation coefficient 0.80 (P<0.001). This study demonstrates the feasibility of fast MPF mapping of the human liver in vivo and confirms the hypothesis that MPF is increased in hepatic fibrosis and associated with fibrosis

  12. Liver Fat Scores Moderately Reflect Interventional Changes in Liver Fat Content by a Low-Fat Diet but Not by a Low-Carb Diet

    PubMed Central

    Kabisch, Stefan; Bäther, Sabrina; Dambeck, Ulrike; Kemper, Margrit; Gerbracht, Christiana; Honsek, Caroline; Sachno, Anna

    2018-01-01

    Background: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder all over the world, mainly being associated with a sedentary lifestyle, adiposity, and nutrient imbalance. The increasing prevalence of NAFLD accommodates similar developments for type 2 diabetes and diabetes-related comorbidities and complications. Therefore, early detection of NAFLD is an utmost necessity. Potentially helpful tools for the prediction of NAFLD are liver fat indices. The fatty liver index (FLI) and the NAFLD-liver fat score (NAFLD-LFS) have been recently introduced for this aim. However, both indices have been shown to correlate with liver fat status, but there is neither sufficient data on the longitudinal representation of liver fat change, nor proof of a diet-independent correlation between actual liver fat change and change of index values. While few data sets on low-fat diets have been published recently, low-carb diets have not been yet assessed in this context. Aim: We aim to provide such data from a highly effective short-term intervention to reduce liver fat, comparing a low-fat and a low-carb diet in subjects with prediabetes. Methods: Anthropometric measurements, magnetic resonance (MR)-based intrahepatic lipid (IHL) content, and several serum markers for liver damage have been collected in 140 subjects, completing the diet phase in this trial. Area-under-the-responder-operator-curves (AUROC) calculations as well as cross-sectional and longitudinal Spearman correlations were used. Results: Both FLI and NAFLD-LFS predict liver fat with moderate accuracy at baseline (AUROC 0.775–0.786). These results are supported by correlation analyses. Changes in liver fat, achieved by the dietary intervention, correlate moderately with changes in FLI and NAFLD-LFS in the low-fat diet, but not in the low-carb diet. A correlation analysis between change of actual IHL content and change of single elements of the liver fat indices revealed diet-specific moderate to

  13. Liver Fat Scores Moderately Reflect Interventional Changes in Liver Fat Content by a Low-Fat Diet but Not by a Low-Carb Diet.

    PubMed

    Kabisch, Stefan; Bäther, Sabrina; Dambeck, Ulrike; Kemper, Margrit; Gerbracht, Christiana; Honsek, Caroline; Sachno, Anna; Pfeiffer, Andreas F H

    2018-01-31

    Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder all over the world, mainly being associated with a sedentary lifestyle, adiposity, and nutrient imbalance. The increasing prevalence of NAFLD accommodates similar developments for type 2 diabetes and diabetes-related comorbidities and complications. Therefore, early detection of NAFLD is an utmost necessity. Potentially helpful tools for the prediction of NAFLD are liver fat indices. The fatty liver index (FLI) and the NAFLD-liver fat score (NAFLD-LFS) have been recently introduced for this aim. However, both indices have been shown to correlate with liver fat status, but there is neither sufficient data on the longitudinal representation of liver fat change, nor proof of a diet-independent correlation between actual liver fat change and change of index values. While few data sets on low-fat diets have been published recently, low-carb diets have not been yet assessed in this context. We aim to provide such data from a highly effective short-term intervention to reduce liver fat, comparing a low-fat and a low-carb diet in subjects with prediabetes. Anthropometric measurements, magnetic resonance (MR)-based intrahepatic lipid (IHL) content, and several serum markers for liver damage have been collected in 140 subjects, completing the diet phase in this trial. Area-under-the-responder-operator-curves (AUROC) calculations as well as cross-sectional and longitudinal Spearman correlations were used. Both FLI and NAFLD-LFS predict liver fat with moderate accuracy at baseline (AUROC 0.775-0.786). These results are supported by correlation analyses. Changes in liver fat, achieved by the dietary intervention, correlate moderately with changes in FLI and NAFLD-LFS in the low-fat diet, but not in the low-carb diet. A correlation analysis between change of actual IHL content and change of single elements of the liver fat indices revealed diet-specific moderate to strong correlations between ΔIHL and

  14. A Western diet induced NAFLD in LDLR−/− mice is associated with reduced hepatic glutathione synthesis

    PubMed Central

    Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F.; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

    2017-01-01

    Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR−/− mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the 2H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P < 0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P <0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the 2H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. PMID:27036364

  15. Vocational Rehabilitation of the Person with Cystic Fibrosis.

    ERIC Educational Resources Information Center

    Isralsky, Marc; And Others

    1979-01-01

    Explored vocational development, self-concept, and vocational adjustment of persons with cystic fibrosis. The following measures of vocational development correlated with work adjustment: vocational plans, educational plans, initiative, occupational information, and average vocational development score. Vocational development did not correlate…

  16. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy

    NASA Astrophysics Data System (ADS)

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-08-01

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P < 0.001). A biphasic scoring method was applied, combining support vector machine and multivariate generalized linear models to assess the early and late stages of fibrosis, respectively, based on these parameters. The verification cohort was used to verify the scoring method, and the area under the receiver operating characteristic curve was >0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  17. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy.

    PubMed

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-08-11

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P < 0.001). A biphasic scoring method was applied, combining support vector machine and multivariate generalized linear models to assess the early and late stages of fibrosis, respectively, based on these parameters. The verification cohort was used to verify the scoring method, and the area under the receiver operating characteristic curve was >0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  18. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy

    PubMed Central

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-01-01

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P < 0.001). A biphasic scoring method was applied, combining support vector machine and multivariate generalized linear models to assess the early and late stages of fibrosis, respectively, based on these parameters. The verification cohort was used to verify the scoring method, and the area under the receiver operating characteristic curve was >0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method. PMID:26260921

  19. Real-time elastography as a noninvasive assessment of liver fibrosis in chronic hepatitis C Egyptian patients: a prospective study.

    PubMed

    Mobarak, Lamiaa; Nabeel, Mohammed M; Hassan, Ehsan; Omran, Dalia; Zakaria, Zeinab

    2016-01-01

    Hepatitis C virus is a worldwide problem. Noninvasive methods for liver fibrosis assessment as ultrasound-based approaches have emerged to replace liver biopsy. The aim of this study was to evaluate the diagnostic accuracy of real-time elastography (RTE) in the assessment of liver fibrosis in patients with chronic hepatitis C (CHC), compared with transient elastography and liver biopsy. RTE, FibroScan and liver biopsy were performed in 50 CHC patients. In addition, aspartate aminotransferase to platelet ratio index (APRI) and routine laboratory values were included in the analysis. RTE was able to diagnose significant hepatic fibrosis (F ≥2) according to METAVIR scoring system at cut-off value of 2.49 with sensitivity 100%, specificity 66%, and area under the receiver-operating characteristics (AUROC) 0.8. FibroScan was able to predict significant fibrosis at cut-off value 7.5 KPa with sensitivity 88%, specificity 100%, and AUROC 0.94.APRI was able to predict significant hepatic fibrosis (F ≥2) with sensitivity 54%, specificity 80%, and AUROC 0.69. There was a significant positive correlation between the FibroScan score and RTE score (r=0.6, P=0.001). Although FibroScan is superior in determining significant hepatic fibrosis, our data suggest that RTE may be a useful and promising noninvasive method for liver fibrosis assessment in CHC patients especially in cases with technical limitations for FibroScan.

  20. Customer satisfaction survey to improve the European cystic fibrosis external quality assessment scheme.

    PubMed

    Berwouts, Sarah; Dequeker, Elisabeth

    2011-08-01

    The Cystic Fibrosis European Network, coordinated from within the Katholieke Universiteit Leuven, is the provider of the European cystic fibrosis external quality assessment (EQA) scheme. The network aimed to seek feedback from laboratories that participated in the cystic fibrosis scheme in order to improve services offered. In this study we analysed responses to an on-line customer satisfaction survey conducted between September and November 2009. The survey was sent to 213 laboratories that participated in the cystic fibrosis EQA scheme of 2008; 69 laboratories (32%) responded. Scores for importance and satisfaction were obtained from a five-point Likert scale for 24 attributes. A score of one corresponded to very dissatisfied/very unimportant and five corresponded to very satisfied/very important. Means were calculated and placed in a two-dimensional grid (importance-satisfaction analysis). Means were subtracted from each other to obtain gap values (gap-analysis). No attribute had a mean score below 3.63. The overall mean of satisfaction was 4.35. Opportunities for improvement enclosed clarity, usefulness and completeness of the general report and individual comments, and user-friendliness of the electronic datasheet. This type of customer satisfaction survey was a valuable instrument to identify opportunities to improve the cystic fibrosis EQA scheme. It should be conducted on a regular basis to reveal new opportunities in the future and to assess effectiveness of actions taken. Moreover, it could be a model for other EQA providers seeking feedback from participants. Overall, the customer satisfaction survey provided a powerful quality of care improvement tool.

  1. Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase.

    PubMed

    van der Veen, Jelske N; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E; Jacobs, René L

    2017-04-01

    Mice lacking phosphatidylethanolamine N -methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt -/- mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt -/- livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt -/- mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt -/- mice were similar to those in Pemt +/+ mice. Importantly, Pemt -/- mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt -/- mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  2. Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: Association of GGT and HOMA-IR with NAFLD.

    PubMed

    Hossain, Israt Ara; Rahman Shah, Md Mijanur; Rahman, Mohammad Khalilur; Ali, Liaquat

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and is frequently associated with insulin resistance (HOMA-IR) syndrome. Recently serum gamma glutamyl transferase (GGT) has been considered as surrogate marker of NAFLD leading to oxidative stress and hepatocellular damage. In the present study we examined the association of serum GGT and HOMA-IR with NAFLD in Bangladeshi adult subjects. Under a cross-sectional analytical design a total of 110 subjects were recruited who came for their routine health check up in the BIHS Hospital, Darussalam, Dhaka, Bangladesh. After whole abdomen ultrasonography, 62 were diagnosed as non-NAFLD and 48 were NAFLD subjects. Serum glucose was measured by glucose-oxidase method, lipid profile and liver enzymes by enzymatic colorimetric method, glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography (HPLC), serum insulin were measured by enzyme-linked immunosorbent assay. HOMA-IR was calculated by homeostasis model assessment (HOMA). NAFLD subjects had significantly higher levels of GGT and HOMA-IR as compared to their non-NAFLD counterparts. Multiple linear regression analysis showed a significant positive association of HOMA-IR with GGT after adjusting the effects of waist circumference (WC) and HbA1c. In binary logistic regression analysis, HOMA-IR and GGT were found to be significant determinants of NAFLD after adjusting the effects of WC and HbA1c. These results suggest that elevated levels of GGT and insulin resistance are more likely to develop NAFLD and thus support a role of these determinants in the pathogenesis of NAFLD in Bangladeshi adult subjects. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  3. MiR-21 promotes fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis by activating IL-6 expression.

    PubMed

    Sun, Chao; Tian, Jiwei; Liu, Xinhui; Guan, Guoping

    2017-08-26

    The molecular mechanism underlying the fibrosis of ligamentum flavum(LF) in patients with lumbar spinal canal stenosis(LSCS) remains unknown. MicroRNAs are reported to play important roles in regulating fibrosis in different organs. The present study aimed to identify fibrosis related miR-21 expression profile and investigate the pathological process of miR-21 in the fibrosis of LF hypertrophy and associated regulatory mechanisms. 15 patients with LSCS underwent surgical treatment were enrolled in this study. For the control group, 11 patients with lumbar disc herniation(LDH) was included. The LF thickness was measured on MRI. LF samples were obtained during the surgery. Fibrosis score was assessed by Masson's trichrome staining. The expression of miR-21 in LF tissues were determined by RT-PCR. Correlation among LF thickness, fibrosis score, and miR-21 expression was analyzed. In addition, Lentiviral vectors for miR-21 mimic were constructed and transfected into LF cells to examine the role of miR-21 in LF fibrosis. Types I and III collagen were used as indicators of fibrosis. IL-6 expression in LF cells after transfection was investigated by RT-PCR and ELISA. Patients in two groups showed similar outcomes regarding age, gender, level of LF tissue. The thickness and fibrosis score of LF in the LSCS group were significantly greater than those in LDH group (all P < 0.05). Similarly, the expression of miR-21 in LSCS group was substantially higher than that in LDH group(P < 0.05). Furthermore, the miR-21 expression exhibited positive correlations with the LF thickness (r = 0.595, P < 0.05) and fibrosis score (r = 0.608, P < 0.05). Of note, miR-21 over-expression increased the expression levels of collagen I and III (P < 0.05). Also, IL-6 expression and secretion in LF cells was elevated after transfection of miR-21 mimic. MiR-21 is a fibrosis-associated miRNA and promotes inflammation in LF tissue by activating IL-6 expression, leading to LF fibrosis and

  4. Family history and obesity in youth, their effect on acylcarnitine/aminoacids metabolomics and non-alcoholic fatty liver disease (NAFLD). Structural equation modeling approach

    PubMed Central

    Vadillo-Ortega, Felipe; Caballero, Augusto Enrique; Ibarra-González, Isabel; Herrera-Rosas, Arturo; Serratos-Canales, María Fabiola; León-Hernández, Mireya; González-Chávez, Antonio; Mummidi, Srinivas; Duggirala, Ravindranath

    2018-01-01

    Background Structural equation modeling (SEM) can help understanding complex functional relationships among obesity, non-alcoholic fatty liver disease (NAFLD), family history of obesity, targeted metabolomics and pro-inflammatory markers. We tested two hypotheses: 1) If obesity precedes an excess of free fatty acids that increase oxidative stress and mitochondrial dysfunction, there would be an increase of serum acylcarnitines, amino acids and cytokines in obese subjects. Acylcarnitines would be related to non-alcoholic fatty disease that will induce insulin resistance. 2) If a positive family history of obesity and type 2 diabetes are the major determinants of the metabolomic profile, there would be higher concentration of amino acids and acylcarnitines in patients with this background that will induce obesity and NAFLD which in turn will induce insulin resistance. Methods/Results 137 normoglycemic subjects, mean age (SD) of 30.61 (8.6) years divided in three groups: BMI<25 with absence of NAFLD (G1), n = 82; BMI>30 with absence of NAFLD (G2), n = 24; and BMI>30 with NAFLD (G3), n = 31. Family history of obesity (any) was present in 53%. Both models were adjusted in SEM. Family history of obesity predicted obesity but could not predict acylcarnitines and amino acid concentrations (effect size <0.2), but did predict obesity phenotype. Conclusion Family history of obesity is the major predictor of obesity, and the metabolic abnormalities on amino acids, acylcarnitines, inflammation, insulin resistance, and NAFLD. PMID:29466466

  5. Family history and obesity in youth, their effect on acylcarnitine/aminoacids metabolomics and non-alcoholic fatty liver disease (NAFLD). Structural equation modeling approach.

    PubMed

    Romero-Ibarguengoitia, Maria Elena; Vadillo-Ortega, Felipe; Caballero, Augusto Enrique; Ibarra-González, Isabel; Herrera-Rosas, Arturo; Serratos-Canales, María Fabiola; León-Hernández, Mireya; González-Chávez, Antonio; Mummidi, Srinivas; Duggirala, Ravindranath; López-Alvarenga, Juan Carlos

    2018-01-01

    Structural equation modeling (SEM) can help understanding complex functional relationships among obesity, non-alcoholic fatty liver disease (NAFLD), family history of obesity, targeted metabolomics and pro-inflammatory markers. We tested two hypotheses: 1) If obesity precedes an excess of free fatty acids that increase oxidative stress and mitochondrial dysfunction, there would be an increase of serum acylcarnitines, amino acids and cytokines in obese subjects. Acylcarnitines would be related to non-alcoholic fatty disease that will induce insulin resistance. 2) If a positive family history of obesity and type 2 diabetes are the major determinants of the metabolomic profile, there would be higher concentration of amino acids and acylcarnitines in patients with this background that will induce obesity and NAFLD which in turn will induce insulin resistance. 137 normoglycemic subjects, mean age (SD) of 30.61 (8.6) years divided in three groups: BMI<25 with absence of NAFLD (G1), n = 82; BMI>30 with absence of NAFLD (G2), n = 24; and BMI>30 with NAFLD (G3), n = 31. Family history of obesity (any) was present in 53%. Both models were adjusted in SEM. Family history of obesity predicted obesity but could not predict acylcarnitines and amino acid concentrations (effect size <0.2), but did predict obesity phenotype. Family history of obesity is the major predictor of obesity, and the metabolic abnormalities on amino acids, acylcarnitines, inflammation, insulin resistance, and NAFLD.

  6. Identifying the superior measure of rapid fibrosis for predicting premature cirrhosis after liver transplantation for hepatitis C.

    PubMed

    Howell, J; Sawhney, R; Angus, P; Fink, M; Jones, R; Wang, B Z; Visvanathan, K; Crowley, P; Gow, P

    2013-12-01

    Hepatitis C virus (HCV) recurrence post liver transplant is universal, with a subgroup of patients developing rapid hepatic fibrosis. Various clinical definitions of rapid fibrosis (RF) have been used to identify risks for rapid progression, but their comparability and efficacy at predicting adverse outcomes has not been determined. Retrospective data analysis was conducted on 100 adult patients with HCV who underwent liver transplantation at a single center. We measured year 1 fibrosis progression (RF defined as METAVIR F score ≥ 1 at 1-year liver biopsy), time to METAVIR F2-stage fibrosis, and fibrosis rate (calculated using liver biopsies graded by METAVIR scoring F0-4; fibrosis rate = fibrosis stage/year post transplant). RF was defined as ≥ 0.5 units/year. Multivariate analysis revealed that donor age and peak HCV viral load were significant risks for RF, when fibrosis rate was used to define RF. Advanced donor age was a risk for rapid progression to F2-stage fibrosis, whereas genotype 2 or 3 HCV infection was protective. Fibrosis rate had the strongest correlation with time to cirrhosis development (P < 0.0001, r = -0.76) and was the most accurate predictor of rapid graft cirrhosis (P < 0.0001, area under the curve 0.979, sensitivity 100%, specificity 94%). Different measures of RF progression identify different risks for RF and are not directly comparable. Fibrosis rate was the most accurate predictor of rapid graft cirrhosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. The diagnostic value of a globulin/platelet model for evaluating liver fibrosis in chronic hepatitis B patients.

    PubMed

    Coskun, Banu Demet; Altinkaya, Engin; Sevinc, Eylem; Ozen, Mustafa; Karaman, Hatice; Karaman, Ahmet; Poyrazoglu, Orhan

    2015-12-01

    Liver biopsy, which is considered the best method for evaluating hepatic fibrosis, has important adverse events. Therefore, non-invasive tests have been developed to determine the degree of hepatic fibrosis in patients with chronic hepatitis B. To verify the usefulness of a new fibrosis index the globulin/platelet model in patients with chronic hepatitis B and to compare it with other noninvasive tests for predicting significant fibrosis. This study was the second to evaluate the globulin/platelet model in HBV patients. We retrospectively investigated 228 patients with chronic hepatitis B who performed liver biopsy from 2013 to 2014. The globulin/platelet model, APGA [AST/Platelet/Gamma-glutamyl transpeptidase/Alfa-fetoprotein], FIB4, fibrosis index, cirrhosis discriminate score, and Fibro-quotient were calculated, and the diagnostic accuracies of all of the fibrosis indices were compared between the F0-2 (no-mild fibrosis) and F3-6 (significant fibrosis) groups. All of the noninvasive markers were significantly correlated with the stage of liver fibrosis (p < 0,001). To predict significant fibrosis (F ≥ 3), the area under the curve (95% CI) was found to be greatest for APGA (0.83 [0.74-0.86]), followed by FIB-4 (0.75[0.69-0.80]), the globulin/platelet model (0.74 [0.68-0.79]), fibrosis index (0.72 [0.6-0.78], cirrhosis discriminate score (0.71 [0.64-0.76]) and Fibro-quotient (0.62 [0.55-0.7]). The area under the receiver operating characteristic curves of APGA was significantly higher than that of the other noninvasive fibrosis markers (p < 0.05). While the APGA index was found to be the most valuable test for the prediction significant fibrosis in patients with chronic hepatitis B, GP model was the thirth valuable test. Therefore, we recommended that APGA could be used instead of the GP model for prediction liver fibrosis.

  8. Detecting liver fibrosis with Gd-EOB-DTPA-enhanced MRI: A confirmatory study.

    PubMed

    Verloh, Niklas; Utpatel, Kirsten; Haimerl, Michael; Zeman, Florian; Beyer, Lukas; Fellner, Claudia; Brennfleck, Frank; Dahlke, Marc H; Stroszczynski, Christian; Evert, Matthias; Wiggermann, Philipp

    2018-04-18

    Strong correlations between the grade of fibrosis and cirrhosis, classified using the Ishak scoring system, and the uptake characteristics of Gd-EOB-DTPA with the relative enhancement (RE) of the liver parenchyma have been reported. To confirm the results of a retrospective analysis, patients undergoing liver surgery were prospectively examined with Gd-EOB-DTPA-enhanced liver 3 Tesla MRI to determine the degree of liver fibrosis. Correlations between the grade of fibrosis and cirrhosis, classified using the Ishak scoring system, and RE were investigated and compared with those derived from an initial retrospective study. After validating the cut-off values in the retrospective study (Ishak ≥ 1, RE-cut-off 0.90; Ishak ≥ 2, RE-cut-off 0.79; Ishak ≥ 4, RE-cut-off 0.60; and Ishak = 6, RE-cut-off 0.47), we showed that Gd-EOB-DTPA has a high sensitivity (≥86%) and a high positive predictive value (≥86%). These results support the use of Gd-EOB-DTPA-enhanced liver MRI as a non-invasive method for determining the degree of liver fibrosis and cirrhosis.

  9. Chronic Azithromycin Use in Cystic Fibrosis and Risk of Treatment-Emergent Respiratory Pathogens.

    PubMed

    Cogen, Jonathan D; Onchiri, Frankline; Emerson, Julia; Gibson, Ronald L; Hoffman, Lucas R; Nichols, David P; Rosenfeld, Margaret

    2018-02-23

    Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in cystic fibrosis patients. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens. To determine if chronic azithromycin use (defined as thrice weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens. We performed a new-user, propensity-score matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity-score matched 1:1 with contemporaneous non-users. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the two years prior to cohort entry. After propensity score matching, mean age of the cohorts was ~12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, non-tuberculous mycobacteria, and Burkholderia cepacia complex compared to non-users. The risk of acquiring the remaining five pathogens was not significantly different between users and non-users. Using an innovative new-user, propensity-score matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric cystic fibrosis patients.

  10. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

    PubMed

    Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

    2018-02-01

    The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

  11. Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis.

    PubMed

    Rich, Nicole E; Oji, Stefany; Mufti, Arjmand R; Browning, Jeffrey D; Parikh, Neehar D; Odewole, Mobolaji; Mayo, Helen; Singal, Amit G

    2018-02-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting 75-100 million Americans. However, the disease burden may not be equally distributed among races or ethnicities. We conducted a systematic review and meta-analysis to characterize racial and ethnic disparities in NAFLD prevalence, severity, and prognosis. We searched MEDLINE, EMBASE, and Cochrane databases through August 2016 for studies that reported NAFLD prevalence in population-based or high-risk cohorts, NAFLD severity including presence of nonalcoholic steatohepatitis (NASH) and significant fibrosis, and NAFLD prognosis including development of cirrhosis complications and mortality. Pooled relative risks, according to race and ethnicity, were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 34 studies comprising 368,569 unique patients that characterized disparities in NAFLD prevalence, severity, or prognosis. NAFLD prevalence was highest in Hispanics, intermediate in Whites, and lowest in Blacks, although differences between groups were smaller in high-risk cohorts (range 47.6%-55.5%) than population-based cohorts (range, 13.0%-22.9%). Among patients with NAFLD, risk of NASH was higher in Hispanics (relative risk, 1.09; 95% CI, 0.98-1.21) and lower in Blacks (relative risk, 0.72; 95% CI, 0.60-0.87) than Whites. However, the proportion of patients with significant fibrosis did not significantly differ among racial or ethnic groups. Data were limited and discordant on racial or ethnic disparities in outcomes of patients with NAFLD. In a systematic review and meta-analysis, we found significant racial and ethnic disparities in NAFLD prevalence and severity in the United States, with the highest burden in Hispanics and lowest burden in Blacks. However, data are discordant on racial or ethnic differences in outcomes of patients with NAFLD. Copyright © 2018 AGA Institute. Published by

  12. A study of the prebiotic-like effects of tomato juice consumption in rats with diet-induced non-alcoholic fatty liver disease (NAFLD).

    PubMed

    García-Alonso, F J; González-Barrio, R; Martín-Pozuelo, G; Hidalgo, N; Navarro-González, I; Masuero, D; Soini, E; Vrhovsek, U; Periago, M J

    2017-10-18

    Gut microbiota may play a role in the pathogenesis of NAFLD. We investigated whether tomato juice consumption for 5 weeks could ameliorate high-fat diet-induced alterations in certain intestinal bacterial groups and products arising from their metabolism (short-chain fatty acids and microbial phenolic catabolites). For this, we used a rat model with NAFLD induced by a high-fat diet, involving four experimental groups: NA (standard diet and water), NL (standard diet and tomato juice), HA (high-fat diet and water) and HL (high-fat diet and tomato juice). The onset of NAFLD impacted the gut microbiota profile, reducing the abundance of Bifidobacterium and Lactobacillus and increasing that of Enterobacteriaceae. Also, reduced concentrations of propionate, butyrate and phenolic catabolites and an increased acetate to propionate (Ac : Pr) ratio were observed. Tomato juice intake partially ameliorated high-fat diet-induced disturbances, particularly by increasing Lactobacillus abundance and diminishing the Ac : Pr ratio, suggesting a potential improvement of the metabolic pattern of NAFLD.

  13. The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes.

    PubMed

    Fu, Bin; Ok, Chi Young; Goswami, Maitrayee; Xei, Wei; Jaso, Jesse M; Muzzafar, Tariq; Bueso-Ramos, Carlos; Verstovsek, Srdan; Garcia-Manero, Guillermo; Medeiros, L Jeffrey; Wang, Sa A

    2013-10-01

    The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS. We retrieved all therapy-related MDS (t-MDS) cases (n = 266) diagnosed at our hospital over a 10-year period (2003-2012). Reticulin and trichrome stains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin and eosin-stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis. Moderate/severe BM fibrosis was found in 47 (17%) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p = 0.039) and higher numbers of circulating blasts (p = 0.051) but with similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p < 0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, -5 and -17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p = 0.031 and p = 0.043, respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses. Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy-related MDS.

  14. Toxic AGE (TAGE) Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD

    PubMed Central

    Takeuchi, Masayoshi; Takino, Jun-ichi; Sakasai-Sakai, Akiko; Takata, Takanobu; Tsutsumi, Mikihiro

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD. PMID:28632197

  15. Evaluating Diagnostic Accuracy of Noninvasive Tests in Assessment of Significant Liver Fibrosis in Chronic Hepatitis C Egyptian Patients.

    PubMed

    Omran, Dalia; Zayed, Rania A; Nabeel, Mohammed M; Mobarak, Lamiaa; Zakaria, Zeinab; Farid, Azza; Hassany, Mohamed; Saif, Sameh; Mostafa, Muhammad; Saad, Omar Khalid; Yosry, Ayman

    2018-05-01

    Stage of liver fibrosis is critical for treatment decision and prediction of outcomes in chronic hepatitis C (CHC) patients. We evaluated the diagnostic accuracy of transient elastography (TE)-FibroScan and noninvasive serum markers tests in the assessment of liver fibrosis in CHC patients, in reference to liver biopsy. One-hundred treatment-naive CHC patients were subjected to liver biopsy, TE-FibroScan, and eight serum biomarkers tests; AST/ALT ratio (AAR), AST to platelet ratio index (APRI), age-platelet index (AP index), fibrosis quotient (FibroQ), fibrosis 4 index (FIB-4), cirrhosis discriminant score (CDS), King score, and Goteborg University Cirrhosis Index (GUCI). Receiver operating characteristic curves were constructed to compare the diagnostic accuracy of these noninvasive methods in predicting significant fibrosis in CHC patients. TE-FibroScan predicted significant fibrosis at cutoff value 8.5 kPa with area under the receiver operating characteristic (AUROC) 0.90, sensitivity 83%, specificity 91.5%, positive predictive value (PPV) 91.2%, and negative predictive value (NPV) 84.4%. Serum biomarkers tests showed that AP index and FibroQ had the highest diagnostic accuracy in predicting significant liver fibrosis at cutoff 4.5 and 2.7, AUROC was 0.8 and 0.8 with sensitivity 73.6% and 73.6%, specificity 70.2% and 68.1%, PPV 71.1% and 69.8%, and NPV 72.9% and 72.3%, respectively. Combined AP index and FibroQ had AUROC 0.83 with sensitivity 73.6%, specificity 80.9%, PPV 79.6%, and NPV 75.7% for predicting significant liver fibrosis. APRI, FIB-4, CDS, King score, and GUCI had intermediate accuracy in predicting significant liver fibrosis with AUROC 0.68, 0.78, 0.74, 0.74, and 0.67, respectively, while AAR had low accuracy in predicting significant liver fibrosis. TE-FibroScan is the most accurate noninvasive alternative to liver biopsy. AP index and FibroQ, either as individual tests or combined, have good accuracy in predicting significant liver fibrosis

  16. Non-alcoholic fatty liver disease and dyslipidemia: An update.

    PubMed

    Katsiki, Niki; Mikhailidis, Dimitri P; Mantzoros, Christos S

    2016-08-01

    Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment

    PubMed Central

    Dongiovanni, Paola; Anstee, Quentin M; Valenti, Luca

    2013-01-01

    Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome. PMID:23394097

  18. Experimenting liver fibrosis diagnostic by two photon excitation microscopy and Bag-of-Features image classification.

    PubMed

    Stanciu, Stefan G; Xu, Shuoyu; Peng, Qiwen; Yan, Jie; Stanciu, George A; Welsch, Roy E; So, Peter T C; Csucs, Gabor; Yu, Hanry

    2014-04-10

    The accurate staging of liver fibrosis is of paramount importance to determine the state of disease progression, therapy responses, and to optimize disease treatment strategies. Non-linear optical microscopy techniques such as two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) can image the endogenous signals of tissue structures and can be used for fibrosis assessment on non-stained tissue samples. While image analysis of collagen in SHG images was consistently addressed until now, cellular and tissue information included in TPEF images, such as inflammatory and hepatic cell damage, equally important as collagen deposition imaged by SHG, remain poorly exploited to date. We address this situation by experimenting liver fibrosis quantification and scoring using a combined approach based on TPEF liver surface imaging on a Thioacetamide-induced rat model and a gradient based Bag-of-Features (BoF) image classification strategy. We report the assessed performance results and discuss the influence of specific BoF parameters to the performance of the fibrosis scoring framework.

  19. Experimenting Liver Fibrosis Diagnostic by Two Photon Excitation Microscopy and Bag-of-Features Image Classification

    PubMed Central

    Stanciu, Stefan G.; Xu, Shuoyu; Peng, Qiwen; Yan, Jie; Stanciu, George A.; Welsch, Roy E.; So, Peter T. C.; Csucs, Gabor; Yu, Hanry

    2014-01-01

    The accurate staging of liver fibrosis is of paramount importance to determine the state of disease progression, therapy responses, and to optimize disease treatment strategies. Non-linear optical microscopy techniques such as two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) can image the endogenous signals of tissue structures and can be used for fibrosis assessment on non-stained tissue samples. While image analysis of collagen in SHG images was consistently addressed until now, cellular and tissue information included in TPEF images, such as inflammatory and hepatic cell damage, equally important as collagen deposition imaged by SHG, remain poorly exploited to date. We address this situation by experimenting liver fibrosis quantification and scoring using a combined approach based on TPEF liver surface imaging on a Thioacetamide-induced rat model and a gradient based Bag-of-Features (BoF) image classification strategy. We report the assessed performance results and discuss the influence of specific BoF parameters to the performance of the fibrosis scoring framework. PMID:24717650

  20. Experimenting Liver Fibrosis Diagnostic by Two Photon Excitation Microscopy and Bag-of-Features Image Classification

    NASA Astrophysics Data System (ADS)

    Stanciu, Stefan G.; Xu, Shuoyu; Peng, Qiwen; Yan, Jie; Stanciu, George A.; Welsch, Roy E.; So, Peter T. C.; Csucs, Gabor; Yu, Hanry

    2014-04-01

    The accurate staging of liver fibrosis is of paramount importance to determine the state of disease progression, therapy responses, and to optimize disease treatment strategies. Non-linear optical microscopy techniques such as two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) can image the endogenous signals of tissue structures and can be used for fibrosis assessment on non-stained tissue samples. While image analysis of collagen in SHG images was consistently addressed until now, cellular and tissue information included in TPEF images, such as inflammatory and hepatic cell damage, equally important as collagen deposition imaged by SHG, remain poorly exploited to date. We address this situation by experimenting liver fibrosis quantification and scoring using a combined approach based on TPEF liver surface imaging on a Thioacetamide-induced rat model and a gradient based Bag-of-Features (BoF) image classification strategy. We report the assessed performance results and discuss the influence of specific BoF parameters to the performance of the fibrosis scoring framework.

  1. Quantitative analysis of diagnosing pancreatic fibrosis using EUS-elastography (comparison with surgical specimens).

    PubMed

    Itoh, Yuya; Itoh, Akihiro; Kawashima, Hiroki; Ohno, Eizaburo; Nakamura, Yosuke; Hiramatsu, Takeshi; Sugimoto, Hiroyuki; Sumi, Hajime; Hayashi, Daijuro; Kuwahara, Takamichi; Morishima, Tomomasa; Funasaka, Kohei; Nakamura, Masanao; Miyahara, Ryoji; Ohmiya, Naoki; Katano, Yoshiaki; Ishigami, Masatoshi; Goto, Hidemi; Hirooka, Yoshiki

    2014-07-01

    An accurate diagnosis of pancreatic fibrosis is clinically important and may have potential for staging chronic pancreatitis. The aim of this study was to diagnose the grade of pancreatic fibrosis through a quantitative analysis of endoscopic ultrasound elastography (EUS-EG). From September 2004 to October 2010, 58 consecutive patients examined by EUS-EG for both pancreatic tumors and their upstream pancreas before pancreatectomy were enrolled. Preoperative EUS-EG images in the upstream pancreas were statistically quantified, and the results were retrospectively compared with postoperative histological fibrosis in the same area. For the quantification of EUS-EG images, 4 parameters (mean, standard deviation, skewness, and kurtosis) were calculated using novel software. Histological fibrosis was graded into 4 categories (normal, mild fibrosis, marked fibrosis, and severe fibrosis) according to a previously reported scoring system. The fibrosis grade in the upstream pancreas was normal in 24 patients, mild fibrosis in 19, marked fibrosis in 6, and severe fibrosis in 9. Fibrosis grade was significantly correlated with all 4 quantification parameters (mean r = -0.75, standard deviation r = -0.54, skewness r = 0.69, kurtosis r = 0.67). According to the receiver operating characteristic analysis, the mean was the most useful parameter for diagnosing pancreatic fibrosis. Using the mean, the area under the ROC curves for the diagnosis of mild or higher-grade fibrosis, marked or higher-grade fibrosis and severe fibrosis were 0.90, 0.90, and 0.90, respectively. An accurate diagnosis of pancreatic fibrosis may be possible by analyzing EUS-EG images.

  2. Treating Obstructive Sleep Apnea and Chronic Intermittent Hypoxia Improves the Severity of Nonalcoholic Fatty Liver Disease in Children.

    PubMed

    Sundaram, Shikha S; Halbower, Ann C; Klawitter, Jelena; Pan, Zhaoxing; Robbins, Kristen; Capocelli, Kelley E; Sokol, Ronald J

    2018-07-01

    To determine the effects of treating obstructive sleep apnea/nocturnal hypoxia on pediatric nonalcoholic fatty liver disease (NAFLD) severity and oxidative stress. Biopsy proven participants (n = 9) with NAFLD and obstructive sleep apnea/hypoxia were studied before and after treatment with continuous positive airway pressure (CPAP) for sleep disordered breathing, including laboratory testing and markers of oxidative stress, urine F(2)-isoprostanes. Adolescents (age 11.5 ± 1.2 years; body mass index, 29.5 ± 3.8 kg/m 2 ) with significant NAFLD (mean histologic necroinflammation grade, 2.3 ± 0.9; fibrosis stage, 1.4 ± 1.3; NAFLD Activity Score summary, 4.8 ± 1.6) had obstructive sleep apnea/hypoxia by polysomnography. At baseline, they had severe obstructive sleep apnea/hypoxia, elevated aminotransferases, the metabolic syndrome, and significant oxidative stress (high F(2)-isoprostanes). Obstructive sleep apnea/hypoxia was treated with home CPAP for a mean 89 ± 62 days. Although body mass index increased, obstructive sleep apnea/hypoxia severity improved on CPAP and was accompanied by reduced alanine aminotransferase, metabolic syndrome markers, and F(2)-isoprostanes. This study provides strong evidence that treatment of obstructive sleep apnea/nocturnal hypoxia with CPAP in children with NAFLD may reverse parameters of liver injury and reduce oxidative stress. These data also suggest CPAP as a new therapy to prevent progression of NAFLD in those children with obesity found to have obstructive sleep apnea/nocturnal hypoxia. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Real-time elastography as a noninvasive assessment of liver fibrosis in chronic hepatitis C Egyptian patients: a prospective study

    PubMed Central

    Mobarak, Lamiaa; Nabeel, Mohammed M.; Hassan, Ehsan; Omran, Dalia; Zakaria, Zeinab

    2016-01-01

    Background Hepatitis C virus is a worldwide problem. Noninvasive methods for liver fibrosis assessment as ultrasound-based approaches have emerged to replace liver biopsy. The aim of this study was to evaluate the diagnostic accuracy of real-time elastography (RTE) in the assessment of liver fibrosis in patients with chronic hepatitis C (CHC), compared with transient elastography and liver biopsy. Methods RTE, FibroScan and liver biopsy were performed in 50 CHC patients. In addition, aspartate aminotransferase to platelet ratio index (APRI) and routine laboratory values were included in the analysis. Results RTE was able to diagnose significant hepatic fibrosis (F ≥2) according to METAVIR scoring system at cut-off value of 2.49 with sensitivity 100%, specificity 66%, and area under the receiver-operating characteristics (AUROC) 0.8. FibroScan was able to predict significant fibrosis at cut-off value 7.5 KPa with sensitivity 88%, specificity 100%, and AUROC 0.94.APRI was able to predict significant hepatic fibrosis (F ≥2) with sensitivity 54%, specificity 80%, and AUROC 0.69. There was a significant positive correlation between the FibroScan score and RTE score (r=0.6, P=0.001). Conclusions Although FibroScan is superior in determining significant hepatic fibrosis, our data suggest that RTE may be a useful and promising noninvasive method for liver fibrosis assessment in CHC patients especially in cases with technical limitations for FibroScan. PMID:27366038

  4. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression

    PubMed Central

    Nallagangula, Krishna Sumanth; Nagaraj, Shashidhar Kurpad; Venkataswamy, Lakshmaiah; Chandrappa, Muninarayana

    2018-01-01

    Liver fibrosis occurs in response to different etiologies of chronic liver injury. Diagnosing degree of liver fibrosis is a crucial step in evaluation of severity of the disease. An invasive liver biopsy is the gold standard method associated with pain and complications. Biomarkers to detect liver fibrosis include direct markers of extracellular matrix turnover and indirect markers as a reflection of liver dysfunction. Although a single marker may not be useful for successful management, a mathematical equation combining tests might be effective. The main purpose of this review is to understand the diagnostic accuracy of biomarkers and scoring systems for liver fibrosis. Advances in -omics approach have generated clinically significant biomarker candidates for liver fibrosis that need further evaluation. PMID:29255622

  5. Significant decrease of saturation index in erythrocytes membrane from subjects with non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Notarnicola, Maria; Caruso, Maria Gabriella; Tutino, Valeria; Bonfiglio, Caterina; Cozzolongo, Raffaele; Giannuzzi, Vito; De Nunzio, Valentina; De Leonardis, Giampiero; Abbrescia, Daniela I; Franco, Isabella; Intini, Vincenza; Mirizzi, Antonella; Osella, Alberto R

    2017-08-23

    The lipidomic profiling of erythrocyte membranes is expected to provide a peculiar scenario at molecular level of metabolic and nutritional pathways which may influence the lipid balance and the adaptation and homeostasis of the organism. Considering that lipid accumulation in the cell is important in promoting tissue inflammation, the purpose of this study is to analyze the fatty acid profile in red blood cell membranes of patients with Non-Alcoholic Fatty Liver Disease (NAFLD), in order to identify and validate membrane profiles possibly associated with the degree of hepatic damage. This work presents data obtained at baseline from 101 subjects that participated to a nutritional trial (registration number: NCT02347696) enrolling consecutive subjects with NAFLD. Diagnosis of liver steatosis was performed by using vibration-controlled elastography implemented on FibroScan. Fatty acids, extracted from phospholipids of erythrocyte membranes, were quantified by gas chromatography method. The subjects with severe NAFLD showed a significant decrease of the ratio of stearic acid to oleic acid (saturation index, SI) compared to controls, 1.281 ± 0.31 vs 1.5 ± 0.29, respectively. Low levels of SI in red blood cell membranes, inversely associated with degree of liver damage, suggest that an impairment of circulating cell membrane structure can reflect modifications that take place in the liver. Subjects with severe NAFLDalso showed higher levels of elongase 5 enzymatic activity, evaluated as vaccenic acid to palmitoleic acid ratio. Starting from these evidences, our findings show the importance of lipidomic approach in the diagnosis and the staging of NAFLD.

  6. Prognostic value of liver fibrosis and steatosis biomarkers in type-2 diabetes and dyslipidaemia.

    PubMed

    Perazzo, H; Munteanu, M; Ngo, Y; Lebray, P; Seurat, N; Rutka, F; Couteau, M; Jacqueminet, S; Giral, P; Monneret, D; Imbert-Bismut, F; Ratziu, V; Hartemann-Huertier, A; Housset, C; Poynard, T

    2014-11-01

    In cardiometabolic disorders, non-alcoholic fatty liver disease is frequent and presumably associated with increased mortality and cardiovascular risk. To evaluate the prognostic value of non-invasive biomarkers of liver fibrosis (FibroTest) and steatosis (SteatoTest) in patients with type-2 diabetes and/or dyslipidaemia. A total of 2312 patients with type-2 diabetes and/or dyslipidaemia were included and prospectively followed up for 5-15 years. The cardiovascular Framingham-risk score was calculated; advanced fibrosis and severe steatosis, were defined by FibroTest >0.48 and SteatoTest >0.69, respectively, as previously established. During a median follow-up of 12 years, 172 patients (7.4%) died. The leading causes of mortality were cancer (31%) and cardiovascular-related death (20%). The presence of advanced fibrosis [HR (95% CI)] [2.98 (95% CI 1.78-4.99); P < 0.0001] or severe steatosis [1.86 (1.34-2.58); P = 0.0002] was associated with an increased risk of mortality. In a multivariate Cox model adjusted for confounders: the presence of advanced fibrosis was associated with overall mortality [1.95 (1.12-3.41); P = 0.02]; advanced fibrosis at baseline [n = 50/677; 1.92 (1.04-3.55); P = 0.04] and progression to advanced fibrosis during follow-up [n = 16/127; 4.8 (1.5-14.9); P = 0.007] were predictors of cardiovascular events in patients with type-2 diabetes. In patients with a Framingham-risk score ≥20%, the presence of advanced fibrosis was predictive of cardiovascular events [2.24 (1.16-4.33); P < 0.05]. Liver biomarkers, such as FibroTest and SteatoTest, have prognostic values in patients with metabolic disorders. FibroTest has prognostic value for predicting overall survival in patients with type-2 diabetes and/or dyslipidaemia. In type-2 diabetes, FibroTest predicted cardiovascular events and improved the Framingham-risk score. © 2014 John Wiley & Sons Ltd.

  7. The Association between Pediatric NAFLD and Common Genetic Variants

    PubMed Central

    Umano, Giuseppina Rosaria; Martino, Mariangela; Santoro, Nicola

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease. PMID:28629152

  8. A simple bedside blood test (Fibrofast; FIB-5) is superior to FIB-4 index for the differentiation between non-significant and significant fibrosis in patients with chronic hepatitis C.

    PubMed

    Shiha, G; Seif, S; Eldesoky, A; Elbasiony, M; Soliman, R; Metwally, A; Zalata, K; Mikhail, N

    2017-05-01

    A simple non-invasive score (Fibrofast, FIB-5) was developed using five routine laboratory tests (ALT, AST, alkaline phosphatase, albumin and platelets count) for the detection of significant hepatic fibrosis in patients with chronic hepatitis C. The FIB-4 index is a non-invasive test for the assessment of liver fibrosis, and a score of ≤1.45 enables the correct identification of patients who have non-significant (F0-1) from significant fibrosis (F2-4), and could avoid liver biopsy. The aim of this study was to compare the performance characteristics of FIB-5 and FIB-4 to differentiate between non-significant and significant fibrosis. A cross-sectional study included 604 chronic HCV patients. All liver biopsies were scored using the METAVIR system. Both FIB-5 and FIB-4 scores were measured and the performance characteristics were calculated using the ROC curve. The performance characteristics of FIB-5 at ≥7.5 and FIB-4 at ≤1.45 for the differentiation between non-significant fibrosis and significant fibrosis were: specificity 94.4%, PPV 85.7%, and specificity 54.9%, PPV 55.7% respectively. FIB-5 score at the new cutoff is superior to FIB-4 index for the differentiation between non-significant and significant fibrosis.

  9. HIV mono-infection is associated with FIB-4 - A noninvasive index of liver fibrosis - in women.

    PubMed

    Blackard, Jason T; Welge, Jeffrey A; Taylor, Lynn E; Mayer, Kenneth H; Klein, Robert S; Celentano, David D; Jamieson, Denise J; Gardner, Lytt; Sherman, Kenneth E

    2011-03-01

    FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women. FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status. The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4(+) cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4(+) cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030). HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions.

  10.  Usefulness of acoustic radiation force impulse and fibrotest in liver fibrosis assessment after liver transplant.

    PubMed

    Bignulin, Sara; Falleti, Edmondo; Cmet, Sara; Cappello, Dario; Cussigh, Annarosa; Lenisa, Ilaria; Dissegna, Denis; Pugliese, Fabio; Vivarelli, Cinzia; Fabris, Carlo; Fabris, Carlo; Toniutto, Pierluigi

    2016-01-01

     Background and rationale. Acoustic radiation force impulse (ARFI) is a non-invasive tool used in the evaluation of liver fibrosis in HCV positive immune-competent patients. This study aimed to assess the accuracy of ARFI in discriminating liver transplanted patients with different graft fibrosis severity and to verify whether ARFI, eventually combined with non-invasive biochemical tests, could spare liver biopsies. This prospective study included 51 HCV positive liver transplanted patients who consecutively underwent to annual liver biopsy concomitantly with ARFI and blood chemistry tests measurements needed to calculate several non-invasive liver fibrosis tests. Overall ARFI showed an AUC of 0.885 in discriminating between patients without or with significant fibrosis (Ishak score 0-2vs. 3-6). Using a cut-off of 1.365 m/s, ARFI possesses a negative predictive value of 100% in identifying patients without significant fibrosis. AUC for Fibrotest was 0.848 in discriminating patients with Ishak fibrosis score 0-2 vs. 3-6. The combined assessment of ARFI and Fibro-test did not improve the results obtained by ARFI alone. ARFI measurement in HCV positive liver transplanted patients can be considered an easy and accurate non-invasive tool in identify patients with a benign course of HCV recurrence.

  11. Lung Ultrasonography in Patients With Idiopathic Pulmonary Fibrosis: Evaluation of a Simplified Protocol With High-Resolution Computed Tomographic Correlation.

    PubMed

    Vassalou, Evangelia E; Raissaki, Maria; Magkanas, Eleftherios; Antoniou, Katerina M; Karantanas, Apostolos H

    2018-03-01

    To compare a simplified ultrasonographic (US) protocol in 2 patient positions with the same-positioned comprehensive US assessments and high-resolution computed tomographic (CT) findings in patients with idiopathic pulmonary fibrosis. Twenty-five consecutive patients with idiopathic pulmonary fibrosis were prospectively enrolled and examined in 2 sessions. During session 1, patients were examined with a US protocol including 56 lung intercostal spaces in supine/sitting (supine/sitting comprehensive protocol) and lateral decubitus (decubitus comprehensive protocol) positions. During session 2, patients were evaluated with a 16-intercostal space US protocol in sitting (sitting simplified protocol) and left/right decubitus (decubitus simplified protocol) positions. The 16 intercostal spaces were chosen according to the prevalence of idiopathic pulmonary fibrosis-related changes on high-resolution CT. The sum of B-lines counted in each intercostal space formed the US scores for all 4 US protocols: supine/sitting and decubitus comprehensive US scores and sitting and decubitus simplified US scores. High-resolution CT-related Warrick scores (J Rheumatol 1991; 18:1520-1528) were compared to US scores. The duration of each protocol was recorded. A significant correlation was found between all US scores and Warrick scores and between simplified and corresponding comprehensive scores (P < .0001). Decubitus simplified US scores showed a slightly higher correlation with Warrick scores compared to sitting simplified US scores. Mean durations of decubitus and sitting simplified protocols were 4.76 and 6.20 minutes, respectively (P < .005). Simplified 16-intercostal space protocols correlated with comprehensive protocols and high-resolution CT findings in patients with idiopathic pulmonary fibrosis. The 16-intercostal space simplified protocol in the lateral decubitus position correlated better with high-resolution CT findings and was less time-consuming compared to the

  12. Non-invasive fibrosis tests are correlated with necroinflammatory actvity of liver in patients with chronic hepatitis B.

    PubMed

    Ozyalvacli, G; Kucukbayrak, A; Kurt, M; Gurel, K; Gunes, O; Ustun, C; Akdeniz, H

    2014-01-01

    The gold standarda method used for assessing necroinflammatory activity and fibrosis in the liver is a liver biopsy which has many disadvantages. Therefore, many investigators have been trying to develop non-invasive tests for predicting liver fibrosis score (LFS) of these patients. The aim of this study is to describe the relationship between certain non-invasive fibrosis markers with LFS and histological activity index (HAI) detected histopathologically by liver biopsy in chronic hepatitis B patients. A total of 54 patients who had undergone a liver biopsy with the diagnosis of chronic HBV infection were included in the study. Ishak scoring was used for the evaluation of liver fibrosis, and a modified Knodell HAI was used for demonstration of necroinflammation. In this study, non-invasive fibrosis tests were calculated as described in previous studies. Histological acitivity index was positively correlated with age, age/platelet index, cirrhosis discriminant score (CDS), AST/platelet ratio index (APRI), AST/platelet/GGT/AFP index (APGA), fibro-quotient (Fibro-Q), Goteburg University Cirrhosis Index (Guci), and Platelet/Age/Phosphatase/AFP/AST index (PAPAS). When divided into two groups according to HAI, Guci and APGA were found significantly different both in >4 and >4 HAI groups than the other group. In ROC analysis performed for LFS; PAPAS, APGA, FFI and APRI were the markers having the highest AUC levels, and in ROC analysis performed for HAI; Guci, APRI and APGA were the markers with the highest AUC levels. APRI, APGA and GUCI tests may be helpful in prediction of necroinflammatory scores in the liver.

  13. Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways.

    PubMed

    Kang, Hyeon Hui; Kim, In Kyoung; Lee, Hye In; Joo, Hyonsoo; Lim, Jeong Uk; Lee, Jongmin; Lee, Sang Haak; Moon, Hwa Sik

    2017-08-19

    Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD), and causes chronic intermittent hypoxia (CIH) during sleep. Inflammation is associated with the development of metabolic complications induced by CIH. Research suggests that innate immune mechanisms are involved in the pro-inflammatory pathways of liver fibrosis. The purpose of this study was to investigate whether innate immune responses induce liver fibrosis, and to evaluate mechanisms underlying hepatic inflammation related to CIH in a murine diet-induced obesity (DIO) model. Inflammatory and oxidative stress markers, TLR4, MyD88, Toll/interleukin-1-receptor-domain-containing adaptor-inducing interferon-β (TRIF), I-κB, NF-κB, p38 MAPK, c-JNK, and ERK activation, were measured in the serum and liver. As a result, α1(I)-collagen mRNA was significantly higher in DIO mice exposed to CIH than in the control groups. CIH mice exhibited liver fibrosis and significantly higher protein expression of TLR4, MyD88, phosphorylated (phospho-) I-κB, and phospho-ERK1/2 activation in the liver, and higher expression of NF-κB than that in the controls. TRIF, p38 MAPK, and JNK activation did not differ significantly between groups. We conclude that CIH in DIO mice leads to liver fibrosis via TLR4/MyD88/MAPK/NF-kB signaling pathways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B.

    PubMed

    Enomoto, Masaru; Morikawa, Hiroyasu; Tamori, Akihiro; Kawada, Norifumi

    2014-09-14

    Infection with hepatitis B virus is an important health problem worldwide: it affects more than 350 million people and is a leading cause of liver-related morbidity, accounting for 1 million deaths annually. Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver. An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease. Liver biopsy has been considered the gold standard for diagnosing disease, grading necroinflammatory activity, and staging fibrosis. However, liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications, including death. Several noninvasive evaluations have been introduced for the assessment of liver fibrosis: serum biomarkers, combined indices or scores, and imaging techniques including transient elastography, acoustic radiation force impulse, real-time tissue elastography, and magnetic resonance elastography. Here, we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C, and later in those with chronic hepatitis B. The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease.

  15. Pathology and biopsy assessment of non-alcoholic fatty liver disease.

    PubMed

    Straub, Beate Katharina; Schirmacher, Peter

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases in Western industrialized countries with dramatically rising incidence. The diagnosis of NAFLD requires the existence of steatosis in the absence of significant alcohol consumption. In cases of relevant inflammation pathogenetically linked to steatosis, it is termed non-alcoholic steatohepatitis (NASH). While pure steatosis represents a relatively harmless and rapidly reversible condition without a significant tendency to progression, NASH carries a significant morbidity and progression risk. Noninvasive methods neither reliably establish the diagnosis nor define the extent of disease in NASH, making histopathology the diagnostic gold standard. Since current therapeutic options in NASH are limited, indication for biopsy is made in the clinical context, predominantly in unclear clinical constellations, prior to invasive measures, for follow-up purposes and in the context of clinical studies. Histological hallmarks of NASH are steatosis, hepatocellular ballooning (with and without Mallory-Denk bodies), necroinflammation, and progressing disease a characteristic with perisinusoidal fibrosis. For semiquantitative assessment of necroinflammation (grading) and fibrosis (staging), a score has recently been implemented. Although histology does not reliably distinguish alcoholic steatohepatitis/alcoholic fatty liver disease from NASH/NAFLD, it may give valuable hints. NASH has a tendency for more steatosis, the so-called glycogenated nuclei, and less necroinflammatory activity. Future development of biopsy diagnosis will be coupled to the development of differential systemic therapeutic approaches. Especially in the context of clinical studies, detailed histological evaluation should be considered for the detection of predictive parameters. Copyright 2010 S. Karger AG, Basel.

  16. Serum Mac-2 binding protein glycosylation isomer predicts grade F4 liver fibrosis in patients with biliary atresia.

    PubMed

    Yamada, Naoya; Sanada, Yukihiro; Tashiro, Masahisa; Hirata, Yuta; Okada, Noriki; Ihara, Yoshiyuki; Urahashi, Taizen; Mizuta, Koichi

    2017-02-01

    Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel fibrosis marker. We examined the ability of M2BPGi to predict liver fibrosis in patients with biliary atresia. Sixty-four patients who underwent living donor liver transplantation (LDLT) were included [median age, 1.1 years (range 0.4-16.0), male 16 patients (25.0 %)]. We examined M2BPGi levels in serum obtained the day before LDLT, and we compared the value of the preoperative M2BPGi levels with the histological evaluation of fibrosis using the METAVIR fibrosis score. Subsequently, we assessed the ability of M2BPGi levels to predict fibrosis. The median M2BPGi level in patients with BA was 6.02 (range, 0.36-20.0), and 0, 1, 1, 11, and 51 patients had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F4 fibrosis, the median M2BPGi level was 6.88 (quartile; 5.235, 12.10), significantly higher than that in patients with F3 fibrosis who had a median level of 2.42 (quartile; 1.93, 2.895, p < 0.01). Area under the curve analysis for the ability of M2BPGi level to predict grade fibrosis was 0.917, with a specificity and sensitivity of 0.923 and 0.941, respectively. In comparison with other fibrosis markers such as hyaluronic acid, procollagen-III-peptide, type IV collagen 7 s, and aspartate aminotransferase platelet ratio index, M2BPGi showed the strongest ability to predict grade F4 fibrosis. M2BPGi is a novel fibrosis marker for evaluating the status of the liver in patients with BA, especially when predicting grade F4 fibrosis.

  17. Serum endocan levels in patients with chronic liver disease

    PubMed Central

    Tok, Duran; Ekiz, Fuat; Basar, Omer; Coban, Sahin; Ozturk, Gulfer

    2014-01-01

    Background and Aim: Early detection of fibrosis should be the main goal of treatment in liver cirrhosis. Endocan, previously called endothelial cell specific molecule-1, is expressed by endothelial cells, primarily in the lung, liver and kidney. In this study, we aimed to examine the correlation of liver fibrosis stage, histological activity and grade of steatosis between serum levels of endocan in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Patients and Methods: This cross-sectional study includes a total of 146 subjects. 55 CHB patients, 19 CHC patients, 38 NAFLD patients and 34 healthy controls were enrolled consecutively. Liver biopsies were performed in all patients with chronic viral hepatitis. NAFLD patients had either grade 2 or grade 3 steatosis on ultrasonography and elevated liver enzymes above the upper normal limits. Serum endocan levels were assessed from blood samples obtained at admission. Results: Gender distribution was similar among the groups (p=0.056). The mean age of the CHB patients was 45.8±12.1, CHC patients was 55.0±12.8 years, NAFLD patients was 42.8±10.8, while control group was 39.4±13.6 years old. Patients with CHC were older than all the others (p=0.001). Serum endocan levels were statistically significantly lower in CHB, CHC and NAFLD groups when compared with controls. Although levels of endocan were lower in CHB and CHC groups when compared with NAFLD group, the difference was not statistically significant. Conclusion: Serum endocan concentrations decrease in patients with liver disease. Unlike previous studies, we showed a negative correlation between endocan levels and inflammation stage of chronic hepatitis. However, further studies are needed to establish the association between endocan levels, liver fibrosis and hepatic inflammation. PMID:25126183

  18. Accuracy of ultrasound in the detection of liver fibrosis in chronic viral hepatitis.

    PubMed

    D'Onofrio, Mirko; Martone, Enrico; Brunelli, Silvia; Faccioli, Niccolò; Zamboni, Giulia; Zagni, Irene; Fattovich, Giovanna; Pozzi Mucelli, Roberto

    2005-10-01

    To assess the accuracy of ultrasonography (US) in the identification and grading of hepatic fibrosis in patients afflicted with chronic viral liver disease, compared to histological examination as a gold standard. We prospectively studied 105 patients (32 F, 73 M) affected by chronic viral liver disease in 36 months. Patients were studied with B-mode US and then underwent US-guided liver biopsy. All the patients were studied with conventional US with a Sequoia 512, 6.0 (Acuson, Mountain View CA, USA). We evaluated the following US parameters: liver margins, parenchymal echotexture, portal vein caliber and spleen diameter. The four B-mode US parameters were used for the US grading (from 0 to 4). Scheuer's grading (from 0 to 4) was used for the histological score. Grades 3 and 4 were considered as positive for fibrosis. Sensitivity, specificity, positive and negative predictive values and accuracy were calculated in the case of absence, positivity of one or all the US parameters. The correlation between US and histological scores was evaluated with Spearman's test. At histology seventy-seven patients (73%) had absent grade 0 (1 patient; 1%), low-moderate grade 1 (35 patients; 33%) or grade 2 (41 patients; 39%) liver fibrosis. Twenty-eight patients (27%) had severe grade 3 (16 patients; 15%) or grade 4 (12 patients; 11%) fibrosis. In the case of absence of US parameters sensitivity was 32%, specificity 32%, positive predictive value 15%, negative predictive value 57% and accuracy 32%. In the case of positivity of at least one of the US parameters the values were 68%, 68%, 43%, 84% and 69%. In the case of presence of all the US signs the results were 25%, 100%, 100%, 79% and 80%. None of the 77 patients with a healthy liver or with low-grade fibrosis was positive for all the US parameters. All the patients positive for all of the ultrasonographic parameters had high-grade fibrosis or cirrhosis at liver biopsy. Correlation between B-mode and histological scores was not

  19. Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry.

    PubMed

    Calès, P; Zarski, J P; Chapplain, J Marc; Bertrais, S; Sturm, N; Michelet, C; Babany, G; Chaigneau, J; Eddine Charaf, M

    2012-02-01

    We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage. © 2011 Blackwell Publishing Ltd.

  20. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2013-11-01

    Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients.

  1. Predictive 5-Year Survivorship Model of Cystic Fibrosis

    PubMed Central

    Liou, Theodore G.; Adler, Frederick R.; FitzSimmons, Stacey C.; Cahill, Barbara C.; Hibbs, Jonathan R.; Marshall, Bruce C.

    2007-01-01

    The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research. PMID:11207152

  2. Physical activity and sedentary behavior can modulate the effect of the PNPLA3 variant on childhood NAFLD: a case-control study in a Chinese population.

    PubMed

    Wang, Shuo; Song, Jieyun; Shang, Xiaorui; Chawla, Nitesh; Yang, Yide; Meng, Xiangrui; Wang, Haijun; Ma, Jun

    2016-12-01

    The patatin like phospholipase containing domain 3 gene (PNPLA3) rs738409 C > G polymorphism, one of the most important gene polymorphisms involved in hepatic steatosis, has been reported to interact with different nutrients and dietary patterns on Non-Alcoholic Fatty Liver Disease (NAFLD), but no studies have focused on its interaction with physical activity or sedentary behavior. Therefore, this study aims at determining whether physical activity or sedentary behavior could modulate the effect of the PNPLA3 variant on childhood NAFLD. A case-control study was conducted including 1027 Chinese children aged 7-18 years old (162 children with NAFLD and 865 children without). The anthropometric measurements, liver ultrasound examination, questionnaires and genotyping of the PNPLA3 rs738409 polymorphism were performed. Stratified analyses showed that the proportions of NAFLD increased with the G-allele number only in children who did not have enough physical activity (physical activity < 1 h/d) (OR 3.05, 95% CI 1.82-5.12, P < 0.001), and in children with a sedentary lifestyle (sedentary behavior ≥ 2 h/d) (OR 3.41, 95% CI 1.88-6.18, P < 0.001). Significant interactions on childhood NAFLD were found between the G-allele number in the PNPLA3 rs738409 polymorphism and behaviors, including physical activity (P = 0.001), sedentary behavior (P = 0.010) and the combination of physical activity and sedentary behavior (P < 0.001). This is the first study to report the interaction between the PNPLA3 rs738409 polymorphism and physical activity or sedentary behavior on NAFLD, providing new clues on the function of the PNPLA3 gene, which will also be useful for future risk assessment and personalized treatment of NAFLD.

  3. Fructose and NAFLD: The Multifaceted Aspects of  Fructose Metabolism.

    PubMed

    Jegatheesan, Prasanthi; De Bandt, Jean-Pascal

    2017-03-03

    Among various factors, such as an unhealthy diet or a sedentarity lifestyle, excessive fructose consumption is known to favor nonalcoholic fatty liver disease (NAFLD), as fructose is both a substrate and an inducer of hepatic de novo lipogenesis. The present review presents some well-established mechanisms and new clues to better understand the pathophysiology of fructose-induced NAFLD. Beyond its lipogenic effect, fructose intake is also at the onset of hepatic inflammation and cellular stress, such as oxidative and endoplasmic stress, that are key factors contributing to the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Beyond its hepatic effects, this carbohydrate may exert direct and indirect effects at the peripheral level. Excessive fructose consumption is associated, for example, with the release by the liver of several key mediators leading to alterations in the communication between the liver and the gut, muscles, and adipose tissue and to disease aggravation. These multifaceted aspects of fructose properties are in part specific to fructose, but are also shared in part with sucrose and glucose present in energy- dense beverages and foods. All these aspects must be taken into account in the development of new therapeutic strategies and thereby to better prevent NAFLD.

  4. Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

    PubMed

    Bellanti, Francesco; Villani, Rosanna; Tamborra, Rosanna; Blonda, Maria; Iannelli, Giuseppina; di Bello, Giorgia; Facciorusso, Antonio; Poli, Giuseppe; Iuliano, Luigi; Avolio, Carlo; Vendemiale, Gianluigi; Serviddio, Gaetano

    2018-05-01

    The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury. Copyright © 2017. Published by Elsevier B.V.

  5. NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet.

    PubMed

    Amato, Antonella; Caldara, Gaetano-Felice; Nuzzo, Domenico; Baldassano, Sara; Picone, Pasquale; Rizzo, Manfredi; Mulè, Flavia; Di Carlo, Marta

    2017-05-13

    Non-alcoholic fatty liver disease (NAFLD) confers an increased risk of cardiovascular diseases. NAFDL is associated with atherogenic dyslipidemia, inflammation and renin-angiotensin system (RAS) imbalance, which in turn lead to atherosclerotic lesions. In the present study, the impact of a natural dietary supplement (NDS) containing Curcuma longa , silymarin, guggul, chlorogenic acid and inulin on NAFLD and atherosclerosis was evaluated, and the mechanism of action was examined. C57BL/6 mice were fed an HFD for 16 weeks; half of the mice were simultaneously treated with a daily oral administration (os) of the NDS. NAFLD and atherogenic lesions in aorta and carotid artery (histological analysis), hepatic expression of genes involved in the NAFLD (PCR array), hepatic angiotensinogen (AGT) and AT₁R mRNA expression (real-time PCR) and plasma angiotensin (ANG)-II levels (ELISA) were evaluated. In the NDS group, steatosis, aortic lesions or carotid artery thickening was not observed. PCR array showed upregulation of some genes involved in lipid metabolism and anti-inflammatory activity (Cpt2, Ifng) and downregulation of some genes involved in pro-inflammatory response and in free fatty acid up-take (Fabp5, Socs3). Hepatic AGT, AT₁R mRNA and ANG II plasma levels were significantly lower with respect to the untreated-group. Furthermore, NDS inhibited the dyslipidemia observed in the untreated animals. Altogether, these results suggest that NDS prevents NAFLD and atherogenesis by modulating the expression of different genes involved in NAFLD and avoiding RAS imbalance.

  6. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

    PubMed

    Glass, Lisa M; Dickson, Rolland C; Anderson, Joseph C; Suriawinata, Arief A; Putra, Juan; Berk, Brian S; Toor, Arifa

    2015-04-01

    Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

  7. Cystic fibrosis - resources

    MedlinePlus

    Resources - cystic fibrosis ... The following organizations are good resources for information on cystic fibrosis : Cystic Fibrosis Foundation -- www.cff.org March of Dimes -- www.marchofdimes.org/baby/cystic-fibrosis-and- ...

  8. Type 2 Diabetes Mellitus and Simple Glucose Metabolism Parameters may Reliably Predict Nonalcoholic Fatty Liver Disease Features.

    PubMed

    Cazzo, Everton; Jimenez, Laísa Simakawa; Gestic, Martinho Antonio; Utrini, Murillo Pimentel; Chaim, Fábio Henrique Mendonça; Chaim, Felipe David Mendonça; Pareja, José Carlos; Chaim, Elinton Adami

    2018-01-01

    This study aims to investigate the correlation between features of NAFLD among individuals with morbid obesity and the surrogate IR markers homeostasis model assessment (HOMA), product of triglycerides and glucose (TyG), and triglyceride-to-high-density-lipoprotein ratio (TG/HDL-c). A cross-sectional study, which enrolled 89 individuals who consecutively underwent bariatric surgery from February through December 2015, was conducted. NAFLD was assessed through histological examination of liver biopsies and correlated with the values of HOMA, TyG, and TG/HDL-c and their respective cutoff points for insulin resistance (IR). xThe prevalence of liver steatosis was 68.5%; the affected individuals presented significantly higher fasting glucose levels (p < 0.01) and hemoglobin A1c (p < 0.01), and a significantly higher prevalence of type 2 diabetes mellitus (T2DM) (p < 0.001). Fibrosis occurred in 66.3% of the individuals and was significantly associated with higher levels of HbA1c (p < 0.05) and a higher prevalence of T2DM (p < 0.05). Steatohepatitis was present in 64% of the individuals and was significantly associated with older age (p < 0.05), higher levels of fasting glucose (p < 0.05), and a higher prevalence of T2DM (p < 0.001). After Bonferroni's adjustment, T2DM was significantly correlated with fibrosis (p < 0.01) and steatohepatitis (p < 0.001) and older age was significantly correlated with fibrosis (p < 0.05). T2DM was the only variable independently associated with fibrosis and steatohepatitis (p < 0.05 in both cases). T2DM was a significant predictor of NAFLD features among individuals undergoing bariatric surgery; higher Hb A1c was correlated with fibrosis. T2DM was independently associated with fibrosis and steatohepatitis. HOMA, TyG, and TG/HDL-c ratio did not present significant associations with NAFLD.

  9. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease.

    PubMed

    Kitamoto, Takuya; Kitamoto, Aya; Ogawa, Yuji; Honda, Yasushi; Imajo, Kento; Saito, Satoru; Yoneda, Masato; Nakamura, Takahiro; Nakajima, Atsushi; Hotta, Kikuko

    2015-08-01

    The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is affected by epigenetic factors as well as by genetic variation. We performed targeted-bisulfite sequencing to determine the levels of DNA methylation of 4 CpG islands (CpG99, CpG71, CpG26, and CpG101) in the regulatory regions of PNPLA3, SAMM50, PARVB variant 1, and PARVB variant 2, respectively. We compared the levels of methylation of DNA in the livers of the first and second sets of patients with mild (fibrosis stages 0 and 1) or advanced (fibrosis stages 2 to 4) NAFLD and in those of patients with mild (F0 to F2) or advanced (F3 and F4) chronic hepatitis C infection. The hepatic mRNA levels of PNPLA3, SAMM50, and PARVB were measured using qPCR. CpG26, which resides in the regulatory region of PARVB variant 1, was markedly hypomethylated in the livers of patients with advanced NAFLD. Conversely, CpG99 in the regulatory region of PNPLA3 was substantially hypermethylated in these patients. These differences in DNA methylation were replicated in a second set of patients with NAFLD or chronic hepatitis C. PNPLA3 mRNA levels in the liver of the same section of a biopsy specimen used for genomic DNA preparation were lower in patients with advanced NAFLD compared with those with mild NAFLD and correlated inversely with CpG99 methylation in liver DNA. Moreover, the levels of CpG99 methylation and PNPLA3 mRNA were affected by the rs738409 genotype. Hypomethylation of CpG26 and hypermethylation of CpG99 may contribute to the severity of fibrosis in patients with NAFLD or chronic hepatitis C infection. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation.

    PubMed

    Liu, Ya-Wei; Chiu, Yung-Tsung; Fu, Shu-Ling; Huang, Yi-Tsau

    2015-08-01

    Hepatic fibrosis is a dynamic process which ultimately leads to cirrhosis in almost patients with chronic hepatic injury. However, progressive fibrosis is a reversible scarring response. Activation of hepatic stellate cells (HSCs) is the prevailing process during hepatic fibrosis. Osthole is an active component majorly contained in the fruit of Cnidium monnieri (L.) Cusson. This present study investigated the therapeutic effects of osthole on rat liver fibrosis and HSC activation. We established the thioacetamide (TAA)-model of Sprague-Dawley (SD) rats to induce hepatic fibrosis. Rats were divided into three groups: control, TAA, and TAA + osthole (10 mg/kg). In vivo, osthole significantly reduced liver injury by diminishing levels of plasma AST and ALT, improving histological architecture, decreasing collagen and α-SMA accumulation, and improving hepatic fibrosis scores. Additionally, osthole reduced the expression of fibrosis-related genes significantly. Osthole also suppressed the production of fibrosis-related cytokines and chemokines. Moreover, nuclear translocation of p65 was significantly suppressed in osthole-treated liver. Osthole also ameliorated TAA-induced injury through reducing cellular oxidation. Osthole showed inhibitory effects in inflammation-related genes and chemokines production as well. In vitro, we assessed osthole effects in activated HSCs (HSC-T6 and LX-2). Osthole attenuated TGF-β1-induced migration and invasion in HSCs. Furthermore, osthole decreased TNF-α-triggered NF-κB activities significantly. Besides, osthole alleviated TGF-β1- or ET-1-induced HSCs contractility. Our study demonstrated that osthole improved TAA-caused liver injury, fibrogenesis and inflammation in rats. In addition, osthole suppressed HSCs activation in vitro significantly.

  11. Evaluation of Acoustic Radiation Force Impulse (ARFI) for Fibrosis Staging in Chronic Liver Diseases.

    PubMed

    Gani, Rino Alvani; Hasan, Irsan; Sanityoso, Andri; Lesmana, Cosmas Rinaldi A; Kurniawan, Juferdy; Jasirwan, Chyntia Olivia Maurine; Kalista, Kemal Fariz; Lutfie, Lutfie

    2017-04-01

    acoustic radiation force impulse (ARFI) is a new proposed noninvasive method for liver fibrosis staging. Integrated with B-mode ultrasonography, ARFI can be used to assess liver tissue condition. However its diagnostic accuracy is still being continuously evaluated. Also, there is lack of data regarding the utilization of ARFI in our population. This study aimed to evaluate the diagnostic value of ARFI as an alternative noninvasive modality for fibrosis staging in chronic hepatitis B and hepatitis C patients in our population. we conducted cross-sectional comparison of ARFI imaging and transient elastography on patients who underwent liver biopsy at Cipto Mangunkusumo Hospital. Fibrosis staging using METAVIR scoring system presented as standard reference. A total of 43 patients underwent liver biopsy was evaluated by ARFI imaging and transient elastography. Cut-off values were determined using receiver-operating characteristic (ROC). both liver stiffness determined by ARFI and transient elastography (TE) were moderately correlated with METAVIR score with value of 0.581 and 0.613, respectively (both P<0.01). Diagnostic accuracy of ARFI predicted significant fibrosis (F≥2) with area under receiver operating characteristic curve (AUROC) of 0.773 (95% CI 0.616-0.930) and even better for cirrhosis (F4 fibrosis), expressed as AUROC of 0.856 (95% CI 0.736-0.975). Transient elastography was better for significant fibrosis with AUROC of 0.761 (95% CI 0.601-0.920) and was best for prediction of cirrhosis, expressed as AUROC of 0.845 (95% CI 0.722-0.968). ARFI is provided with more convenient evaluation of liver tissue condition, and its diagnostic accuracy is not significantly different from TE for staging liver fibrosis.

  12. Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis.

    PubMed

    Kongstad, Thomas; Green, Kent; Buchvald, Frederik; Skov, Marianne; Pressler, Tania; Nielsen, Kim Gjerum

    2017-01-01

    Background : Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods : CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results : Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections ( N  = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% ( p  < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions : The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with

  13. Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea.

    PubMed

    Mesarwi, Omar A; Shin, Mi-Kyung; Drager, Luciano F; Bevans-Fonti, Shannon; Jun, Jonathan C; Putcha, Nirupama; Torbenson, Michael S; Pedrosa, Rodrigo P; Lorenzi-Filho, Geraldo; Steele, Kimberley E; Schweitzer, Michael A; Magnuson, Thomas H; Lidor, Anne O; Schwartz, Alan R; Polotsky, Vsevolod Y

    2015-10-01

    Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis. Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia. The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School. In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion. The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease. © 2015 Associated Professional Sleep Societies, LLC.

  14. Endocrine causes of nonalcoholic fatty liver disease

    PubMed Central

    Marino, Laura; Jornayvaz, François R

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed. PMID:26494962

  15. Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non-Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B.

    PubMed

    Hodge, Alexander; Lim, Sarah; Goh, Evan; Wong, Ophelia; Marsh, Philip; Knight, Virginia; Sievert, William; de Courten, Barbora

    2017-01-10

    There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females ( p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness ( p = 0.044). Tea consumption had no effect ( p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease.

  16. Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non-Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B

    PubMed Central

    Hodge, Alexander; Lim, Sarah; Goh, Evan; Wong, Ophelia; Marsh, Philip; Knight, Virginia; Sievert, William; de Courten, Barbora

    2017-01-01

    There is emerging evidence for the positive effects or benefits of coffee in patients with liver disease. We conducted a retrospective cross-sectional study on patients with non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection to determine the effects of coffee intake on a non-invasive marker of liver fibrosis: liver stiffness assessed by transient elastography (TE). We assessed coffee and tea intake and measured TE in 1018 patients with NAFLD, HCV, and HBV (155 with NAFLD, 378 with HCV and 485 with HBV). Univariate and multivariate regression models were performed taking into account potential confounders. Liver stiffness was higher in males compared to females (p < 0.05). Patients with HBV had lower liver stiffness than those with HCV and NAFLD. After adjustment for age, gender, smoking, alcohol consumption, M or XL probe, and disease state (NAFLD, HCV, and HBV status), those who drank 2 or more cups of coffee per day had a lower liver stiffness (p = 0.044). Tea consumption had no effect (p = 0.9). Coffee consumption decreases liver stiffness, which may indicate less fibrosis and inflammation, independent of disease state. This study adds further evidence to the notion of coffee maybe beneficial in patients with liver disease. PMID:28075394

  17. Gallic Acid Ameliorated Impaired Glucose and Lipid Homeostasis in High Fat Diet-Induced NAFLD Mice

    PubMed Central

    Chao, Jung; Huo, Teh-Ia; Cheng, Hao-Yuan; Tsai, Jen-Chieh; Liao, Jiunn-Wang; Lee, Meng-Shiou; Qin, Xue-Mei; Hsieh, Ming-Tsuen; Pao, Li-Heng; Peng, Wen-Huang

    2014-01-01

    Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more “holistic view” approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help

  18. Advanced liver fibrosis by transient elastography, fibrosis 4, and alanine aminotransferase/platelet ratio index among Asian hepatitis C with and without human immunodeficiency virus infection: role of vitamin D levels.

    PubMed

    Avihingsanon, Anchalee; Jitmitraparp, Salyavit; Tangkijvanich, Pisit; Ramautarsing, Reshmie A; Apornpong, Tanakorn; Jirajariyavej, Supunee; Putcharoen, Opass; Treeprasertsuk, Sombat; Akkarathamrongsin, Srunthron; Poovorawan, Yong; Matthews, Gail V; Lange, Joep M A; Ruxrungtham, Kiat

    2014-09-01

    Vitamin D insufficiency plays an important role in liver fibrosis in hepatitis C virus (HCV)-infected patients. We assessed liver fibrosis by transient elastography and 25 hydroxy vitamin D [25(OH)D] status in HCV-infected patients, with (HIV/HCV) or without HIV co-infection (HCV) from Thailand. Fibrosis stage was defined as mild (< 7.1 kPa); moderate (7.2-9.4 kPa); severe (9.5-14 kPa), and cirrhosis (> 14 kPa). Hypovitaminosis D was defined as 25(OH)D < 30 ng/mL. Logistic regression analyses were used to assess predictors for significant fibrosis. Serum 25(OH) D levels, HCV genotypes (GT), interleukin-28B (IL28B) and HCV-RNA were assessed. A total of 331 HCV and 130 HIV/HCV patients were enrolled (70% male, 35% people who inject drugs [PWIDs]). HCV GT distribution was as follows: GT3 47%, GT1 34%, GT6 17%. IL-28B CC genotype (rs12979860) were found in 88% of HIV/HCV and 85% of HCV. In HCV, liver fibrosis was mild in 56.5%; moderate in 18.4%; severe in 12.4%; and cirrhosis in 12.7%. In HIV/HCV, these figures were 30.6%, 27.8%, 17.6%, and 24.1%, respectively. Patients with significant fibrosis were more often male, older, with HIV infection, hypovitaminosis D, and less likely to be infected with GT6. Factors associated with significant fibrosis by multivariate analysis were HIV infection (adjusted odd ratio [95% confidential interval]: 2.67, 1.20-5.93), P = 0.016, Fib-4 score > 1.45 (6.30, 2.70-14.74), P < 0.001, and hypovitaminosis D (2.48, 1.09-5.67), P = 0.031. GT 6 was less likely to have advanced liver fibrosis (0.17, 0.05-0.65), P = 0.01. HIV infection, Fib-4 score > 1.45, and hypovitaminosis D are strong and independent predictors for the presence of advanced fibrosis in our HCV-infected patients. These data highlight the urgent need of HCV treatment and vitamin D supplement in resource-limited settings. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  19. Routine Laboratory Blood Tests May Diagnose Significant Fibrosis in Liver Transplant Recipients with Chronic Hepatitis C: A 10 Year Experience.

    PubMed

    Sheen, Victoria; Nguyen, Heajung; Jimenez, Melissa; Agopian, Vatche; Vangala, Sitaram; Elashoff, David; Saab, Sammy

    2016-03-28

    The aims of our study were to determine whether routine blood tests, the aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) and Fibrosis 4 (Fib-4) scores, were associated with advanced fibrosis and to create a novel model in liver transplant recipients with chronic hepatitis C virus (HCV). We performed a cross sectional study of patients at The University of California at Los Angeles (UCLA) Medical Center who underwent liver transplantation for HCV. We used linear mixed effects models to analyze association between fibrosis severity and individual biochemical markers and mixed effects logistic regression to construct diagnostic models for advanced fibrosis (METAVIR F3-4). Cross-validation was used to estimate a receiving operator characteristic (ROC) curve for the prediction models and to estimate the area under the curve (AUC). The mean (± standard deviation [SD]) age of our cohort was 55 (±7.7) years, and almost three quarter were male. The mean (±SD) time from transplant to liver biopsy was 19.9 (±17.1) months. The mean (±SD) APRI and Fib-4 scores were 3 (±12) and 7 (±14), respectively. Increased fibrosis was associated with lower platelet count and alanine aminotransferase (ALT) values and higher total bilirubin and Fib-4 scores. We developed a model that takes into account age, gender, platelet count, ALT, and total bilirubin, and this model outperformed APRI and Fib-4 with an AUC of 0.68 (p < 0.001). Our novel prediction model diagnosed the presence of advanced fibrosis more reliably than APRI and Fib-4 scores. This noninvasive calculation may be used clinically to identify liver transplant recipients with HCV with significant liver damage.

  20. Molecular pathways in non-alcoholic fatty liver disease

    PubMed Central

    Berlanga, Alba; Guiu-Jurado, Esther; Porras, José Antonio; Auguet, Teresa

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the “double-hit” hypothesis. The primary insult or the “first hit” includes lipid accumulation in the liver, followed by a “second hit” in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD. PMID:25045276

  1. NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet

    PubMed Central

    Amato, Antonella; Caldara, Gaetano-Felice; Nuzzo, Domenico; Baldassano, Sara; Picone, Pasquale; Rizzo, Manfredi; Mulè, Flavia; Di Carlo, Marta

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) confers an increased risk of cardiovascular diseases. NAFDL is associated with atherogenic dyslipidemia, inflammation and renin-angiotensin system (RAS) imbalance, which in turn lead to atherosclerotic lesions. In the present study, the impact of a natural dietary supplement (NDS) containing Curcuma longa, silymarin, guggul, chlorogenic acid and inulin on NAFLD and atherosclerosis was evaluated, and the mechanism of action was examined. C57BL/6 mice were fed an HFD for 16 weeks; half of the mice were simultaneously treated with a daily oral administration (os) of the NDS. NAFLD and atherogenic lesions in aorta and carotid artery (histological analysis), hepatic expression of genes involved in the NAFLD (PCR array), hepatic angiotensinogen (AGT) and AT1R mRNA expression (real-time PCR) and plasma angiotensin (ANG)-II levels (ELISA) were evaluated. In the NDS group, steatosis, aortic lesions or carotid artery thickening was not observed. PCR array showed upregulation of some genes involved in lipid metabolism and anti-inflammatory activity (Cpt2, Ifng) and downregulation of some genes involved in pro-inflammatory response and in free fatty acid up-take (Fabp5, Socs3). Hepatic AGT, AT1R mRNA and ANG II plasma levels were significantly lower with respect to the untreated-group. Furthermore, NDS inhibited the dyslipidemia observed in the untreated animals. Altogether, these results suggest that NDS prevents NAFLD and atherogenesis by modulating the expression of different genes involved in NAFLD and avoiding RAS imbalance. PMID:28505074

  2. Effects of shenling baizhu powder herbal formula on intestinal microbiota in high-fat diet-induced NAFLD rats.

    PubMed

    Zhang, Yupei; Tang, Kairui; Deng, Yuanjun; Chen, Runsen; Liang, Shu; Xie, Huijun; He, Yifang; Chen, Yanning; Yang, Qinhe

    2018-06-01

    Worldwide, non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease closely associated with obesity, diabetes and other metabolic diseases. Shenling Baizhu powder (SLBZP), a formulation of a variety of natural medicinal plants, has hepatoprotective properties and clinical efficacy in treating non-infectious intestinal disease. SLBZP has improved NAFLD symptoms; however, its mechanism of action is unknown. We established an NAFLD model in rats given a high-fat diet (HFD), administered different interventions and measured serum biochemical indices and inflammatory factors. Liver tissues were stained with hematoxylin and eosin (HE) and oil red O, and colon tissues were analyzed by immunohistochemistry. The expression profiles of liver TLR4 pathway related protein was confirmed by western blotting. Changes in intestinal microbiota composition were analyzed using a 16S rDNA sequencing technique. Of note, SLBZP effectively reduced body weight in HFD-fed rats (p < 0.05). Serum biochemical analysis indicated that SLBZP decreased the serum level of total cholesterol (TC) and improved liver function. Additionally, SLBZP decreased the serum level of endotoxin, tumor necrosis factor α (TNF-α), interleukin-1β (IL-β) (p < 0.05), and decreased the expression of TLR4 pathway related protein. Pathological examination showed that SLBZP alleviates hepatic steatosis and repairs colon mucosa. Microbiome analysis revealed that SLBZP improved the abundance of intestinal microbiota. In taxonomy-based analysis, compared with control rats, SLBZP-treated rats showed obvious changes in intestinal microbiota composition. Moreover, SLBZP increased the relative abundance of short-chain fatty acid (SCFA)-producing bacteria, including Bifidobacterium and Anaerostipes. Taken together, these results suggest that the effects of SLBZP against NAFLD may be related to the increased abundance of beneficial gut microbiota and decreased levels of LPS in the portal vein

  3. Congruence Between Pulmonary Function and Computed Tomography Imaging Assessment of Cystic Fibrosis Severity.

    PubMed

    Rybacka, Anna; Goździk-Spychalska, Joanna; Rybacki, Adam; Piorunek, Tomasz; Batura-Gabryel, Halina; Karmelita-Katulska, Katarzyna

    2018-05-04

    In cystic fibrosis, pulmonary function tests (PFTs) and computed tomography are used to assess lung function and structure, respectively. Although both techniques of assessment are congruent there are lingering doubts about which PFTs variables show the best congruence with computed tomography scoring. In this study we addressed the issue by reinvestigating the association between PFTs variables and the score of changes seen in computed tomography scans in patients with cystic fibrosis with and without pulmonary exacerbation. This retrospective study comprised 40 patients in whom PFTs and computed tomography were performed no longer than 3 weeks apart. Images (inspiratory: 0.625 mm slice thickness, 0.625 mm interval; expiratory: 1.250 mm slice thickness, 10 mm interval) were evaluated with the Bhalla scoring system. The most frequent structural abnormality found in scans were bronchiectases and peribronchial thickening. The strongest relationship was found between the Bhalla sore and forced expiratory volume in 1 s (FEV1). The Bhalla sore also was related to forced vital capacity (FVC), FEV1/FVC ratio, residual volume (RV), and RV/total lung capacity (TLC) ratio. We conclude that lung structural data obtained from the computed tomography examination are highly congruent to lung function data. Thus, computed tomography imaging may supersede functional assessment in cases of poor compliance with spirometry procedures in the lederly or children. Computed tomography also seems more sensitive than PFTs in the assessment of cystic fibrosis progression. Moreover, in early phases of cystic fibrosis, computed tomography, due to its excellent resolution, may be irreplaceable in monitoring pulmonary damage.

  4. Assessment of health utilities and quality of life in patients with non-alcoholic fatty liver disease

    PubMed Central

    Sayiner, Mehmet; Stepanova, Maria; Pham, Huong; Noor, Bashir; Walters, Mercedes; Younossi, Zobair M

    2016-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease associated with increased liver-related mortality. Additionally, NAFLD could potentially impair health-related quality of life. Although an approved treatment for NAFLD does not exist, a number of new drugs for treatment of NAFLD are being developed. As the efficacy and safety of these regimens are being established, their cost-effectiveness, which requires the use of quality of life metrics and health utility scores to quality-adjusted outcomes, must also be assessed. The aim of this study was to report quality of life and health utilities in patients with NAFLD with and without cirrhosis for future use. Methods Patients with NAFLD were seen in an outpatient clinic setting. Each patient had extensive clinical data and completed the Short Form-36 (SF-36 V.1) questionnaire. The SF-6D health utility scores were calculated. Results There were 89 patients with the spectrum of NAFLD completed the SF-36 questionnaire: 59 with non-cirrhotic NAFLD and 30 with cirrhosis. Patients with NAFLD had significantly lower quality of life and health utility scores than the general population (all p<0.0001). Furthermore, patients with cirrhosis had lower quality of life and utility scores than non-cirrhotic NAFLD patients: SF-6D 0.660±0.107 in non-cirrhotic NAFLD vs 0.551±0.138 in cirrhotic NAFLD (p=0.0003). Conclusions Health utilities and quality of life scores are impaired in patients with cirrhotic NAFLD. These values should be used in cost-effectiveness analysis of the upcoming treatment regimens for advanced NAFLD. PMID:27648297

  5. Nonalcoholic fatty liver disease (NAFLD)--is it a new marker of hyporesponsiveness to recombinant human erythropoietin in patients that are on chronic hemodialysis?

    PubMed

    Orlic, L; Mikolasevic, I; Lukenda, V; Racki, S; Stimac, D; Milic, S

    2014-12-01

    Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in

  6. Managing non-alcoholic fatty liver disease

    PubMed Central

    Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy

    2016-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment. PMID:27439352

  7. Psychological Concomitants of Cystic Fibrosis in Children and Adolescents.

    ERIC Educational Resources Information Center

    Kashani, Javad H.; And Others

    1988-01-01

    Administered several psychiatric inventories to 30 cystic fibrosis and 30 matched control children and their parents. Data analysis revealed few differences in either psychopathological symptoms or psychiatric diagnoses between groups. Differences were either physical in nature or did not depart enough from normal scores to merit label of high…

  8. Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.

    PubMed

    Zarski, Jean-Pierre; Sturm, Nathalie; Desmorat, Hervé; Melin, Pascal; Raabe, Jean-Jacques; Bonny, Corinne; Sogni, Philippe; Pinta, Alexandrina; Rouanet, Stéphanie; Babany, Gérard; Cheveau, Alice; Chevallier, Michèle

    2010-08-01

    The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.

  9. HIV Mono-infection Is Associated With FIB-4 – A Noninvasive Index of Liver Fibrosis – in Women

    PubMed Central

    Welge, Jeffrey A.; Taylor, Lynn E.; Mayer, Kenneth H.; Klein, Robert S.; Celentano, David D.; Jamieson, Denise J.; Gardner, Lytt; Sherman, Kenneth E.

    2011-01-01

    Background. FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women. Methods. FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status. Results. The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4+ cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4+ cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030). Conclusions. HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions. PMID:21248367

  10. Comparison of acoustic radiation force impulse imaging (ARFI) to liver biopsy histologic scores in the evaluation of chronic liver disease: A pilot study.

    PubMed

    Haque, Mazhar; Robinson, Charlotte; Owen, David; Yoshida, Eric M; Harris, Alison

    2010-01-01

    Acoustic Radiation Force Impulse Imaging (ARFI) is a novel non invasive technique studying the localized mechanical properties of tissue by utilising short, high intensity acoustic pulses (shear wave pulses) to assess the mechanical response (tissue displacement), providing a measure of tissue elasticity. The aim of this study is to investigate the feasibility of ARFI imaging as a non-invasive method for the assessment of liver fibrosis compared to liver biopsy scores. A prospective blind comparison study of ARFI elastography (Virtual Touch Imaging., ACUSON S2000 Ultrasound Unit, Siemens, Mountain View CA) in a consecutive series of patients who underwent liver biopsy for assessment of fibrosis in chronic liver disease. ARFI shear-wave propagation velocity was measured in meters per second. Mean ARFI velocities were compared with both Batts-Ludwig (F0 to F4) and Modified Ishak scores (F0 to F4) for fibrosis in liver biopsy findings. Twenty-one patients with chronic liver disease (Hepatitis C (HCV) =16, Hepatitis B (HBV) = 1, both HCV and HBV = 1 Alcoholic liver disease (ALD) = 1, others = 2) underwent ARFI and liver biopsy on the same day. The Spearman correlation coefficients between the median values of the ARFI measurements and the histological fibrosis stage of the Modified Ishak score and Batts-Lud- (3) wig score were both highly significant (p < 0.01) with rho = 0.69 and rho = 0.72 respectively. The median ARFI (total 180 replications; minimum 5, maximum 10 measurements per patients) velocities for our study population range from 0.92 to 4.17 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging was 1.00 and 0.35, for the diagnosis of moderate fibrosis (histologic fibrosis stage, F (3) 2) and 0.85 and 0.85 respectively for Ishak and Batts-Ludwig score, for the diagnosis of cirrhosis. ARFI imaging has a strong correlation with the fibrosis stage of both Batts-Ludwig and shak score in chronic liver disease. It

  11. [Comparison of various noninvasive serum markers of liver fibrosis in chronic viral liver disease].

    PubMed

    Kim, Sun Min; Sohn, Joo Hyun; Kim, Tae Yeob; Roh, Young Wook; Eun, Chang Soo; Jeon, Yong Cheol; Han, Dong Soo; Oh, Young Ha

    2009-12-01

    The aim of this study was to determine the clinical performances of noninvasive serum markers for the prediction of liver fibrosis in chronic viral liver diseases. We analyzed a total of 225 patients with chronic viral liver diseases (180 with hepatitis B virus, 43 with hepatitis C virus, and 2 with hepatitis B+C virus) who underwent a liver biopsy procedure at the Hanyang University Guri Hospital between March 2002 and February 2007. Serum was also obtained at the time of liver biopsy. Liver fibrosis was staged according to the scoring system proposed by the Korean Study Group for the Pathology of Digestive Diseases. Various noninvasive serum markers were evaluated, including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST/platelet ratio index (APRI), cirrhosis discriminant score (CDS), platelet count, hyaluronic acid (HA), and type IV collagen. There were 17, 40, 61, 74, and 33 patients at stages F0, F1, F2, F3, and F4, respectively. The overall diagnostic accuracies of each marker, as determined by the area under receiver operating characteristics curves, were APRI=0.822, CDS=0.776, platelet count=0.773, AP index=0.756, HA=0.749, type IV collagen=0.718, and AAR=0.642 for predicting significant fibrosis (> or =F2); and CDS=0.835, platelet count=0.795, AP index=0.794, HA=0.766, AAR=0.711, type IV collagen=0.697, and APRI=0.691 for predicting extensive fibrosis (> or =F3). All noninvasive serum markers evaluated in this study were useful for predicting significant or extensive liver fibrosis in chronic viral liver diseases. In particular, APRI was most useful for the prediction of significant fibrosis, and CDS was most useful for the prediction of extensive fibrosis.

  12. Human germline hedgehog pathway mutations predispose to fatty liver.

    PubMed

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2 +/- ) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 +/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 +/- mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  13. Efficacy of synbiotic supplementation in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of clinical trials: Synbiotic supplementation and NAFLD.

    PubMed

    Hadi, Amir; Mohammadi, Hamed; Miraghajani, Maryam; Ghaedi, Ehsan

    2018-03-27

    We systematically reviewed available randomized clinical trials (RCTs) to elucidate the overall effects of synbiotic supplementation in patients with nonalcoholic fatty liver disease (NAFLD). PubMed, Scopus, ISI Web of science and Google Scholar were searched up to December, 2017. All RCTs using synbiotic supplements to treat NAFLD included in this systematic review and meta-analysis. Mean Difference (MD) was pooled using a random-effects model. Eleven eligible databases from seven RCTs were identified for the present meta-analysis. Our results showed that synbiotic supplementation can decrease body weight, fasting blood sugar, insulin, low density lipoprotein cholesterol, total cholesterol, triglyceride, high-sensitivity C-reactive protein, tumor necrosis factor alpha, alanine transaminase and aspartate transaminase levels among patients with NAFLD. In contrast, synbiotic did not have favorable effects on body mass index (BMI), waist circumference, homeostasis model assessment for insulin resistance (HOMA-IR), and high density lipoprotein cholesterol (HDL) levels compared with the placebo group. The current study revealed that synbiotic supplementation has favorable effect on inflammatory factors, liver enzymes and some anthropometric indices, lipid profiles and glucose homeostasis parameters in patients with NAFLD.

  14. Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

    PubMed Central

    Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2–deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2–deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2–induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2–deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis. PMID:26147947

  15. Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation.

    PubMed

    Grgic, Aleksandar; Lausberg, Henning; Heinrich, Marc; Koenig, Jochem; Uder, Michael; Sybrecht, Gerhard W; Wilkens, Heinrike

    2008-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Usual interstitial pneumonia (UIP) is the histopathological pattern identifying patients with the clinical entity of IPF. Despite aggressive immunosuppressive therapy the clinical course is usually dismal. For selected patients only lung transplantation improves prognosis and quality of life. After lung transplantation patients often receive a potent cyclosporine-based immunosuppressive therapy. Some reports suggest that cyclosporine has the potential to prevent progression of fibrosis. In patients with single lung transplantation (sLTx) for UIP we evaluated the effect of cyclosporine-based immunosuppressive therapy on progression of fibrosis using a high-resolution computed tomography (HRCT) scoring system. This retrospective observational study included 13 patients (24-64 years old) with histologically confirmed UIP who had HRCT scans preceding and following sLTx and who survived at least 6 months after sLTx. All patients were initially treated with cyclosporin A, prednisone and azathioprine. Three radiologists analyzed HRCT scans by setting a score regarding fibrosis [fibrosis score (FS); range 0-5 for each lobe] and ground-glass opacity [ground-glass score (GGS); range 0-5 for each lobe]. A comparison of serial changes (interval: 12-96 months posttransplant, 2-4 HRCT examinations/patient) was performed with the sign test. Mean pretransplant FS and GGS of the nontransplanted lung were 1.80 and 1.61, respectively. Comparing pre- and posttransplant HRCT scans, mean lung FS significantly increased (0.35 +/- 0.15/year; p = 0.00024), while GGS tended to decrease (0.06 +/- 0.26/year; p = 0.5). A cyclosporin A based triple immunosuppressive regimen following sLTx does not seem to prevent progression of the fibrotic changes of the native lung in patients with IPF. Copyright 2007 S. Karger AG, Basel.

  16. Heart involvement in cystic fibrosis: A specific cystic fibrosis-related myocardial changes?

    PubMed

    Labombarda, Fabien; Saloux, Eric; Brouard, Jacques; Bergot, Emmanuel; Milliez, Paul

    2016-09-01

    Cystic fibrosis is a complex multi-systemic chronic disease characterized by progressive organ dysfunction with development of fibrosis, possibly affecting the heart. Over the last four decades pathological, experimental, and clinical evidence points towards the existence of a specific myocardial involvement in cystic fibrosis. Multi-modality cardiac imaging, especially recent echocardiographic techniques, evidenced diastolic and/or systolic ventricular dysfunction in cystic fibrosis leading to the concept of a cystic fibrosis-related cardiomyopathy. Hypoxemia and inflammation are among the most important factors for heart involvement in cystic fibrosis. Cystic Fibrosis Transmembrane Regulator was found to be involved in the regulation of cardiomyocyte contraction and may also account for cystic fibrosis-related myocardial dysfunction. This review, mainly focused on echocardiographic studies, seeks to synthesize the existing literature for and against the existence of heart involvement in cystic fibrosis, its mechanisms and prognostic implications. Careful investigation of the heart function may be helpful for risk stratification and therapeutic decisions in patients with cystic fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Lung function imaging methods in Cystic Fibrosis pulmonary disease.

    PubMed

    Kołodziej, Magdalena; de Veer, Michael J; Cholewa, Marian; Egan, Gary F; Thompson, Bruce R

    2017-05-17

    Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

  18. Liver fibrosis diagnosis by blood test and elastography in chronic hepatitis C: agreement or combination?

    PubMed

    Calès, P; Boursier, J; Lebigot, J; de Ledinghen, V; Aubé, C; Hubert, I; Oberti, F

    2017-04-01

    In chronic hepatitis C, the European Association for the Study of the Liver and the Asociacion Latinoamericana para el Estudio del Higado recommend performing transient elastography plus a blood test to diagnose significant fibrosis; test concordance confirms the diagnosis. To validate this rule and improve it by combining a blood test, FibroMeter (virus second generation, Echosens, Paris, France) and transient elastography (constitutive tests) into a single combined test, as suggested by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. A total of 1199 patients were included in an exploratory set (HCV, n = 679) or in two validation sets (HCV ± HIV, HBV, n = 520). Accuracy was mainly evaluated by correct diagnosis rate for severe fibrosis (pathological Metavir F ≥ 3, primary outcome) by classical test scores or a fibrosis classification, reflecting Metavir staging, as a function of test concordance. Score accuracy: there were no significant differences between the blood test (75.7%), elastography (79.1%) and the combined test (79.4%) (P = 0.066); the score accuracy of each test was significantly (P < 0.001) decreased in discordant vs. concordant tests. Classification accuracy: combined test accuracy (91.7%) was significantly (P < 0.001) increased vs. the blood test (84.1%) and elastography (88.2%); accuracy of each constitutive test was significantly (P < 0.001) decreased in discordant vs. concordant tests but not with combined test: 89.0 vs. 92.7% (P = 0.118). Multivariate analysis for accuracy showed an interaction between concordance and fibrosis level: in the 1% of patients with full classification discordance and severe fibrosis, non-invasive tests were unreliable. The advantage of combined test classification was confirmed in the validation sets. The concordance recommendation is validated. A combined test, expressed in classification instead of score, improves this rule and validates the

  19. Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis.

    PubMed

    Gilhodes, Jean-Claude; Julé, Yvon; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

    2017-01-01

    Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes

  20. Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis

    PubMed Central

    Gilhodes, Jean-Claude; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

    2017-01-01

    Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001) was found between automated analysis and the above standard evaluation methods. This correlation establishes

  1. Assessing liver fibrosis: comparison of arterial enhancement fraction and diffusion-weighted imaging.

    PubMed

    Bonekamp, David; Bonekamp, Susanne; Ou, Hsin-You; Torbenson, Michael S; Corona-Villalobos, Celia Pamela; Mezey, Esteban; Kamel, Ihab R

    2014-11-01

    Noninvasive markers have been developed to reduce the need for liver biopsy. The aim of this study was to compare the strength of association of the arterial enhancement fraction (AEF), apparent diffusion coefficient (ADC), and serum biomarkers for staging hepatic fibrosis. Eighty-five patients with chronic liver disease underwent triple-phase contrast-enhanced MRI, used to calculate AEF, and diffusion-weighted MRI (b = 0,750 s/mm(2) ), used to calculate ADC. Hepatic fibrosis was staged according METAVIR criteria. The overall association of the four biomarkers (AEF, ADC, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, and aspartate aminotransferase to platelet ratio index [APRI]) was compared using nonparametric tests and receiver operating characteristic (ROC) curve, using histopathologic analysis as the reference standard. AEF and ADC values differed significantly between histopathologic fibrosis stages. AEF values correlated with fibrosis stage, ADC values correlated negatively with fibrosis stage. Compared with ADC, AEF showed a trend toward an improved capability of discriminating fibrosis stages. A weighted composite score of AEF and ADC had significantly better diagnostic accuracy than ADC alone (P ≤ 0.023). Imaging parameters had a significantly better diagnostic accuracy than AST/ALT ratio or APRI. AEF may be able to detect the presence of mild, moderate, and advanced liver fibrosis, and its value is increased with concomitant use of ADC. © 2013 Wiley Periodicals, Inc.

  2. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

    PubMed

    Suzuki-Kemuriyama, Noriko; Matsuzaka, Takashi; Kuba, Motoko; Ohno, Hiroshi; Han, Song-Iee; Takeuchi, Yoshinori; Isaka, Masaaki; Kobayashi, Kazuto; Iwasaki, Hitoshi; Yatoh, Shigeru; Suzuki, Hiroaki; Miyajima, Katsuhiro; Nakae, Dai; Yahagi, Naoya; Nakagawa, Yoshimi; Sone, Hirohito; Yamada, Nobuhiro; Shimano, Hitoshi

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

  3. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression.

    PubMed

    Eraky, Salma M; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El-Gayar, Amal M

    2018-05-01

    Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  4. Ultrastructural investigation of the protective effects of propolis on bleomycin induced pulmonary fibrosis.

    PubMed

    Bilgin, G; Kismet, K; Kuru, S; Kaya, F; Senes, M; Bayrakceken, Y; Yumusak, N; Celikkan, F T; Erdemli, E; Celemli, O G; Sorkun, K; Koca, G

    2016-01-01

    We investigated the antioxidant and anti-inflammatory effects of propolis on bleomycin induced lung fibrosis and compared these effects to prednisolone treatment. Forty rats were divided into four groups of ten: group 1 was treated with intratracheal infusion of 0.2 ml physiological saline followed by daily treatment with 0.5 ml physiological saline for 20 days. In the remaining groups (groups 2 - 4), 5 mg/kg bleomycin was given via the trachea. Rats in group 2 were given 0.5 ml physiological saline. Rats in group 3 were treated with 100 mg/kg propolis, and 10 mg/kg prednisolone was given to rats in group 4. The treatments for all groups were continued for 20 days. On postoperative day 21, blood and lung samples were taken for biochemistry, histopathology and electron microscopy evaluation. We compared oxidative stress parameters and found lower malondialdehyde and myeloperoxidase levels, and higher total sulfhydryl levels and catalase activities for the bleomycin + propolis group than for the bleomycin and bleomycin + prednisolone groups. The highest mean fibrosis score was detected in the bleomycin group. Although the mean fibrosis scores of the bleomycin + propolis and bleomycin + prednisolone groups were not significantly different, electron microscopy revealed that propolis diminished bleomycin induced lung fibrosis more effectively than prednisolone. The effects of propolis might be due to its potent antioxidant and anti-inflammatory properties.

  5. Non-alcoholic Fatty Liver Disease: East Versus West

    PubMed Central

    Agrawal, Swastik; Duseja, Ajay K

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West. PMID:25755421

  6. Attenuated progression of diet-induced steatohepatitis in glutathione-deficient mice

    PubMed Central

    Haque, Jamil A; McMahan, Ryan S; Campbell, Jean S; Shimizu-Albergine, Masami; Wilson, Angela M; Botta, Dianne; Bammler, Theo K; Beyer, Richard P; Montine, Thomas J; Yeh, Matthew M; Kavanagh, Terrance J; Fausto, Nelson

    2011-01-01

    In nonalcoholic fatty liver disease (NAFLD), depletion of hepatic antioxidants may contribute to the progression of steatosis to nonalcoholic steatohepatitis (NASH) by increasing oxidative stress that produces lipid peroxidation, inflammation, and fibrosis. We investigated whether depletion of glutathione (GSH) increases NASH-associated hepatic pathology in mice fed a diet deficient in methionine and choline (MCD diet). Wild-type (wt) mice and genetically GSH-deficient mice lacking the modifier subunit of glutamate cysteine ligase (Gclm null mice), the rate-limiting enzyme for de novo synthesis of GSH, were fed the MCD diet, a methionine/choline-sufficient diet, or standard chow for 21 days. We assessed NASH-associated hepatic pathology, including steatosis, fibrosis, inflammation, and hepatocyte ballooning, and used the NAFLD Scoring System to evaluate the extent of changes. We measured triglyceride levels, determined the level of lipid peroxidation products, and measured by qPCR the expression of mRNAs for several proteins associated with lipid metabolism, oxidative stress, and fibrosis. MCD-fed GSH-deficient Gclm null mice were to a large extent protected from MCD diet-induced excessive fat accumulation, hepatocyte injury, inflammation, and fibrosis. Compared with wt animals, MCD-fed Gclm null mice had much lower levels of F2-isoprostanes, lower expression of acyl-CoA oxidase, carnitine palmitoyltransferase 1a, uncoupling protein-2, stearoyl-coenzyme A desaturase-1, transforming growth factor-β, and plas-minogen activator inhibitor-1 mRNAs, and higher activity of catalase, indicative of low oxidative stress, inhibition of triglyceride synthesis, and lower expression of profibrotic proteins. Global gene analysis of hepatic RNA showed that compared with wt mice, the livers of Gclm null mice have a high capacity to metabolize endogenous and exogenous compounds, have lower levels of lipogenic proteins, and increased antioxidant activity. Thus, metabolic adaptations

  7. Protein-protein interaction analysis of Alzheimer`s disease and NAFLD based on systems biology methods unhide common ancestor pathways.

    PubMed

    Karbalaei, Reza; Allahyari, Marzieh; Rezaei-Tavirani, Mostafa; Asadzadeh-Aghdaei, Hamid; Zali, Mohammad Reza

    2018-01-01

    Analysis reconstruction networks from two diseases, NAFLD and Alzheimer`s diseases and their relationship based on systems biology methods. NAFLD and Alzheimer`s diseases are two complex diseases, with progressive prevalence and high cost for countries. There are some reports on relation and same spreading pathways of these two diseases. In addition, they have some similar risk factors, exclusively lifestyle such as feeding, exercises and so on. Therefore, systems biology approach can help to discover their relationship. DisGeNET and STRING databases were sources of disease genes and constructing networks. Three plugins of Cytoscape software, including ClusterONE, ClueGO and CluePedia, were used to analyze and cluster networks and enrichment of pathways. An R package used to define best centrality method. Finally, based on degree and Betweenness, hubs and bottleneck nodes were defined. Common genes between NAFLD and Alzheimer`s disease were 190 genes that used construct a network with STRING database. The resulting network contained 182 nodes and 2591 edges and comprises from four clusters. Enrichment of these clusters separately lead to carbohydrate metabolism, long chain fatty acid and regulation of JAK-STAT and IL-17 signaling pathways, respectively. Also seven genes selected as hub-bottleneck include: IL6, AKT1, TP53, TNF, JUN, VEGFA and PPARG. Enrichment of these proteins and their first neighbors in network by OMIM database lead to diabetes and obesity as ancestors of NAFLD and AD. Systems biology methods, specifically PPI networks, can be useful for analyzing complicated related diseases. Finding Hub and bottleneck proteins should be the goal of drug designing and introducing disease markers.

  8. Biomarkers for liver fibrosis

    DOEpatents

    Jacobs, Jon M.; Burnum-Johnson, Kristin E.; Baker, Erin M.; Smith, Richard D.; Gritsenko, Marina A.; Orton, Daniel

    2017-05-16

    Methods and systems for diagnosing or prognosing liver fibrosis in a subject are provided. In some examples, such methods and systems can include detecting liver fibrosis-related molecules in a sample obtained from the subject, comparing expression of the molecules in the sample to controls representing expression values expected in a subject who does not have liver fibrosis or who has non-progressing fibrosis, and diagnosing or prognosing liver fibrosis in the subject when differential expression of the molecules between the sample and the controls is detected. Kits for the diagnosis or prognosis of liver fibrosis in a subject are also provided which include reagents for detecting liver fibrosis related molecules.

  9. Biomarkers for liver fibrosis

    DOEpatents

    Jacobs, Jon M.; Burnum-Johnson, Kristin E.; Baker, Erin M.; Smith, Richard D.; Gritsenko, Marina A.; Orton, Daniel

    2015-09-15

    Methods and systems for diagnosing or prognosing liver fibrosis in a subject are provided. In some examples, such methods and systems can include detecting liver fibrosis-related molecules in a sample obtained from the subject, comparing expression of the molecules in the sample to controls representing expression values expected in a subject who does not have liver fibrosis or who has non-progressing fibrosis, and diagnosing or prognosing liver fibrosis in the subject when differential expression of the molecules between the sample and the controls is detected. Kits for the diagnosis or prognosis of liver fibrosis in a subject are also provided which include reagents for detecting liver fibrosis related molecules.

  10. Association between continuous positive airway pressure and serum aminotransferases in patients with obstructive sleep apnea.

    PubMed

    Chen, Li-Da; Zhang, Liang-Ji; Lin, Xue-Jun; Qi, Jia-Chao; Li, Hao; Wu, Zhi; Xu, Qiao-Zhen; Huang, Ya-Ping; Lin, Li

    2018-02-01

    Obstructive sleep apnea (OSA) has been suggested to be a potential contributing factor for nonalcoholic fatty liver disease (NAFLD). Studies on the association between continuous positive airway pressure (CPAP) and NAFLD in OSA patients are limited and controversial. The aim of this study was to assess the relationship between OSA and NAFLD and the effect of CPAP therapy on serum aminotransferase levels in OSA patients. A total of 160 consecutive patients who underwent standard polysomnography were enrolled. Blood samples were obtained in the morning after sleep for biological profile measurements. Non-invasive ultrasound techniques were used to assess liver steatosis and fibrosis. Within the OSA group, serum aminotransferases were detected before and after CPAP treatment. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, and liver steatosis score increased significantly with an increase in OSA severity. Stepwise multiple regression with liver steatosis score, ALT, AST as dependent variable, respectively, apnea-hypopnea index (β = 0.447, p = 0.020; β = 0.266, p = 0.001; β = 0.351, p = 0.020, respectively) significantly predicted the liver steatosis score, ALT, AST after adjustment for confounders. After 3 months of CPAP treatment, there was a significant decrease in both ALT (54.20 ± 24.34 vs. 46.52 ± 24.95, p = 0.000) and AST (31.82 ± 8.91 vs. 29.00 ± 8.34, p = 0.039). OSA severity was independently associated with liver steatosis and elevation of serum aminotransferases. 3 months of CPAP therapy were associated with a statistically significant improvement on liver injury in OSA patients.

  11. The role of bariatric surgery in the management of nonalcoholic fatty liver disease and metabolic syndrome.

    PubMed

    Aguilar-Olivos, Nancy E; Almeda-Valdes, Paloma; Aguilar-Salinas, Carlos A; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD is strongly associated with obesity and metabolic syndrome (MetS). Current treatment of NAFLD is based on weight reduction. Bariatric surgery is the most effective treatment for morbid obesity and its associated metabolic comorbidities. There is evidence indicating that bariatric surgery improves histological and biochemical parameters of NAFLD, but currently is not considered a treatment option for NAFLD. The aim of this work is to review the evidence for the effects of bariatric surgery on NAFLD and the MetS. We found that insulin resistance, alterations in glucose metabolism, hypertension, plasma lipids, transaminases, liver steatosis, steatohepatitis and fibrosis improve after bariatric surgery. Weight loss and improvement of NAFLD are greater after RYGB than after other interventions. These findings were obtained from retrospective or cohort studies. There are no studies designed to evaluate liver-specific mortality, liver transplantation, or quality of life. Patients with indications for bariatric surgery will benefit from the improvements in the MetS and NAFLD. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Zinc and Selenium Co-supplementation Reduces Some Lipid Peroxidation and Angiogenesis Markers in a Rat Model of NAFLD-Fed High Fat Diet.

    PubMed

    Mousavi, Seyedeh Neda; Faghihi, Amirhosein; Motaghinejad, Majid; Shiasi, Maryam; Imanparast, Fatemeh; Amiri, Hamid Lorvand; Shidfar, Farzad

    2018-02-01

    Studies have shown that non-alcoholic fatty liver disease (NAFLD) patients are more prone to cardiovascular disease (CVD). Zinc and selenium deficiency are common in NAFLD. But the effects of zinc and selenium co-supplementation before and/or after disease progression on CVD markers are not clear in NAFLD patients. This study aimed to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on some of the CVD markers in an experimental model of NAFLD. Forty male Sprague Dawley rats (197 ± 4 g) were randomly assigned into four dietary groups: control group (C; received 9% of calorie as fat), model group (M; received 82% of calorie as fat), and supplementation before (BS) or after (AS) disease progression. Animals were fed diets for 20 weeks in all groups. Fasting plasma glucose (FPG), insulin, HOMA-IR, ALT, AST, lipid profile, malondialdehyde (MDA) and vascular endothelial growth factor (VEGF) levels were measured as CVD indices. Serum ALT, AST, FPG, insulin, MDA, VEGF and HOMA-IR were significantly higher in the M than C group. Co-supplementation reduced serum ALT and AST levels in the BS and AS groups compared with the M group. FPG, insulin, HOMA-IR, VEGF, MDA, LDL/HDL-c and TC/HDL-c ratio were significantly reduced in the AS compared with the M group. TG/HDL-c ratio was significantly reduced in the BS and AS compared with the M group. Serum MDA, VEGF, Insulin and HOMA-IR were significantly lowered in the AS than BS group (p < 0.05). Zinc and selenium co-supplementation after NAFLD progression reduced CVD risk indices in an experimental model.

  13. Influence of type 2 diabetes mellitus on liver histology among morbidly obese individuals. A cross-sectional study.

    PubMed

    Cazzo, Everton; Jimenez, Laísa Simakawa; Gallo, Fábio de Felice; Pareja, José Carlos; Chaim, Elinton Adami

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has become a public health concern. It encompasses a wide spectrum of histological abnormalities and has close relationships with insulin resistance and type 2 diabetes mellitus (T2DM). This study sought to compare the histological alterations observed in morbidly obese individuals with and without T2DM who underwent Roux-en-Y gastric bypass. Cross-sectional study in a tertiary-level public hospital. This was a cross-sectional study on 197 individuals who underwent gastric bypass surgery between 2011 and 2013. NAFLD was assessed through liver biopsies. T2DM was diagnosed through the International Diabetes Federation criteria. Non-diabetics presented significantly more biopsies without any histological abnormalities, regarding steatosis (42.6% versus 25.5%; P = 0.0400), fibrosis (60.6% versus 36.2%; P = 0.0042) and steatohepatitis (27.3% versus 12.8%; P = 0.0495), while diabetics presented significantly higher frequency of moderate forms of steatosis (36.2% versus 20%; P = 0.0307) and fibrosis (23.4% versus 4%; P = 0.0002). T2DM was associated with more advanced forms of NAFLD within the population studied. NAFLD has previously been correlated with severe forms of heart disease. Screening for and early detecting of NAFLD in high-risk populations are important for avoiding further development of severe forms and the need for liver transplantation.

  14. Cadherin-11 Regulation of Fibrosis through Modulation of Epithelial-to-Mesenchymal Transition: Implications for Pulmonary Fibrosis in Scleroderma

    DTIC Science & Technology

    2014-10-01

    fibrosis, interstitial lung diseases 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...cadherin-11 in scleroderma patients with interstitial lung disease . We have been working with our collaborators at UTHSC to identify and sera that...83% female, avg age 49, avg disease duration 2.5 years, 59% with diffuse SSc, 28% with ILD and avg skin score of 16 at enrollment). Since there is

  15. Non-alcoholic fatty liver disease fibrosis score predicts hematological toxicity of chemotherapy including irinotecan for colorectal cancer.

    PubMed

    Yahagi, Masashi; Tsuruta, Masashi; Hasegawa, Hirotoshi; Okabayashi, Koji; Kitagawa, Yuko

    2017-04-01

    Liver dysfunction that may affect drug metabolism is a major concern in patients treated with chemotherapy. Thus, assessment of the degree of liver dysfunction is crucial for predicting the adverse events of chemotherapy. The non-alcoholic fatty liver disease fibrosis score (NFS) is a non-invasive clinical scoring system constructed from routine clinical and laboratory variables. The aim of this study was to evaluate whether NFS was useful for predicting the adverse events of chemotherapy including irinotecan (CPT-11) for colorectal cancer. Between January, 2007 and May, 2013, a total of 87 patients with unresectable/recurrent colorectal cancer who received first-line chemotherapy including CPT-11 were reviewed. Demographic variables, including pretreatment NFS, were retrospectively collected from medical records. The primary outcome was the association between pretreatment NFS and adverse events, such as hematological and non-hematological toxicity, of chemotherapy including CPT-11. The median pretreatment NFS was 1.302 (range, 5.158-2.620). Pretreatment NFS was an independent risk factor for hematological toxicity in a multivariate analysis (coefficient=0.932, 95% CI: 0.083-1.781; P=0.031). Receiver operating characteristic curve analysis identified 0.347 as the optimal cut-off value associated with hematological toxicity. Using this cut-off, high NFS was found to be a significant risk factor for hematological toxicity (coefficient=2.019, 95% CI: 0.239-3.798, P=0.026), but not for non-hematological toxicity (P=0.546). Therefore, based on these results, NFS appears to be a significant predictor of hematological adverse events in chemotherapy including CPT-11 for colorectal cancer and it is a non-invasive, useful tool that may be used for determining regimens or doses of chemotherapy including CPT-11.

  16. Obstructive Sleep Apnea Is Associated with Liver Damage and Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Petta, Salvatore; Marrone, Oreste; Torres, Daniele; Buttacavoli, Maria; Cammà, Calogero; Di Marco, Vito; Licata, Anna; Lo Bue, Anna; Parrinello, Gaspare; Pinto, Antonio; Salvaggio, Adriana; Tuttolomondo, Antonino; Craxì, Antonio; Bonsignore, Maria Rosaria

    2015-01-01

    Background/Aims We assessed whether obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with severity of liver fibrosis and carotid atherosclerosis in patients with biopsy-proven NAFLD and low prevalence of morbid obesity. Secondary aim was to explore the association of OSA and hypoxemia with NASH and severity of liver pathological changes. Methods Consecutive patients (n = 126) with chronically elevated ALT and NAFLD underwent STOP-BANG questionnaire to estimate OSA risk and ultrasonographic carotid assessment. In patients accepting to perform cardiorespiratory polygraphy (PG, n = 50), OSA was defined as an apnea/hypopnea index ≥5. A carotid atherosclerotic plaque was defined as a focal thickening >1.3 mm. Results Prevalence of high OSA risk was similar in patients refusing or accepting PG (76% vs 68%, p = 0.17). Among those accepting PG, overall OSA prevalence was significantly higher in patients with F2-F4 fibrosis compared to those without (72% vs 44%; p = 0.04). Significant fibrosis was independently associated with mean nocturnal oxygen saturation (SaO2)<95% (OR 3.21, 95%C.I. 1.02–7.34; p = 0.04). Prevalence of OSA tended to be higher in patients with, than in those without, carotid plaques (64% vs 40%; p = 0.08). Carotid plaques were independently associated with %time at SaO2<90% >1 (OR 6.30, 95%C.I. 1.02–12.3; p = 0.01). Conclusions In NAFLD patients with chronically elevated ALT at low prevalence of morbid obesity, OSA was highly prevalent and indexes of SaO2 resulted independently associated with severity of liver fibrosis and carotid atherosclerosis. These data suggest to consider sleep disordered breathing as a potential additional therapeutic target in severe NAFLD patients. PMID:26672595

  17. Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis.

    PubMed

    Sun, Chao; Wang, Zhen; Tian, Ji-Wei; Wang, Yun-Hao

    2018-04-27

    The ongoing chronic inflammation and subsequent fibrosis play an important role in ligamentum flavum (LF) fibrosis and hypertrophy in patients with lumbar spinal canal stenosis (LSCS). Leptin is a chronic inflammatory mediator and involved in the fibrotic process in multiple organ systems. The present study aimed to investigate the role of leptin in LF fibrosis and its related regulatory mechanisms. The LF specimens were obtained during the surgery from 12 patients with LSCS (LSCS group) and 12 control patients with lumbar disc herniation (LDH) group. The morphologic changes and fibrosis score of LF were assessed by Hematoxylin and eosin (H&E) and Masson's trichrome staining respectively. The location and expression of leptin in LF tissues were determined. Then, the LF cells were cultured and exposed to recombinant human leptin (rhleptin). Collagen I and III were used as fibrosis markers and IL-6 was used as the inflammatory factor. As a result, the LF thickness and fibrosis score in the LSCS group were significantly higher than those in the LDH group ( P <0.05). Leptin was detected in the hypertrophied LF and its expression was substantially increased in the LSCS group and positively correlated with LF thickness and fibrosis score ( P <0.05). Moreover, our in vitro experiments revealed that rhleptin treated LF cells elevated the expression of collagen I and III. Finally, leptin administration induced IL-6 expression via nuclear factor-κB (NF-κB) pathway in LF cell ( P <0.05). Our study demonstrated novel molecular events for leptin-induced inflammation in LF tissue by promoting IL-6 expression and thus might have potential implications for clarifying the mechanism underlying LF fibrosis and hypertrophy. © 2018 The Author(s).

  18. Non-invasive diagnosis of advanced fibrosis and cirrhosis

    PubMed Central

    Sharma, Suraj; Khalili, Korosh; Nguyen, Geoffrey Christopher

    2014-01-01

    Liver cirrhosis is a common and growing public health problem globally. The diagnosis of cirrhosis portends an increased risk of morbidity and mortality. Liver biopsy is considered the gold standard for diagnosis of cirrhosis and staging of fibrosis. However, despite its universal use, liver biopsy is an invasive and inaccurate gold standard with numerous drawbacks. In order to overcome the limitations of liver biopsy, a number of non-invasive techniques have been investigated for the assessment of cirrhosis. This review will focus on currently available non-invasive markers of cirrhosis. The evidence behind the use of these markers will be highlighted, along with an assessment of diagnostic accuracy and performance characteristics of each test. Non-invasive markers of cirrhosis can be radiologic or serum-based. Radiologic techniques based on ultrasound, magnetic resonance imaging and elastography have been used to assess liver fibrosis. Serum-based biomarkers of cirrhosis have also been developed. These are broadly classified into indirect and direct markers. Indirect biomarkers reflect liver function, which may decline with the onset of cirrhosis. Direct biomarkers, reflect extracellular matrix turnover, and include molecules involved in hepatic fibrogenesis. On the whole, radiologic and serum markers of fibrosis correlate well with biopsy scores, especially when excluding cirrhosis or excluding fibrosis. This feature is certainly clinically useful, and avoids liver biopsy in many cases. PMID:25492996

  19. Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

    PubMed

    Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

    2017-09-21

    To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

  20. Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis.

    PubMed

    Thiele, Maja; Detlefsen, Sönke; Sevelsted Møller, Linda; Madsen, Bjørn Stæhr; Fuglsang Hansen, Janne; Fialla, Annette Dam; Trebicka, Jonel; Krag, Aleksander

    2016-01-01

    Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score and collagen-proportionate area were used as reference. We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver clinics (in Southern Denmark). The second, lower-risk group, was recruited from municipal alcohol rehabilitation centers and the Danish national public health portal. All subjects underwent same-day transient elastography (FibroScan), 2-dimensional shear wave elastography (Supersonic Aixplorer), and liver biopsy after an overnight fast. Transient elastography and 2-dimensional shear wave elastography identified subjects in each group with significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) with high accuracy (area under the curve ≥0.92). There was no difference in diagnostic accuracy between techniques. The cutoff values for optimal identification of significant fibrosis by transient elastography and 2-dimensional shear wave elastography were 9.6 kPa and 10.2 kPa, and for cirrhosis 19.7 kPa and 16.4 kPa. Negative predictive values were high for both groups, but the positive predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified individuals with significant fibrosis and cirrhosis. In a prospective study of individuals at risk for liver fibrosis due to alcohol consumption, we found elastography to be an excellent tool for diagnosing liver

  1. Appetite stimulants for people with cystic fibrosis.

    PubMed

    Chinuck, Ruth; Dewar, Jane; Baldwin, David R; Hendron, Elizabeth

    2014-07-27

    Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index and nutritional status. However, these may have adverse effects on clinical status. The aim of this review is to systematically search for and evaluate evidence on the beneficial effects of appetite stimulants in the management of CF-related anorexia and synthesize reports of any side-effects. Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, CINAHL, handsearching reference lists and contacting local and international experts.Last search of online databases: 01 April 2014.Last search of the Cystic Fibrosis Trials Register: 08 April 2014. Randomised and quasi-randomised controlled trials of appetite stimulants, compared to placebo or no treatment for at least one month in adults and children with cystic fibrosis. Authors independently extracted data and assessed the risk of bias within eligible trials. Meta-analyses were performed. Three trials (total of 47 recruited patients) comparing appetite stimulants (cyproheptadine hydrochloride and megesterol acetate) to placebo were included; the numbers of adults or children within each trial were not always reported. The risk of bias of the included trials was graded as moderate.A meta-analysis of all three trials showed appetite stimulants produced a larger increase in weight z score at three months compared to placebo, mean difference 0.61 (95% confidence interval 0.29 to 0.93) (P < 0.001) (n = 40) with no evidence of a difference in effect between two different appetite stimulants. One of these trials also reported a significant weight increase with megesterol acetate compared to placebo at six months (n = 17). The three trials reported no significant differences in forced expiratory volume at one second (per cent predicted

  2. Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications.

    PubMed

    Kumar, Ramesh; Mohan, Shantam

    2017-09-28

    Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach.

  3. Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications

    PubMed Central

    Kumar, Ramesh; Mohan, Shantam

    2017-01-01

    Abstract Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach. PMID:28936403

  4. Cannabinoid receptor 2 activation restricts fibrosis and alleviates hydrocephalus after intraventricular hemorrhage.

    PubMed

    Tan, Qiang; Chen, Qianwei; Feng, Zhou; Shi, Xia; Tang, Jun; Tao, Yihao; Jiang, Bing; Tan, Liang; Feng, Hua; Zhu, Gang; Yang, Yunfeng; Chen, Zhi

    2017-01-01

    Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-β 1(TGF-β1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-β1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver.

    PubMed

    Takahashi, Yutaka

    2017-07-05

    Adult growth hormone deficiency (GHD) is characterized by metabolic abnormalities associated with visceral obesity, impaired quality of life, and increased mortality. Patients with adult GHD show increased prevalence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and growth hormone (GH) replacement therapy has been shown to improve these conditions. It has also been demonstrated that a decrease in the GH insulin-like growth factor-I (IGF-I) axis is closely associated with the progression of general NAFLD, suggesting a physiological role of these hormones for the maintenance of the liver. NASH histologically demonstrates inflammation, necrosis, and fibrosis, in addition to steatosis (and is a serious disease because it can progress to liver cirrhosis and hepatocellular carcinoma in a subset of cases). While fibrosis determines the prognosis of the patient, efficacious treatment for fibrosis is crucial; however, it has not yet been established. Recent studies have clarified the essential roles of GH and IGF-I in the liver. GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes. IGF-I induces cellular senescence and inactivates hepatic stellate cells, therefore ameliorating fibrosis. IGF-I treatment has been shown to improve animal models of NASH and cirrhosis, suggesting potential clinical applications of IGF-I in these conditions. In this review, I will focus on the important roles of GH and IGF-I in the liver, their underlying mechanisms, and their potential therapeutic applications.

  6. Noninvasive Assessment of Liver Fibrosis By Transient Elastography and FIB4/APRI for Prediction of Treatment Response in Chronic Hepatitis C-An Experience from a Tertiary Care Hospital.

    PubMed

    Taneja, Sunil; Tohra, Sunil; Duseja, Ajay; Dhiman, Radha Krishan; Chawla, Yogesh Kumar

    2016-12-01

    Liver fibrosis and its sequel cirrhosis represent a major health care burden, and assessment of fibrosis by biopsy is gradually being replaced by noninvasive methods. In clinical practice, the determination of fibrosis stage is important, since patients with advanced fibrosis have faster progression to cirrhosis and antiviral therapy is indicated in these patients. To assess the role of transient elastography (TE) and compare it with APRI and FIB4 for predicting liver fibrosis and assessing the effect of host and viral factors on fibrosis and treatment outcome in CHC patients. In a retrospective analysis, 330 CHC patients underwent liver stiffness measurement (LSM) by TE and tests needed for calculating APRI and FIB4 scores at baseline. 228 patients received a combination of Pegylated IFN-based antiviral therapy and were analyzed for therapeutic response. The study included 330 patients (median age 39 years [range 18-67]), predominantly males ( n  = 227, 68.8%) with baseline LSMs. The median liver stiffness was 7.8 kPa (range 3.2-69.1 kPa). LSMs and its thresholds for severe fibrosis progression (≥9.5 kPa) and cirrhosis (≥12.5 kPa) were significantly higher in patients with age ≥40 years, diabetes mellitus, and patients with significant alcohol intake ( P  = 0.003 to P  < 0.001). By taking TE as a reference, the diagnostic accuracy of FIB4 scores for predicting cirrhosis (AUROC 0.896) was good (+LR 13.4) compared to APRI (AUROC 0.823) with moderate likelihood ratio (+LR 6.9). Among 228 treated patients the SVR rate in genotype 3 was 70% versus 57.8% in genotype 1. Fibrosis score F4 ( P  = 0.023) and HCV genotype ( P  = 0.008) were independent predictors of SVR. The study shows that LSM by TE and fibrosis assessment by FIB4/APRI scores can be used with fair reliability to predict fibrosis and treatment response in patients with CHC infection.

  7. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis

    PubMed Central

    Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition. PMID:26666259

  8. Angiotensin-converting enzyme gene polymorphism (insertion/deletion) and liver fibrosis in Turkish patients from the western Black Sea region, Turkey.

    PubMed

    Turhan, N K; Ilikhan, S Uygun; Hamamcioglu, A C; Ustundag, Y; Dursun, A; Kokturk, F

    2015-12-16

    Chronic viral hepatitis B, chronic viral hepatitis C, non-alcoholic steatohepatitis, alcoholic liver disease, autoimmune hepatitis, primary biliary cirrhosis, and secondary biliary cirrhosis are important health issues worldwide. While an association between angiotensin-converting enzyme gene insertion/deletion (ACE gene I/D) polymorphism and liver fibrosis has been demonstrated in rat studies, the results of clinical studies area have been contradictory. The aim of this study was to assess the possible association between ACE gene I/D polymorphism and liver fibrosis in a large group of Turkish patients from the western Black Sea region. In 418 patients with different etiologies, ACE gene I/D polymorphism and serum ACE levels were investigated. The distribution of the "DD", "ID", "II" genotypes of the ACE gene were 32.5, 48.8, and 18.7% in the mild to moderate fibrosis group (N = 246, F:1-3 according to Ishak's score) and 39.0, 44.2, and 16.9% in the advanced fibrosis group (N = 172, F:4-6 according to Ishak's score). A significant correlation between serum ACE levels and ACE gene alleles was identified (P < 0.001): serum ACE levels of patients with D alleles were higher than those of patients with I alleles [44 (min 7-max 101) versus 29 (min 7-max 96)]. Patients with advanced fibrosis were also found to be older than those with mild to moderate fibrosis (P < 0.001). No significant association was noted between the patient gender and fibrosis severity. We conclude that ACE I/D polymorphism is not associated with the degree of liver fibrosis.

  9. Adiponectin Attenuates Lung Fibroblasts Activation and Pulmonary Fibrosis Induced by Paraquat

    PubMed Central

    He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  10. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    PubMed

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05). Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05). APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a dose

  11. Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter?

    PubMed Central

    Behairy, Behairy El-Sayed; Sira, Mostafa Mohamed; Zalata, Khaled Refat; Salama, El-Sayed Ebrahem; Abd-Allah, Mohamed Ahmed

    2016-01-01

    AIM: To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. METHODS: A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. RESULTS: The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 ± 7.23 kPa) compared to Wilson disease (8.30 ± 0.84 kPa) and HCV groups (7.43 ± 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable

  12. The impact of slice-reduced computed tomography on histogram-based densitometry assessment of lung fibrosis in patients with systemic sclerosis.

    PubMed

    Nguyen-Kim, Thi Dan Linh; Maurer, Britta; Suliman, Yossra A; Morsbach, Fabian; Distler, Oliver; Frauenfelder, Thomas

    2018-04-01

    To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051-0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity

  13. The impact of slice-reduced computed tomography on histogram-based densitometry assessment of lung fibrosis in patients with systemic sclerosis

    PubMed Central

    Maurer, Britta; Suliman, Yossra A.; Morsbach, Fabian; Distler, Oliver; Frauenfelder, Thomas

    2018-01-01

    Background To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. Methods From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. Results With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051–0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Conclusions Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis

  14. Nutritional status is associated with health-related quality of life in children with cystic fibrosis aged 9-19 years.

    PubMed

    Shoff, Suzanne M; Tluczek, Audrey; Laxova, Anita; Farrell, Philip M; Lai, HuiChuan J

    2013-12-01

    The impact of improved nutritional status on health-related quality of life (HRQOL) is unknown for children with cystic fibrosis (CF). Associations between nutritional status and HRQOL were examined over 2 years in 95 children, aged 9-19 years, who were followed in the Wisconsin Newborn Screening Project. HRQOL was assessed using the Cystic Fibrosis Questionnaire (CFQ). Associations between height z-score (HtZ), BMI z-score (BMIZ) and seven CFQ dimensions were evaluated. Mean values of at least 80 were observed for all CFQ dimensions except respiratory symptoms and treatment burden. Treatment burden was significantly worse in patients with meconium ileus (57) compared to pancreatic insufficient (65) and sufficient (78) subjects, p<0.0001. HtZ and BMIZ were positively associated with physical functioning and body image (p<0.05). Better nutritional status was associated with increased HRQOL scores. Early diagnosis through newborn screening and improved nutrition provides an opportunity to enhance quality of life and body image perception. Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  15. Characteristics of liver fibrosis with different etiologies using a fully quantitative fibrosis assessment tool.

    PubMed

    Wu, Q; Zhao, X; You, H

    2017-05-18

    This study aimed to test the diagnostic performance of a fully quantitative fibrosis assessment tool for liver fibrosis in patients with chronic hepatitis B (CHB), primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH). A total of 117 patients with liver fibrosis were included in this study, including 50 patients with CHB, 49 patients with PBC and 18 patients with NASH. All patients underwent liver biopsy (LB). Fibrosis stages were assessed by two experienced pathologists. Histopathological images of LB slices were processed by second harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy without staining, a system called qFibrosis (quantitative fibrosis) system. Altogether 101 quantitative features of the SHG/TPEF images were acquired. The parameters of aggregated collagen in portal, septal and fibrillar areas increased significantly with stages of liver fibrosis in PBC and CHB (P<0.05), but the same was not found for parameters of distributed collagen (P>0.05). There was a significant correlation between parameters of aggregated collagen in portal, septal and fibrillar areas and stages of liver fibrosis from CHB and PBC (P<0.05), but no correlation was found between the distributed collagen parameters and the stages of liver fibrosis from those patients (P>0.05). There was no significant correlation between NASH parameters and stages of fibrosis (P>0.05). For CHB and PBC patients, the highest correlation was between septal parameters and fibrosis stages, the second highest was between portal parameters and fibrosis stages and the lowest correlation was between fibrillar parameters and fibrosis stages. The correlation between the septal parameters of the PBC and stages is significantly higher than the parameters of the other two areas (P<0.05). The qFibrosis candidate parameters based on CHB were also applicable for quantitative analysis of liver fibrosis in PBC patients. Different parameters should be selected for liver

  16. Characteristics of liver fibrosis with different etiologies using a fully quantitative fibrosis assessment tool

    PubMed Central

    Wu, Q.; Zhao, X.; You, H.

    2017-01-01

    This study aimed to test the diagnostic performance of a fully quantitative fibrosis assessment tool for liver fibrosis in patients with chronic hepatitis B (CHB), primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH). A total of 117 patients with liver fibrosis were included in this study, including 50 patients with CHB, 49 patients with PBC and 18 patients with NASH. All patients underwent liver biopsy (LB). Fibrosis stages were assessed by two experienced pathologists. Histopathological images of LB slices were processed by second harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy without staining, a system called qFibrosis (quantitative fibrosis) system. Altogether 101 quantitative features of the SHG/TPEF images were acquired. The parameters of aggregated collagen in portal, septal and fibrillar areas increased significantly with stages of liver fibrosis in PBC and CHB (P<0.05), but the same was not found for parameters of distributed collagen (P>0.05). There was a significant correlation between parameters of aggregated collagen in portal, septal and fibrillar areas and stages of liver fibrosis from CHB and PBC (P<0.05), but no correlation was found between the distributed collagen parameters and the stages of liver fibrosis from those patients (P>0.05). There was no significant correlation between NASH parameters and stages of fibrosis (P>0.05). For CHB and PBC patients, the highest correlation was between septal parameters and fibrosis stages, the second highest was between portal parameters and fibrosis stages and the lowest correlation was between fibrillar parameters and fibrosis stages. The correlation between the septal parameters of the PBC and stages is significantly higher than the parameters of the other two areas (P<0.05). The qFibrosis candidate parameters based on CHB were also applicable for quantitative analysis of liver fibrosis in PBC patients. Different parameters should be selected for liver

  17. Design and rationale of the WELCOME trial: A randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected].

    PubMed

    Scorletti, E; Bhatia, L; McCormick, K G; Clough, G F; Nash, K; Calder, P C; Byrne, C D

    2014-03-01

    Non-alcoholic fatty liver disease (NAFLD) represents a range of liver conditions from simple fatty liver to progressive end stage liver disease requiring liver transplantation. NAFLD is common in the population and in certain sub groups (e.g. type 2 diabetes) up to 70% of patients may be affected. NAFLD is not only a cause of end stage liver disease and hepatocellular carcinoma, but is also an independent risk factor for type 2 diabetes and cardiovascular disease. Consequently, effective treatments for NAFLD are urgently needed. The WELCOME study is testing the hypothesis that treatment with high dose purified long chain omega-3 fatty acids will have a beneficial effect on a) liver fat percentage and b) two histologically validated algorithmically-derived biomarker scores for liver fibrosis. In a randomised double blind placebo controlled trial, 103 participants with NAFLD were randomised to 15-18months treatment with either 4g/day purified long chain omega-3 fatty acids (Omacor) or 4g/day olive oil as placebo. Erythrocyte percentage DHA and EPA enrichment (a validated proxy for hepatic enrichment) was determined by gas chromatography. Liver fat percentage was measured in three discrete liver zones by magnetic resonance spectroscopy (MRS). We also measured body fat distribution, physical activity and a range of cardiometabolic risk factors. Recruitment started in January 2010 and ended in June 2011. We identified 178 potential participants, and randomised 103 participants who met the inclusion criteria. The WELCOME study was approved by the local ethics committee (REC: 08/H0502/165; www.clinicalTrials.gov registration number NCT00760513). Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients

    PubMed Central

    Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

    2016-01-01

    AIM To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. METHODS A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). RESULTS Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage (P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. CONCLUSION Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy. PMID:27917265

  19. Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients.

    PubMed

    Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

    2016-11-18

    To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage ( P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy.

  20. Fibrosis assessment in chronic hepatitis C--is the liver biopsy still necessary? The pathologist point of view.

    PubMed

    Moroşan, Eugenia; Mihailovici, Maria-Sultana

    2014-01-01

    The aim of this study was to compare the histological stage of fibrosis determined by liver biopsy with the stage of fibrosis assessed by Fibroscan, to analyze the correspondences and inconsistencies between obtained values and to discuss the role of the microscopic exam, from the pathologist point of view. The study group consisted of 185 patients diagnosed with chronic hepatitis. Serological tests diagnosed chronic hepatitis C in 183 patients, and chronic hepatitis B and C for 2 patients. The patients were evaluated to determine the stage of fibrosis using two methods: liver biopsy and elastography (Fibroscan). Based on the pathologic evaluation, 124 cases were diagnosed as moderate chronic hepatitis (score 6-8), and the remaining 60 cases as severe hepatitis (score 9-12). Comparison of data from examination of liver biopsy with that obtained by Fibroscan examination revealed overlapping and divergent aspects. The fibrosis stage established through liver biopsy did not always coincide with the one assigned by liver stiffness measurement, particularly for intermediate stages F2 and F3. The best overlap was noted for F0-F1 and F4 stages, which indicates the evident ability of transient elastography to separate patients with minimal or no fibrosis from patients with extensive fibrosis. Our data concurs with the literature, which confirms presence of differences between Fibroscan and biopsy. From the point of view of the pathologist, liver biopsy still remains a valuable instrument, offering a relevant image of liver changes--as it is regarded more rather a selective than routine technique.