... remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis A, ... the skin, can be one sign of liver disease. Cancer can affect the liver. You could also ...
Safaei, Akram; Rezaei Tavirani, Mostafa; Arefi Oskouei, Afsaneh; Zamanian Azodi, Mona; Mohebbi, Seyed Reza; Nikzamir, Abdol Rahim
Evaluation of biological characteristics of 13 identified proteins of patients with cirrhotic liver disease is the main aim of this research. In clinical usage, liver biopsy remains the gold standard for diagnosis of hepatic fibrosis. Evaluation and confirmation of liver fibrosis stages and severity of chronic diseases require a precise and noninvasive biomarkers. Since the early detection of cirrhosis is a clinical problem, achieving a sensitive, specific and predictive novel method based on biomarkers is an important task. Essential analysis, such as gene ontology (GO) enrichment and protein-protein interactions (PPI) was undergone EXPASy, STRING Database and DAVID Bioinformatics Resources query. Based on GO analysis, most of proteins are located in the endoplasmic reticulum lumen, intracellular organelle lumen, membrane-enclosed lumen, and extracellular region. The relevant molecular functions are actin binding, metal ion binding, cation binding and ion binding. Cell adhesion, biological adhesion, cellular amino acid derivative, metabolic process and homeostatic process are the related processes. Protein-protein interaction network analysis introduced five proteins (fibroblast growth factor receptor 4, tropomyosin 4, tropomyosin 2 (beta), lectin, Lectin galactoside-binding soluble 3 binding protein and apolipoprotein A-I) as hub and bottleneck proteins. Our result indicates that regulation of lipid metabolism and cell survival are important biological processes involved in cirrhosis disease. More investigation of above mentioned proteins will provide a better understanding of cirrhosis disease.
Safaei, Akram; Rezaei Tavirani, Mostafa; Arefi Oskouei, Afsaneh; Zamanian Azodi, Mona; Mohebbi, Seyed Reza; Nikzamir, Abdol Rahim
Aim: Evaluation of biological characteristics of 13 identified proteins of patients with cirrhotic liver disease is the main aim of this research. Background: In clinical usage, liver biopsy remains the gold standard for diagnosis of hepatic fibrosis. Evaluation and confirmation of liver fibrosis stages and severity of chronic diseases require a precise and noninvasive biomarkers. Since the early detection of cirrhosis is a clinical problem, achieving a sensitive, specific and predictive novel method based on biomarkers is an important task. Methods: Essential analysis, such as gene ontology (GO) enrichment and protein-protein interactions (PPI) was undergone EXPASy, STRING Database and DAVID Bioinformatics Resources query. Results: Based on GO analysis, most of proteins are located in the endoplasmic reticulum lumen, intracellular organelle lumen, membrane-enclosed lumen, and extracellular region. The relevant molecular functions are actin binding, metal ion binding, cation binding and ion binding. Cell adhesion, biological adhesion, cellular amino acid derivative, metabolic process and homeostatic process are the related processes. Protein-protein interaction network analysis introduced five proteins (fibroblast growth factor receptor 4, tropomyosin 4, tropomyosin 2 (beta), lectin, Lectin galactoside-binding soluble 3 binding protein and apolipoprotein A-I) as hub and bottleneck proteins. Conclusion: Our result indicates that regulation of lipid metabolism and cell survival are important biological processes involved in cirrhosis disease. More investigation of above mentioned proteins will provide a better understanding of cirrhosis disease. PMID:27099671
Resources - liver disease ... The following organizations are good resources for information on liver disease : American Liver Foundation -- www.liverfoundation.org Children's Liver Association for Support Services -- www.classkids.org Hepatitis ...
Kolcun, John Paul George; Gernsback, Joanna Elizabeth; Richardson, Angela Mae; Jagid, Jonathan Russell
Chronic subdural hematoma (cSDH) is a common neurosurgical ailment, particularly in elderly patients. A recent study uncovered an association between liver disease and recurrence in patients with cSDH. Here, we explored that relationship to identify recurrence predictors in at-risk patients. We hypothesized that the association between liver disease and recurrence was attributable to coagulopathy secondary to liver disease. We retrospectively reviewed all patients with cSDH treated with burr-hole drainage by 2 surgeons between 2007 and 2015. Comorbidities and laboratory findings for each patient were examined by Pearson χ(2) analysis or Mann-Whitney U tests. We identified 261 cSDH in 215 patients. Patients were a mean age of 65.6 years, and 72% were male. Sixteen patients with cSDH required repeat surgery (6.1%). There were 123 coagulopathic patients (47.1%), and 14 with liver disease (5.4%), all of whom were coagulopathic (P < 0.001). Coagulopathic patients with liver disease were more likely to experience recurrence than patients with coagulopathy alone (relative risk = 4.09, P = 0.019). Patients with liver disease had significantly elevated prothrombin time (P = 0.013) and reduced platelet counts (P < 0.001). Platelets also were reduced in coagulopathic patients with liver disease, as compared with those with coagulopathy alone (P = 0.002). Thrombocytopenia remained significant in a multivariate analysis (P < 0.001). Liver disease is significantly associated with the recurrence of cSDH. Although coagulopathy alone does not predict recurrence, patients with coagulopathy and liver disease are at greater risk for recurrence than those with coagulopathy alone. Liver disease effects are reflected in certain hematologic laboratory values. Copyright © 2017 Elsevier Inc. All rights reserved.
Motiwala, Tasneem; Kite, Bobbie; Regan, Kelly; Gascon, Gregg M; Payne, Philip R O
Liver cancer, the fifth most common cancer and second leading cause of cancer-related death among men worldwide, is plagued by not only lack of clinical research, but informatics tools for early detection. Consequently, it presents a major health and cost burden. Among the different types of liver cancer, hepatocellular carcinoma (HCC) is the most common and deadly form, arising from underlying liver disease. Current models for predicting risk of HCC and liver disease are limited to clinical data. A domain analysis of existing research related to screening for HCC and liver disease suggests that metabolic syndrome (MetS) may present oppportunites to detect early signs of liver disease. The purpose of this paper is to (i) provide a domain analysis of the relationship between HCC, liver disease, and metabolic syndrome, (ii) a review of the current disparate sources of data available for MetS diagnosis, and (iii) recommend informatics solutions for the diagnosis of MetS from available administrative (Biometrics, PHA, claims) and laboratory data, towards early prediction of liver disease. Our domain analysis and recommendations incorporate best practices to make meaningful use of available data with the goal of reducing cost associated with liver disease.
Gevers, Tom J G; Nevens, Frederik; Torres, Vicente E; Hogan, Marie C; Drenth, Joost P H
Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Yin, Xueru; Yang, Jiqiao; Li, Tony; Song, Liyan; Han, Tinglu; Yang, Mei; Liao, Huihua; He, Jianjun; Zhong, Xiaozhu
There have been many reports on the reduction of liver disease with green tea consumption. This study aims to evaluate the body of evidence related to green tea consumption on the risk of liver disease and determine the effectiveness. Electronic searches were conducted in PubMed, CNKI, Wanfang and Weipu databases. Statistical analysis was performed using the software Revman 5.2 and Stata 12.0. Meta-analysis revealed that among green tea drinkers, there was a significant reduction in the risk of liver disease (RR=0.68, 95% CI=0.56-0.82, P=0.000). This trend extends to a broad spectrum of liver conditions including hepatocellular carcinoma (RR=0.74, 95% CI=0.56-0.97, P=0.027), liver steatosis (RR=0.65, 95% CI=0.44-0.98, P=0.039), hepatitis (RR=0.57, 95% CI=0.45-0.73, P=0.000), liver cirrhosis (RR=0.56, 95% CI=0.31-1.01, P=0.053) and chronic liver disease (RR=0.49, 95% CI=0.29-0.82, P=0.007). This trend is also observed regardless of the race of the individual concerned where the Asian, American and European subgroups all demonstrated a reduced risk of liver disease. Green tea intake reduces the risk of liver disease. However, more long term randomized clinical trials are needed to comprehensively evaluate the health benefits of green tea.
Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider ...
Yan, Jie; Xie, Wen; Ou, Wei-ni; Zhao, Hong; Wang, Su-yun; Wang, Jian-hui; Wang, Qi; Yang, Yu-ying; Feng, Xin; Cheng, Jun
With the changes in diet structure and lifestyle, the incidence of fatty liver disease is increasing in China, especially in cities. The goal of the present study was to accurately determine the prevalence and risk factors of fatty liver disease in Beijing residents, China. By using random multistage stratification and cluster sampling, residents aged > 20 years in Dongcheng District and Tongzhou District were recruited, and questionnaire survey, physical examination, detection of fasting glucose, blood lipids and liver biochemistry, and ultrasonography of the liver, gallbladder, and spleen were carried out. Database EpiData 3.0 was employed for data input, followed by statistical analysis with SPSS version 11.0. A total of 3762 residents were included in the present study including 2328 males and 1434 females with a mean age of 46.37 ± 14.28 years (range 20-92 years). Ultrasonography revealed fatty liver in 1486 residents with a prevalence of 39.5%. Moreover, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease were found in 1177 (31.3%) and 309 (8.2%) residents, respectively. After adjustment of prevalence based on the age and gender constituents of Beijing residents, the standardized prevalence of overall fatty liver disease, NAFLD, and alcoholic fatty liver disease was 35.1%, 31.0%, and 4.1%, respectively. Binary logistic regression analysis revealed waist-to-hip ratio, diastolic pressure, fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, and low density lipoprotein cholesterol were closely related to NAFLD. The Beijing residents have a high prevalence of fatty liver disease as much as 35.1%, which is characterized by NAFLD. Obesity, and glucose and lipid metabolism disorders are the main risk factors of fatty liver disease. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
Brady, Carla W
There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure.
Liver disease due to alcohol; Cirrhosis or hepatitis - alcoholic; Laennec's cirrhosis ... Alcoholic liver disease occurs after years of heavy drinking. Over time, scarring and cirrhosis can occur. Cirrhosis is the ...
Xu, Guan; Meng, Zhuoxian; Lin, Jiandie; Carson, Paul; Wang, Xueding
To provide more information for classification and assessment of biological tissues, photoacoustic spectrum analysis (PASA) moves beyond the quantification of the intensities of the photoacoustic (PA) signals by the use of the frequency-domain power distribution, namely power spectrum, of broadband PA signals. The method of PASA quantifies the linear-fit to the power spectrum of the PA signals from a biological tissue with 3 parameters, including intercept, midband-fit and slope. Intercept and midband-fit reflect the total optical absorption of the tissues whereas slope reflects the heterogeneity of the tissue structure. Taking advantage of the optical absorption contrasts contributed by lipid and blood at 1200 and 532 nm, respectively and the heterogeneous tissue microstructure in fatty liver due to the lipid infiltration, we investigate the capability of PASA in identifying histological changes of fatty livers in mouse model. 6 and 9 pairs of normal and fatty liver tissues from rat models were examined by ex vivo experiment with a conventional rotational PA measurement system. One pair of rat models with normal and fatty livers was examined non-invasively and in situ with our recently developed ultrasound and PA parallel imaging system. The results support our hypotheses that the spectrum analysis of PA signals can provide quantitative measures of the differences between the normal and fatty liver tissues and that part of the PA power spectrum can suffice for characterization of microstructures in biological tissues. Experimental results also indicate that the vibrational absorption peak of lipid at 1200nm could facilitate fatty liver diagnosis.
Lee, Noel M; Brady, Carla W
Liver diseases in pregnancy may be categorized into liver disorders that occur only in the setting of pregnancy and liver diseases that occur coincidentally with pregnancy. Hyperemesis gravidarum, preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests and low platelets (HELLP), acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy are pregnancy-specific disorders that may cause elevations in liver tests and hepatic dysfunction. Chronic liver diseases, including cholestatic liver disease, autoimmune hepatitis, Wilson disease, and viral hepatitis may also be seen in pregnancy. Management of liver disease in pregnancy requires collaboration between obstetricians and gastroenterologists/hepatologists. Treatment of pregnancy-specific liver disorders usually involves delivery of the fetus and supportive care, whereas management of chronic liver disease in pregnancy is directed toward optimizing control of the liver disorder. Cirrhosis in the setting of pregnancy is less commonly observed but offers unique challenges for patients and practitioners. This article reviews the epidemiology, pathophysiology, diagnosis, and management of liver diseases seen in pregnancy. PMID:19248187
Wadhawan, Manav; Anand, Anil C.
Coffee is the most popular beverage in the world. Consumption of coffee has been shown to benefit health in general, and liver health in particular. This article reviews the effects of coffee intake on development and progression of liver disease due to various causes. We also describe the putative mechanisms by which coffee exerts the protective effect. The clinical evidence of benefit of coffee consumption in Hepatitis B and C, as well as nonalcoholic fatty liver disease and alcoholic liver disease, has also been presented. Coffee consumption is associated with improvement in liver enzymes (ALT, AST, and GGTP), especially in individuals with risk for liver disease. Coffee intake more than 2 cups per day in patients with preexisting liver disease has been shown to be associated with lower incidence of fibrosis and cirrhosis, lower hepatocellular carcinoma rates, as well as decreased mortality. PMID:27194895
Liver Disease Pulmonary & PH Hypertension Did you know that if you have liver disease, you are at risk for pulmonary hypertension? ... tissue diseases (scleroderma and lupus for example), chronic liver disease, congenital heart disease, or HIV infec- tion. ...
Russ, Tom C; Kivimäki, Mika; Morling, Joanne R; Starr, John M; Stamatakis, Emmanuel; Batty, G David
Risk factors for cardiovascular disease, such as obesity and hypertension, have been associated with nonalcoholic fatty liver disease. Psychological distress (symptoms of anxiety and depression) is a risk factor for cardiovascular disease, so it might also be associated, directly or indirectly, with liver disease. We investigated the relationship between psychological distress (measured by the 12-item General Health Questionnaire [GHQ]) and liver disease mortality. We performed a meta-analysis of data from individual participants in 16 prospective studies of the general population in the United Kingdom, initiated from 1994 through 2008. Subjects were assigned to groups based on GHQ score: 0 (no distress), 1-3, 4-6, or 7-12. We analyzed data from 166,631 individuals (55% women; mean ± SD age, 46.6 ± 18.4 years; range, 16-102 years). During a mean follow-up period of 9.5 years, 17,368 participants died (457 with liver disease). We found a significant increase in liver disease mortality with increase in GHQ score (Ptrend < .001). The age- and sex-adjusted hazard ratio for the highest GHQ score category (ie, 7-12), compared with the 0 score category, was 3.48 (95% confidence interval: 2.68-4.52). After adjustment for health behaviors, socioeconomic status, body mass index, and diabetes, this hazard ratio decreased to 2.59 (95% confidence interval: 1.82-3.68). Based on a meta-analysis, psychological distress is associated with liver disease mortality, although this finding requires additional analysis. Although one is not likely to cause the other, we provide additional evidence for the deleterious effects of psychological problems on physical health. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Carrion, Andres F; Bhamidimarri, Kalyan Ram
Cholestatic liver diseases include a group of diverse disorders with different epidemiology, pathophysiology, clinical course, and prognosis. Despite significant advances in the clinical care of patients with cholestatic liver diseases, liver transplant (LT) remains the only definitive therapy for end-stage liver disease, regardless of the underlying cause. As per the United Network for Organ Sharing database, the rate of cadaveric LT for cholestatic liver disease was 18% in 1991, 10% in 2000, and 7.8% in 2008. This review summarizes the available evidence on various common and rare cholestatic liver diseases, disease-specific issues, and pertinent aspects of LT.
Westbrook, Rachel H; Dusheiko, Geoffrey; Williamson, Catherine
Pregnancy associated liver diseases affect up to 3% of pregnant women and are the most frequent cause of liver dysfunction in pregnancy. When severe, they are associated with significant morbidity and mortality for both mother and infant. A rapid evaluation to distinguish them from non-pregnancy related liver dysfunction is essential, in order to facilitate appropriate management. Liver disease unrelated to pregnancy can present de novo in pregnancy, or pregnancy can occur in women with preexisting liver pathology (Table 1). Research and subsequent advances in medical care have resulted in improved but still not satisfactory maternal and fetal outcomes. In this review we provide an overview of the liver diseases specific to the pregnant state and an update on their pathogenesis, treatment and outcomes. The risks of pregnancy in women with pre-existent liver pathology is detailed and recent advances in our understanding of specific risks and outcomes are discussed.
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Owjimehr, Mehri; Danyali, Habibollah; Helfroush, Mohammad Sadegh
Ultrasound imaging is a popular and noninvasive tool frequently used in the diagnoses of liver diseases. A system to characterize normal, fatty and heterogeneous liver, using textural analysis of liver Ultrasound images, is proposed in this paper. The proposed approach is able to select the optimum regions of interest of the liver images. These optimum regions of interests are analyzed by two level wavelet packet transform to extract some statistical features, namely, median, standard deviation, and interquartile range. Discrimination between heterogeneous, fatty and normal livers is performed in a hierarchical approach in the classification stage. This stage, first, classifies focal and diffused livers and then distinguishes between fatty and normal ones. Support vector machine and k-nearest neighbor classifiers have been used to classify the images into three groups, and their performance is compared. The Support vector machine classifier outperformed the compared classifier, attaining an overall accuracy of 97.9%, with a sensitivity of 100%, 100% and 95.1% for the heterogeneous, fatty and normal class, respectively. The Acc obtained by the proposed computer-aided diagnostic system is quite promising and suggests that the proposed system can be used in a clinical environment to support radiologists and experts in liver diseases interpretation.
Guettrot-Imbert, G; Plessier, A; Hillaire, S; Delluc, C; Leroux, G; Le Guern, V; Costedoat-Chalumeau, N
Liver disease can be observed in pregnant women whether or not related to pregnancy. Liver disorders can be revealed by pruritus, vomiting, jaundice or abnormal liver blood tests during pregnancy. These liver manifestations can lead to the diagnosis of liver disease specifically associated to pregnancy as intrahepatic pregnancy, intrahepatic cholestasis of pregnancy, Hyperemesis gravidarum, acute fatty liver of pregnancy and preeclampsia-induced liver injury. Pregnancy may also be a risk factor for other liver diseases coincident with pregnancy as viral hepatitis, thrombosis, drug toxicity or gallstone. Finally, pre-existing liver disease must be taken into account given the risk of fœto-maternal transmission risk as well as the risk of decompensation of underlying cirrhosis secondary to the hemodynamic changes caused by pregnancy. The aim of this revue is to perform an update on the various situations that can be observed, the principles of management of these liver diseases, in order to reduce the risk of complications and to ensure the best maternal and fetal prognosis.
Peng, H; He, Y; Zheng, G; Zhang, W; Yao, Z; Xie, W
Traditional Chinese herbal medicine (TCM) has been found effective for nonalcoholic fatty liver disease (NAFLD) based on its unique theory system and substantial herb remedies. The aim of this meta-analysis was to evaluate the efficiency and safety of one of the TCM, Danshen in the treatment of NAFLD. Seven English and Chinese databases were searched from inceptions to December 2015. RCTs which compared Danshen with placebo in adult patients with NAFLD were included. Totally, 8 RCTs with a total of 800 patients were identified. The results showed that compared with placebo, Danshen had increased total effectiveness rate, lower level of ALT, AST, TC and TG, LDL and higher level of liver/spleen computed tomography ratio. The present meta-analysis suggests that Danshen may have positive effects on nonalcoholic fatty liver disease. Future multicenter large-sample randomized clinical trials are still needed to confirm the efficacy and safety of our study.
Howell, Jessica; Balderson, Glenda; Hellard, Margaret; Gow, Paul; Strasser, Simone; Stuart, Katherine; Wigg, Alan; Jeffrey, Gary; Gane, Ed; Angus, Peter W
Hepatitis C (HCV), hepatitis B (HBV), alcohol-related liver disease (ALD), and non-alcohol-related fatty liver disease (NAFLD) are leading indications for adult liver transplantation in Australia and New Zealand. However, these diseases are potentially preventable through effective primary and/or secondary prevention strategies. This study evaluates the relative contribution of potentially preventable liver diseases to liver transplant numbers in Australia and New Zealand over time. Prospectively recorded clinical, demographic, and outcome data were collected from the Australian and New Zealand Liver Transplant Registry for all primary adult liver transplants performed in Australia and New Zealand from 1 January 1985 until 31 December 2012. Potentially preventable liver disease was defined as HBV, HCV, NAFLD, ALD, and HCC. The etiology of liver disease leading to liver transplantation and the proportion of preventable liver disease-related liver transplantation was compared between Era 1 (1985-1993), Era 2 (1994-2003), and Era 3 (2004-2012). Overall, 1252 of 3266 adult primary liver transplants (38.3%) were performed for potentially preventable liver disease. There was a significant increase in the proportion of liver transplants because of preventable liver disease from 21.2% (93 of 439) in Era 1, to 49.8% (623 of 1252) in Era 2 and 63.5% (1000 of 1575) in Era 3 (P < 0.0001). Over time, there was a significant increase in HCV (P < 0.0001), ALD (P = 0.002), and NAFLD (P < 0.0001) as a primary indication for adult liver transplant, whereas HBV has significantly decreased from Era 1 to Era 3 as an indication for transplant (P < 0.0001). The number of transplants performed for HCC also increased across Eras (P < 0.0001), with 84% due to underlying potentially preventable liver disease. Since 2004, the majority of primary adult liver transplants within Australia and New Zealand have been because of potentially preventable liver diseases and the
Walsh, K.; Alexander, G.
Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognised forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as γ-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant. Keywords: cirrhosis; liver disease; alcohol PMID:10775280
Guerra Montero, Luis; Ortega Álvarez, Félix; Sumire Umeres, Julia; Cok García, Jaime
Wilson disease (WD) is a disorder of copper metabolism that is inherited as an autosomal recessive, which produces toxic copper accumulation mainly in the liver and brain, in general has two ways presentation, liver at early ages and neurological in later ages. We present the case of a female patient of 21 years diagnosed of WD in liver cirrhosis that started with an edematous ascites without any neurological symptoms despite the age. Their laboratory studies showed decrease in serum ceruloplasmin and high cupruria within 24 hours of the disease , characteristic data of WD. Although WD is not a common disease should be suspected in all chronic liver disease of unknown etiology with negative viral markers and autoimmunity with or without neurological manifestations as soon as posible and starting treatment with copper chelating mainly leads to a substantial improvement the prognosis of these patients.
Thrasher, Tyler; Abdelmalek, Manal F
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is the leading cause of chronic liver disease. Treatments target lifestyle modification and improvement of underlying risk factors. Noninvasive biomarkers for diagnosis and staging of NAFLD and safe, cost-effective treatments for patients with nonalcoholic steatohepatitis (NASH) and/or NASH-related cirrhosis are currently under investigation. ©2016 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.
Wijarnpreecha, Karn; Thongprayoon, Charat; Ungprasert, Patompong
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.
Soriano, Germán; Sánchez, Elisabet; Guarner, Carlos
Alterations in intestinal microbiota and inflammatory response play a key role in disease progression and development of complications in liver diseases, mainly in cirrhosis and non-alcoholic steatohepatitis. Probiotics can be useful to delay disease progression and to prevent development of complications due to their ability to modulate intestinal flora, intestinal permeability and inflammatory response. Several studies have shown the efficacy of probiotics in the treatment of minimal hepatic encephalopathy and the prevention of episodes of overt hepatic encephalopathy. Probiotics have also been observed to prevent postoperative bacterial infections and to improve liver damage in non-alcoholic steatohepatitis. However, more studies are needed in order to confirm the efficacy and safety of probiotics in patients with liver diseases, and to better understanding of the mechanisms implicated in their effects.
Burroughs, A K
Liver disease in pregnancy should be considered in 3 categories: pre-existing disease, disease peculiar to pregnancy and coincident acute liver or gall-stone disease. In addition the time of onset of diagnosis in terms of the trimester of gestation must be verified, as the diseases peculiar to pregancy have a characteristic time of onset. In the last trimester closes obstetric management is required for the constellation of abnormal liver function tests, nausea and/or vomiting and abdominal pain. This may be due to severe pre-eclampsia, HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome or acute fatty liver of pregnancy with or without sub-capsular hepatic haematomas, amongst which there is an overlap. Early delivery is curative. A molecular basis consisting of long chain 3-hydroxyl CoA dehydroxegenase deficiency in heterozygote mothers underlies this clinical syndrome. Ursodeoxycholic acid is now established treatment for intra-hepatic cholestasis of pregnancy and appears to improve foetal outcome. Hepatitis B vaccination and immunoglobulin at birth prevents chronic hepatitis B in children of HBsAg (hepatitis B surface antigen) positive carrier mothers.
Liao, Yin-Yin; Yang, Kuen-Cheh; Lee, Ming-Ju; Huang, Kuo-Chin; Chen, Jin-De; Yeh, Chih-Kuang
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome. This study applied an integrated analysis based on texture, backscattering, and attenuation features in ultrasound imaging with the aim of assessing the severity of NAFLD. Ultrasound radiofrequency data obtained from 394 clinical cases were analyzed to extract three texture features (autocorrelation, sum average, and sum variance), the signal-to-noise ratio (SNR), and the slope of the center-frequency downshift (CFDS slope). The texture, SNR, and CFDS slope were combined to produce a quantitative diagnostic index (QDI) that ranged from 0 to 6. We trained the QDI using training data and then applied it to test data to assess its utility. In training data, the areas (AUCs) under the receiver operating characteristic curves for NAFLD and severe NAFLD were 0.81 and 0.84, respectively. In test data, the AUCs were 0.73 and 0.81 for NAFLD and severe NAFLD, respectively. The QDI was able to distinguish severe NAFLD and a normal liver from mild NAFLD, and it was significantly correlated with metabolic factors. This study explored the potential of using the QDI to supply information on different physical characteristics of liver tissues for advancing the ability to grade NAFLD. PMID:27734972
Minemura, Masami; Shimizu, Yukihiro
Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933
Liberal, Rodrigo; Vergani, Diego; Mieli-Vergani, Giorgina
In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: 'classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the
Jaruvongvanich, Veeravich; Riangwiwat, Tanawan; Sanguankeo, Anawin; Upala, Sikarin
Background/Aims: No medications have been approved for managing nonalcoholic fatty liver disease (NAFLD). Lifestyle intervention is the mainstay for its treatment. Hyperferritinemia, which appears to be associated with the severity of liver injury and insulin resistance, is frequently observed in patients with NAFLD. Patients and Methods: We conducted a systematic review and meta-analysis of the outcomes of four interventional trials regarding the effect of phlebotomy in patients with NAFLD versus the outcomes of NAFLD patients who did not undergo phlebotomy. Primary outcome was the pooled mean difference (MD) of the homeostasis model assessment of insulin resistance (HOMA-IR). The secondary outcomes were the changes in liver enzymes and the lipid profile. Results: Four interventional studies involving 438 participants were included in the meta-analysis. HOMA-IR was lower in patients who underwent phlebotomy, with an MD of 0.84 [95% confidence interval (CI) 0.01 to 1.67, I2 = 72%]. Phlebotomy also significantly reduced the alanine aminotransferase (MD = 10.05, 95% CI 7.19–12.92, I2 = 34%) and triglyceride (MD = 9.89, 95% CI 4.96–14.83, I2 = 22%) levels and increased the high-density cholesterol level (MD = 3.48, 95% CI 2.03–4.92, I2 = 18%). Conclusion: Phlebotomy decreased insulin resistance and liver transaminase levels in patients with NAFLD. In addition, it improved their lipid profile. PMID:27976635
Krawczyk, Marcin; Bonfrate, Leonilde; Portincasa, Piero
Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted. Copyright © 2010 Elsevier Ltd. All rights reserved.
Abdullah, Zeinab; Knolle, Percy A
Kupffer cells, the largest tissue resident macrophage population, are key for the maintenance of liver integrity and its restoration after injury and infections, as well as the local initiation and resolution of innate and adaptive immunity. These important roles of Kupffer cells were recently identified in healthy and diseased liver revealing diverse functions and phenotypes of hepatic macrophages. High-level phenotypic and genomic analysis revealed that Kupffer cells are not a homogenous population and that the hepatic microenvironment actively shapes both phenotype and function of liver macrophages. Compared to macrophages from other organs, hepatic macrophages bear unique properties that are instrumental for their diverse roles in local immunity as well as liver regeneration. The diverse and, in part, contradictory roles of hepatic macrophages in anti-tumor and inflammatory immune responses as well as regulatory and regenerative processes have been obscured by the lack of appropriate technologies to specifically target or ablate Kupffer cells or monocyte-derived hepatic macrophages. Future studies will need to dissect the exact role of the hepatic macrophages with distinct functional properties linked to their differentiation status and thereby provide insight into the functional plasticity of hepatic macrophages.
Liu, Xiao-Lin; Ming, Ya-Nan; Zhang, Jing-Yi; Chen, Xiao-Yu; Zeng, Min-De; Mao, Yi-Min
We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high-fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations. PMID:28082742
... Foods Diet Recommendations Pediatric Liver Disease Q&A Life After Diagnosis Support for Chronic Illness Corporate Partnerships Interview ... from doing its job – or from growing back after injury – may put your life in danger. Inflammation In the early stage of ...
Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro
Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648
Ma, Xiaowen; Wang, Le; Wu, Hao; Feng, Yuemin; Han, Xibiao; Bu, Haoran; Zhu, Qiang
Background and Aims Liver stiffness (LS) and spleen stiffness (SS) are two most widely accessible non-invasive parameters for predicting esophageal varices (EV), but the reported accuracy of the two predictors have been inconsistent across studies. This meta-analysis aims to evaluate the diagnostic performance of LS and SS measurement for detecting EV in patients with chronic liver disease (CLD), and compare their accuracy. Methods Pubmed/Medline, Embase, Cochrane Library and Ovid were searched for all studies assessing SS and LS simultaneously in EV diagnosis. A total of 16 studies including 1892 patients were included in this meta-analysis, and the pooled statistical parameters were calculated using the bivariate mixed effects models. Results In detection of any EV, for LS measurement, the summary sensitivity was 0.83 (95% confidence interval [CI]: 0.78–0.87), and the specificity was 0.66 (95% CI: 0.60–0.72). While for SS measurement, the pooled sensitivity and specificity was 0.88 (95% CI: 0.83–0.92) and 0.78 (95% CI: 0.73–0.83). The summary receiver operating characteristic (SROC) curve values of LS and SS were 0.81 (95% CI: 0.77–0.84) and 0.88 (95% CI: 0.85–0.91) respectively, and the results had statistical significance (P<0.01). The diagnostic odds ratio (DOR) of SS (25.73) was significantly higher than that of LS (9.54), with the relative DOR value was 2.48 (95%CI: 1.10–5.60), P<0.05. Conclusions Under current techniques, SS is significantly superior to LS for identifying the presence of EV in patients with CLD. SS measurement may help to select patients for endoscopic screening. PMID:27829057
Alonso, José Castellote
Hepatic hydrothorax is the paradigmatic pleural effusion in liver cirrhosis. It is defined as a pleural effusion in a patient with portal hypertension and no cardiopulmonary disease. The estimated prevalence of this complication in patients with liver cirrhosis is 5 to 6%. Its pathophysiology involves movement of ascitic fluid from the peritoneal cavity into the pleural space through diaphragmatic defects. Thoracentesis and pleural fluid analysis are necessary for diagnosis. Initial management consists of sodium restriction, diuretics, and therapeutic thoracentesis. A transjugular intrahepatic portosystemic shunt may provide a bridge prior to liver transplantation. Spontaneous bacterial empyema is the infection of a preexisting hydrothorax. The more frequent bacteria involved are ENTEROBACTERIACEAE and gram-positive cocci. Antibiotic therapy is the cornerstone of therapy. This article reviews etiology, clinical manifestations, and therapy of these two complications of liver cirrhosis and portal hypertension.
Donaldson, P T
Recent advances in molecular biology, in particular X-ray crystallography of the purified antigens A2 and DR1 and development of PCR-based HLA genotyping techniques, has revolutionized our understanding of immunogenetics and cellular immunology. The application of molecular immunogenetics has refined our understanding of HLA-encoded susceptibility and resistance to both autoimmune and chronic viral liver disease. Recent studies of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) have identified substitutions of specific amino acid residues in the HLA DR beta-polypeptide (AIH and PSC) and DP beta-polypeptide (PBC) which may determine susceptibility to and resistance from disease. Although these models of HLA-encoded susceptibility in PSC and PBC are currently controversial, the model for AIH, based on lysine residue at DR beta 71 has recently been confirmed in an independent series. Data on chronic viral liver disease are less abundant, but a number of interesting observations are beginning to emerge. In the Gambia, resistance to chronic hepatitis B infection has been associated with the HLA DRB1*1302 allele, and in studies of patients with chronic hepatitis C virus infection DQA1*03 and DQB1*05 have been identified as a possible protective factors. Clarifying these HLA associations is not simply an academic pursuit; in addition to providing useful clues to the pathogenesis of these diseases, HLA associations may be important indicators of prognosis. In AIH, patients with the DRB1*0301-DRB3*0101 haplotype appear to have more severe disease than those with DRB1*0401, while in PSC, DRB3*0101 is associated with early onset of disease and DRB1*0401 may be a marker of more rapid disease progression. To date, our knowledge of immunogenetic susceptibility in liver disease is incomplete and further work is needed.
Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona
Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies.
Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona
Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508
Tam, Joseph; Liu, Jie; Mukhopadhyay, Bani; Cinar, Resat; Godlewski, Grzegorz; Kunos, George
Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists.
Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.
Review article is dealing with the problems of infectious diseases of the liver. Attention is paid to the basic infectious agents, jaundice accompanying infectious diseases and focal infections of the liver. Specific infections of the liver are supplemented by brief pathological and anatomical characteristics.
Liver disease, the most common disease in Taiwan, is not easily discovered in its initial stage; early diagnosis of this leading cause of mortality is therefore highly important. The design of an effective diagnosis model is therefore an important issue in liver disease treatment. This study accordingly employs classification and regression tree (CART) and case-based reasoning (CBR) techniques to structure an intelligent diagnosis model aiming to provide a comprehensive analytic framework to raise the accuracy of liver disease diagnosis. Based on the advice and assistance of doctors and medical specialists of liver conditions, 510 outpatient visitors using ICD-9 (International Classification of Diseases, 9th Revision) codes at a medical center in Taiwan from 2005 to 2006 were selected as the cases in the data set for liver disease diagnosis. Data on 340 patients was utilized for the development of the model and on 170 patients utilized to perform comparative analysis of the models. This paper accordingly suggests an intelligent model for the diagnosis of liver diseases which integrates CART and CBR. The major steps in applying the model include: (1) adopting CART to diagnose whether a patient suffers from liver disease; (2) for patients diagnosed with liver disease in the first step, employing CBR to diagnose the types of liver diseases. In the first phase, CART is used to extract rules from health examination data to show whether the patient suffers from liver disease. The results indicate that the CART rate of accuracy is 92.94%. In the second phase, CBR is developed to diagnose the type of liver disease, and the new case triggers the CBR system to retrieve the most similar case from the case base in order to support the treatment of liver disease. The new case is supported by a similarity ratio, and the CBR diagnostic accuracy rate is 90.00%. Actual implementation shows that the intelligent diagnosis model is capable of integrating CART and CBR techniques to
A 77-year-old African American male presented with intermittent abdominal pain for one week. He denied nausea, vomiting, diarrhea, constipation, fevers, anorexia, or weight loss. He denied a family history of liver disease, recent travel, or history of intravenous drug abuse. His vital signs were normal. Labs revealed total bilirubin of 1.5 mg/dl, hypoalbuminaemia 3.0 gm/dl and prolonged prothrombin time of 14.8 sec. Computed Tomography of the abdomen and pelvis with contrast showed multiple hepatic cysts with the largest cyst occupying the right abdomen, measuring 20.6 cm (Panel A and). This cyst had predominantly fluid attenuation, but also contained several septations. The patient underwent laparoscopic fenestration of the large hepatic cyst with hepatic cyst wall biopsy. Pathology revealed blood without malignant cells. The patient tolerated the procedure well with improvement of his abdominal pain and normalization of his liver function tests and coagulation profile.
Saab, Sammy; Hunt, Douglas R; Stone, Michael A; McClune, Amy; Tong, Myron J
Antiviral therapy for the treatment of hepatitis C virus (HCV) infection is used before and after liver transplantation. The objective of this study was to determine the most cost-effective timing for pegylated interferon/ribavirin therapy in patients with advanced liver disease infected with genotype 1 HCV. A Markov model was constructed to compare treatment strategies: (1) no treatment, (2) antiviral therapy in patients with compensated cirrhosis, (3) antiviral therapy in patients with decompensated cirrhosis, and (4) antiviral therapy in patients with progressive fibrosis due to recurrent HCV post-transplantation. Outcomes of interest included the total cost per patient, number of quality-adjusted life years (QALYs) saved, cost per QALY saved, number of deaths and hepatocellular carcinomas (HCCs), and number of transplants required. Compared to the no-antiviral treatment strategy, treatment during compensated cirrhosis increased QALYs by 0.950 and saved $55,314. Treatment during decompensated cirrhosis increased QALYs by 0.044 and saved $5511. Treatment during posttransplant advanced recurrence increased QALYs by 0.061 and saved $3223. Treatment of patients with compensated cirrhosis resulted in 119 fewer deaths, 54 fewer HCCs, and 66 fewer transplants with respect to the no-treatment strategy. The model was sensitive to the rate of graft failure in patients with and without sustained virological response. The model was otherwise robust to all variables tested in sensitivity analysis. In conclusion, the treatment of patients with compensated cirrhosis was found to be the most cost-effective strategy and resulted in improved survival and decreased cost in comparison with all other strategies. This study provides pharmacoeconomic evidence in support of treating HCV in patients with compensated cirrhosis before progression to more advanced liver disease. (c) 2010 AASLD.
Hessel, Franz P; Mitzner, Steffen R; Rief, Jana; Guellstorff, Britta; Steiner, Susanne; Wasem, Jürgen
Objective of this study was to determine 1-year survival, costs and cost-effectiveness of the artificial liver support system Molecular Adsorbent Recirculating System (MARS) in patients with acute-on-chronic liver failure (ACLF) and an underlying alcoholic liver disease. In a case-control study, 13 patients treated with MARS were compared to 23 controls of similar age, sex and severity of disease. Inpatient hospital costs data were extracted from patients' files and hospital's internal costing. Patients and treating GPs were contacted, thus determining resource use and survival 1-year after treatment. Mean 1-year survival time in MARS group was 261 days and 148 days in controls. Kaplan-Meier analysis shows advantages of MARS patients (Logrank: P=0.057). Direct medical costs per patient for initial hospital stay and 1-year follow-up from a payer's perspective were Euro 18,792 for MARS patients and Euro 9638 for controls. The costs per life-year gained are Euro 29,719 (time horizon 1 year). From a societal perspective, the numbers are higher (costs per life-year gained: Euro 79,075), mainly because of the fact that there is no regular reimbursement of MARS and therefore intervention costs were not calculated from payer's perspective. A trade-off between medical benefit and higher costs has to be made, but 1-year results suggest an acceptable cost-effectiveness of MARS. Prolonging the time horizon and including indirect costs, which will be done in future research, would probably improve cost-effectiveness.
... liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Weight loss can reduce fat in the liver, inflammation, and fibrosis. No medicines have been approved to treat NAFLD and NASH. Eating, ... Clinical Trials The National Institute ...
Shi, Xue; Wahlang, Banrida; Wei, Xiaoli; Yin, Xinmin; Falkner, K. Cameron; Prough, Russell A.; Kim, Seong Ho; Mueller, Eugene G.; McClain, Craig J.; Cave, Matthew; Zhang, Xiang
Polychlorinated Biphenyls (PCBs) are persistent organic pollutants and have been associated with abnormal liver enzymes and suspected non-alcoholic fatty liver disease (NAFLD), obesity, and the metabolic syndrome in epidemiological studies. In epidemiological surveys of human PCB exposure, PCB 153 has the highest serum levels among PCB congeners. To determine the hepatic effects of PCB 153 in mice, C57BL/6J mice were fed either a control diet (CD) or a high fat diet (HFD) for 12 weeks, with or without PCB 153 co-exposure. The metabolite extracts from mouse livers were analyzed using linear trap quadruple - Fourier transform ion cyclotron resonance mass spectrometer (LTQ-FTICR MS) via direct infusion nano-electrospray ionization (DI-nESI) mass spectrometry. The metabolomics analysis indicated no difference in the metabolic profile between mice fed the control diet with PCB 153 exposure (CD+PCB 153) and mice fed the control diet (CD) without PCB 153 exposure. However, compared with CD group, levels of 10 metabolites were increased and 15 metabolites were reduced in mice fed HFD. Moreover, compared to CD+PCB 153 group, the abundances of 6 metabolites were increased and 18 metabolites were decreased in the mice fed high fat diet with PCB 153 exposure (HFD+PCB 153). Compared with HFD group, the abundances of 2 metabolites were increased and of 12 metabolites were reduced in HFD+PCB 153 group. These observations agree with the histological results and indicate that the metabolic effects of PCB 153 were highly dependent on macronutrient interactions with HFD. Antioxidant depletion is likely to be an important consequence of this interaction, as this metabolic disturbance has previously been implicated in obesity and NAFLD. PMID:22686559
Everson, Gregory T; Taylor, Matthew R G
The adult forms of polycystic liver disease are characterized by autosomal dominant inheritance and numerous hepatic cysts, with or without renal involvement. Mutations in two distinct genes predispose to renal and liver cysts (PKD1 and PKD2), and mutations in two different genes yield isolated liver cysts (PRKCSH and SEC63). Mutations at certain loci of PKD1 may predispose to more severe renal cystic disease or cerebral aneurysms. Risk factors for severe hepatic cystic disease include aging, female sex, pregnancy, use of exogenous female steroid hormones, degree of renal cystic disease, or severity of renal dysfunction (in patients with mutations in PKD1 or PKD2). Although liver failure or complications of advanced liver disease is rare, some patients develop massive hepatic cystic disease and become clinically symptomatic. There is no effective medical therapy. Treatment options include cyst aspiration and sclerosis, open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation.
The gut-liver axis involves complex interaction between the intestinal microbiome and the liver parenchyma. Probiotics are live microorganisms that are used in a variety of diseases. With currently only 2 randomized-controlled studies (one with Lactobacillus GG and the other with VSL #3), data are scarce to support the clinical effect of probiotic use in children with nonalcoholic fatty liver disease. There is evidence that probiotics decrease the risk of necrotizing enterocolitis and thereby reduce the prevalence of total parenteral nutrition-induced chronic liver disease. Probiotics are used with a few reported positive outcomes in patients with cystic fibrosis and familial hypercholesterolemia and may be promising in other liver conditions. Probiotics are generally safe and well tolerated in children, premature infants, and in patients after liver transplantation. Large, prospective, randomized clinical trials are needed to evaluate the benefit of probiotics in children with liver diseases.
Shen, Huafeng; Lipka, Seth; Kumar, Ambuj; Mustacchia, Paul
Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MetS) and the most common chronic liver disease worldwide. The association between NAFLD and colorectal adenoma has been investigated in multiples studies but the results have been conflicting. We performed a systematic review and meta-analysis to evaluate this in asymptomatic patients who underwent screening colonoscopy. We searched the literatures of all languages from PubMed, EMBASE and the Cochrane library from January 1, 1980 through July 15, 2014. Combined and subgroup analyses stratified by study designs, study locations, characteristics of adenoma (location, size, number, and advanced adenoma) were performed. Four cross-sectional and one cohort studies with a total of 6,263 subjects were included in the meta-analysis. NAFLD was significantly associated with colorectal adenoma [pooled odds ratio (OR) 1.74, 95% confidence interval (CI): 1.53-1.97]. The association was more significant in Asian population (pooled OR =1.77, 95% CI: 1.52-2.05, n=3 studies), compared to European/North American population (pooled OR =1.42, 95% CI: 0.75-2.67, n=2 studies). NAFLD was significantly associated with the number of colorectal adenoma (pooled OR =1.78, 95% CI: 1.10-2.86, n=2 studies), but not the location, size, or presence of advanced adenoma. Our results suggest NAFLD is significantly associated with the presence of colorectal adenoma in asymptomatic patients undergoing screening colonoscopy. This finding provides additional risk stratifications for applying colorectal cancer (CRC) screening strategies. However, more studies of western population are needed to further investigate the ethnic disparity.
Poggio, Paolo Del; Mazzoleni, Marzio
A disease is suitable for screening if it is common, if the target population can be identified and reached and if both a good screening test and an effective therapy are available. Of the most common liver diseases only viral hepatitis and genetic hemochromatosis partially satisfy these conditions. Hepatitis C is common, the screening test is good and the therapy eliminates the virus in half of the cases, but problems arise in the definition of the target population. In fact generalized population screening is not endorsed by international guidelines, although some recommend screening immigrants from high prevalence countries. Opportunistic screening (case finding) of individuals with classic risk factors, such as transfusion before 1992 and drug addiction, is the most frequently used strategy, but there is disagreement whether prison inmates, individuals with a history of promiscuous or traumatic sex and health care workers should be screened. In a real practice setting the performance of opportunistic screening by general practitioners is low but can be ameliorated by training programs. Screening targeted to segments of the population or mass campaigns are expensive and therefore interventions should be aimed to improve opportunistic screening and the detection skills of general practitioners. Regarding genetic hemochromatosis there is insufficient evidence for population screening, but individual physicians can decide to screen racial groups with a high prevalence of the disease, such as people in early middle age and of northern European origin. In the other cases opportunistic screening of high risk individuals should be performed, with a high level of suspicion in case of unexplained liver disease, diabetes, juvenile artropathy, sexual dysfunction and skin pigmentation. PMID:16981254
Hartleb, Marek; Gutkowski, Krzysztof
Acute kidney injury (AKI), defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL, occurs in about 20% of patients hospitalized for decompensating liver cirrhosis. Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state, reduced effective blood volume and stimulation of vasoconstrictor hormones. The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome and acute tubular necrosis. Differential diagnosis is based on analysis of circumstances of AKI development, natriuresis, urine osmolality, response to withdrawal of diuretics and volume repletion, and rarely on renal biopsy. Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients. AKI is one of the last events in the natural history of chronic liver disease, therefore, such patients should have an expedited referral for liver transplantation. Hepatorenal syndrome (HRS) is initiated by progressive portal hypertension, and may be prematurely triggered by bacterial infections, nonbacterial systemic inflammatory reactions, excessive diuresis, gastrointestinal hemorrhage, diarrhea or nephrotoxic agents. Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy. The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion, which is effective in about 50% of patients. The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt, renal vasoprotection or systems of artificial liver support. PMID:22791939
Khan, Zahida; Orr, Anne; Michalopoulos, George K; Ranganathan, Sarangarajan
Aims In regenerating liver, hepatic progenitor cells (HPCs) are recruited in response to injury; however, few highly specific human HPC markers exist for the hepatocyte lineage. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a Wnt-associated stem cell marker, has been extensively studied in intestinal stem cells, but little is known about its expression in human liver. We hypothesized that LGR5+ HPCs are induced in the regenerative response to pediatric liver injury. Methods and results Immunohistochemistry was used to characterize LGR5 expression in pediatric liver explants (n = 36). We found cytoplasmic LGR5 expression in all cases; although, much less was observed in acute hepatic necrosis compared to chronic liver diseases. In the latter cases, >50% of hepatocytes were LGR5+, signifying a robust regenerative response mainly in the periphery of regenerative nodules. Only weak LGR5 staining was noted in bile ducts, suggesting hepatocyte-specific expression at the interface. Conclusions Although we observed some degree of regenerative response in all cases, LGR5 was highly expressed in chronic liver disease, possibly due to alternate regeneration and reprogramming pathways. LGR5 is predominant in peri-septal hepatocytes rather than epithelial cell adhesion molecule (EpCAM) positive ductular reactions in chronic pediatric liver diseases and may represent a transitional HPC phenotype for the hepatocyte lineage. These studies are the first to support a unique role for LGR5 in human hepatocyte regeneration and as a potential predictive biomarker for recovery of liver function in children. Future work will also investigate the molecular mechanisms behind LGR5 expression.
Duncan, Marten; Hirota, William K; Tsuchida, Amy
There are few prospective studies estimating the prevalence of hepatitis A in chronic liver disease patients. Furthermore, there are minimal cost-comparative data as to whether or not screening for hepatitis A exposure before immunization is an effective fiscal strategy. The objectives of this study were to determine the prevalence of prior hepatitis A infection and to perform a prospective cost analysis for hepatitis A immunization in patients with chronic liver disease. This is a prospective cohort study of 100 patients with chronic liver diseases. Patients were screened for potential risk factors for hepatitis A including history of jaundice, socioeconomic status, birth origin, and ethnic background. Each patient underwent testing for evidence of prior infection using an ELISA. Seronegative patients then went on to receive an immunization series. Cost analysis of vaccination without prescreening (universal strategy) was compared to cost analysis of prescreening and selective immunization of those without prior infection (selective strategy). Fifty-three patients (53%) had serological evidence of prior hepatitis A infection (95% CI = 43-63%). Of the risk factors assessed, foreign birth was associated with prior hepatitis A exposure (p = 0.0002). Cost analysis revealed that prescreening for hepatitis A before vaccination was cost saving given the current prevalence. The seroprevalence of hepatitis A in those with chronic liver diseases was 53%. Cost analysis revealed that screening for hepatitis A before immunization is cost saving, and this strategy should be applied to follow current vaccination guidelines.
Javid, Patrick J; Malone, Frances R; Dick, André A S; Hsu, Evelyn; Sunseri, Maria; Healey, Patrick; Horslen, Simon P
Despite advances in pediatric nutritional support and a renewed focus on management of intestinal failure, there are limited recent data regarding the risk of parenteral nutrition (PN)-associated liver disease in surgical infants. This study investigated the incidence of cholestasis from PN and risk factors for its development in this population. A retrospective review was performed of all neonates in our institution who underwent abdominal surgery and required postoperative PN from 2001 to 2006. Cholestasis was defined as 2 conjugated bilirubin levels greater than 2 mg/dL over 14 days. Nonparametric univariate analyses and multivariate logistic regression were used to model the likelihood of developing cholestasis. Median values with range are presented. One hundred seventy-six infants met inclusion criteria, and patients received PN for 28 days (range, 2-256 days). The incidence of cholestasis was 24%. Cholestatic infants were born at an earlier gestational age (34 vs 36 weeks; P < .01), required a 3-fold longer PN duration (76 vs 21 days; P < .001), had longer inpatient stays (86 vs 29 days; P < .001), and were more likely to be discharged on PN. The median time to cholestasis was 23 days. Cholestasis was an early development; 77% of cholestatic infants developed cholestasis by 5 weeks of PN exposure. On multivariate regression, only prematurity was significantly associated with development of cholestasis (P < .05). In this analysis, the development of PN-associated liver disease occurred early in the course of exposure to PN. These data help to define the time course and prognosis for PN-associated cholestasis in surgical infants. Copyright © 2011 Elsevier Inc. All rights reserved.
Tilg, Herbert; Cani, Patrice D; Mayer, Emeran A
The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Medici, Valentina; Halsted, Charles H.
Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of alcoholic liver disease with particular focus on ethanol-induced alterations in methionine metabolism which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of alcoholic liver disease based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. PMID:23136133
Background Observational studies have shown inconsistent results regarding alcohol consumption and risk of fatty liver. We performed a meta-analysis of published literature to investigate the association between alcohol consumption and fatty liver disease (FLD). Methods We searched Medline, Embase, Web of Science, and several Chinese databases, identifying studies that reported an association between alcohol consumption and the risk of FLD. Results A total of 16 studies with 76,608 participants including 13 cross-sectional studies, two cross-sectional following longitudinal studies, and one cohort study met the inclusion criteria. For light to moderate alcohol consumption (LMAC), there was a 22.6% reduction in risk of FLD (odds ratio [OR] = 0.774, 95% confidence interval CI [0.695–0.862], P <0.001), and subgroup analysis showed that a greater reduction in risk of FLD was found in the female drinkers (30.2%) and the drinkers with BMI ≥25 kg/m2(31.3%) compared with the male drinkers (22.6%) and the drinkers with BMI <25 kg/m2(21.3%), respectively. For heavy alcohol consumption, there was no significant influence on risk of FLD (OR = 0.869, 95% CI [0.553–1.364], P = 0.541) in Japanese women, but there was a 33.7% reduction in risk of FLD (OR = 0.663, 95% CI [0.574–0.765], P < 0.001) in Japanese men and a significant increased risk of FLD (OR = 1.785, 95% CI [1.064–2.996], P = 0.028) in Germans. Conclusion LMAC is associated with a significant protective effect on FLD in the studied population, especially in the women and obese population. However, the effect of heavy alcohol consumption on FLD remains unclear due to limited studies and small sample sizes. PMID:27812428
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Liver cancer is a major global health problem and hepatocellular carcinoma (HCC) accounts for 75% of all liver carcinoma. HCC occurs more often in men than in women and mostly in people 50 to 60 years old. The disease is more common in parts of sub-Saharan Africa and Asia than in North and South America and Europe. Nevertheless its incidence increased over the past 4 decades in some Western countries. Worldwide, liver carcinoma is the 5th most common cancer and 3rd most common cause of cancer mortality (behind only lung and colorectal cancer) with approximately 680,000 annual deaths. Unlike most of the other malignancies, HCC almost entirely develops in the context of inflammation and organ injury and is related to cirrhosis in about 85% of the cases. Among underlying etiologies of liver cirrhosis, most frequent are viral infection and toxic substances, mostly alcohol. The main HCC risk factor in Eastern Asia and Africa is hepatitis B virus infection. Hepatitis C virus infection is the main risk factor in Western countries. Hereditary hemochromatosis is not a very frequent cause of liver cirrhosis, but these patients are at higher risk for HCC compared with other etiologies of cirrhosis. Aflatoxins, cancer-causing substances made by a type of plant mold, can play a role in some countries in Asia and Africa, and can have a synergistic effect with hepatitis B infection. Copyright © 2010 S. Karger AG, Basel.
Li, Yan; Liu, Lei; Wang, Bin; Wang, Jun; Chen, Dongfeng
Non-alcoholic fatty liver disease (NAFLD) related to insulin resistance (IR) is a growing global health concern. Recent studies have indicated that metformin could improve IR and may be beneficial in the treatment of NAFLD. This study aimed to assess the beneficial or harmful effects of metformin in NAFLD. We searched Medline and four other databases during April 2012. Selection criteria were randomized clinical trials comparing metformin with placebo or other interventions for treating NAFLD patients. The primary outcome was histological response. The secondary outcomes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), homeostasis model assessment of IR (HOMA-IR), body mass index (BMI) and adverse events. Dichotomous data were reported as odds ratio (OR), while continuous data were calculated as the mean difference (MD), both with 95% confidence intervals (CI). Random and fixed effects meta-analyses were performed. Nine studies were included, involving 417 participants, and conducted for a time period ranging from 4 to 12 months. In the treated participants, improvements were observed in ALT (MD, -8.12 U/l; P=0.03), AST (MD, -4.52 U/l; P=0.04), HOMA-IR (MD, -0.61; P=0.005) and BMI (MD, -0.82 kg/m(2); P=0.04), but not in histological response: steatosis (P=0.66), inflammation (P=0.91), hepatocellular ballooning (P= 0.25) and fibrosis (P= 0.90). Sub-analysis of non-alcoholic fatty steatohepatitis showed that metformin failed to improve any pooled outcome. Adverse events were poorly reported. Current information indicates that metformin improves liver function, HOMA-IR and BMI to some extent, but not histological response in NAFLD patients. This finding could serve as a stimulus for future studies investigating issues such as dose-responsiveness, safety and patient tolerance to metformin therapy.
Onori, P.; Franchitto, A.; Mancinelli, R.; Carpino, G.; Alvaro, D.; Francis, H.; Alpini, G.; Gaudio, E.
Polycystic liver diseases (PCLDs) are genetic disorders with heterogeneous etiologies and a range of phenotypic presentations. PCLD exhibits both autosomal or recessive dominant pattern of inheritance and is characterized by the progressive development of multiple cysts, isolated or associated with polycystic kidney disease, that appear more extensive in women. Cholangiocytes have primary cilia, functionally important organelles (act as mechanosensors) that are involved in both normal developmental and pathological processes. The absence of polycystin-1, 2, and fibrocystin/polyductin, normally localized to primary cilia, represent a potential mechanism leading to cyst formation, associated with increased cell proliferation and apoptosis, enhanced fluid secretion, abnormal cell–matrix interactions, and alterations in cell polarity. Proliferative and secretive activities of cystic epithelium can be regulated by estrogens either directly or by synergizing growth factors including nerve growth factor, IGF1, FSH and VEGF. The abnormalities of primary cilia and the sensitivity to proliferative effects of estrogens and different growth factors in PCLD cystic epithelium provide the morpho-functional basis for future treatment targets, based on the possible modulation of the formation and progression of hepatic cysts. PMID:20138815
Millonig, Gunda; Praun, Siegfried; Netzer, Michael; Baumgartner, Christian; Dornauer, Albert; Mueller, Sebastian; Villinger, Johannes; Vogel, Wolfgang
Breath composition is altered in liver diseases. We tested if ion-molecule-reaction mass spectrometry (IMR-MS) combined with a new statistical modality improves the diagnostic accuracy of breath analysis in liver diseases. We analysed 114 molecules in the breath of 126 individuals (healthy controls, and patients with non-alcoholic and alcoholic fatty liver disease and liver cirrhosis) by IMR-MS. Characteristic exhalation patterns were identified for each group. Combining two to seven molecules in the new stacked feature ranking model reached a diagnostic accuracy (area under the curve) for individual liver diseases between 0.88 and 0.97. IMR-MS followed by sophisticated statistical analysis is a promising tool for liver diagnostics by breath analysis.
The problem of liver damage in alcoholic patients is widespread. This review discusses hepatic damage on the basis of a histologic classification of increasing severity. In the early stages, or with compensated cirrhosis, clinical and laboratory findings may not accurately reflect hepatic involvement. Furthermore, there exists a group of alcoholic patients in whom liver disease may be caused by factors other than alcohol. Nevertheless, in most patients with liver disease, certain biochemical features help to establish an alcoholic etiology. These features and the use of liver biopsy are discussed, and a practical guideline for diagnosis and follow-up is offered. PMID:21267299
Bozic, Molly A; Subbarao, Girish; Molleston, Jean P
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy-proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease.
Carbone, Marco; Neuberger, James M
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune
Yang, Zhen; Yan, Chonghuai; Liu, Gang; Niu, Yixin; Zhang, Weiwei; Lu, Shuai; Li, Xiaoyong; Zhang, Hongmei; Ning, Guang; Fan, Jiangao; Qin, Li; Su, Qing
Selenium exposure can induce liver insulin resistance and increased liver triglyceride concentrations in animals, which may link to an increased risk of nonalcoholic fatty liver disease (NAFLD). However, epidemiological studies investigating the association between elevated plasma selenium levels and NAFLD were not available. We aimed to investigate the association of selenium levels with the prevalence of NAFLD in Chinese adults. This was a cross-sectional study of 8550 Chinese adults aged 40 yr or older in Shanghai, China. A questionnaire, anthropometric measurements, and laboratory tests were conducted. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Plasma selenium concentration was assessed by inductively coupled plasma mass spectroscopy. The median concentration of plasma selenium was 213.0 μg/L. Elevated plasma selenium levels were associated with higher triglycerides, LDL-cholesterol, fasting plasma glucose, post-loading plasma glucose, A1c, HOMA-IR, as well as ALT, AST and γ-GT (all P < 0.05). The odds ratios were substantially higher for NAFLD (OR = 1.54, 95% CI 1.13–2.18) in the highest selenium quartile compared with those in the lowest quartile, after adjustment for potential cofounder. The results of this study provided epidemiological evidence that increased plasma selenium level is associated with elevated prevalence of NAFLD. PMID:27853246
Background The analysis of multiple causes of death data has been applied in the United States to examine the population burden of chronic liver disease (CLD) and to assess time trends of alcohol-related and hepatitis C virus (HCV)-related CLD mortality. The aim of this study was to assess the mortality for CLD by etiology in the Veneto Region (northeastern Italy). Methods Using the 2008–2010 regional archive of mortality, all causes registered on death certificates were extracted and different descriptive epidemiological measures were computed for HCV-related, alcohol-related, and overall CLD-related mortality. Results The crude mortality rate of all CLD was close to 40 per 100,000 residents. In middle ages (35 to 74 years) CLD was mentioned in about 10% and 6% of all deaths in males and females, respectively. Etiology was unspecified in about half of CLD deaths. In females and males, respectively, HCV was mentioned in 44% and 21% and alcohol in 11% and 26% of overall CLD deaths. A bimodal distribution with age was observed for HCV-related proportional mortality among females, reflecting the available seroprevalence data. Conclusions Multiple causes of death analyses can provide useful insights into the burden of CLD mortality according to etiology among different population subgroups. PMID:24112320
Shen, Na; Wang, Peng; Yan, Weiming
Recent studies have reported inconsistent results on the association between sleep duration and the risk of fatty liver disease (FLD). Thus, we quantitatively evaluated this association by performing a systematic review and meta-analysis, based on a comprehensive electronic search in databases of PubMed, Web of Science, EMBASE, ClinicalTrials.gov, Wanfangdata and Chinese National Knowledge Infrastructure (CNKI) (updated to April 2016). Multivariate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were extracted and pooled by using a random-effects model. Eight eligible studies involving 97,371 participants were included. We found that neither short nor long sleep duration was significantly related with FLD risk. For short sleep duration, the pooled OR was 1.17 (95% CI = 0.98–1.38), and for long sleep duration, the pooled OR was 1.01 (95% CI = 0.72–1.41). Subgroup analyses by sex, outcome, and exposure reference also did not identify any effect of sleep duration on FLD onset. In summary, our findings suggested that short or long sleep duration was not significantly associated with FLD risk. Further cohort studies with refined designs are still warranted to validate our results.
Shen, Na; Wang, Peng; Yan, Weiming
Recent studies have reported inconsistent results on the association between sleep duration and the risk of fatty liver disease (FLD). Thus, we quantitatively evaluated this association by performing a systematic review and meta-analysis, based on a comprehensive electronic search in databases of PubMed, Web of Science, EMBASE, ClinicalTrials.gov, Wanfangdata and Chinese National Knowledge Infrastructure (CNKI) (updated to April 2016). Multivariate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were extracted and pooled by using a random-effects model. Eight eligible studies involving 97,371 participants were included. We found that neither short nor long sleep duration was significantly related with FLD risk. For short sleep duration, the pooled OR was 1.17 (95% CI = 0.98-1.38), and for long sleep duration, the pooled OR was 1.01 (95% CI = 0.72-1.41). Subgroup analyses by sex, outcome, and exposure reference also did not identify any effect of sleep duration on FLD onset. In summary, our findings suggested that short or long sleep duration was not significantly associated with FLD risk. Further cohort studies with refined designs are still warranted to validate our results.
Mehta, Shivang S; Fallon, Michael B
Muscle cramps are common in patients with liver disease and adversely influence quality of life. The exact mechanisms by which they occur remain unclear, although a number of pathophysiological events unique to liver disease may contribute. Clinical studies have identified alterations in 3 areas: nerve function, energy metabolism, and plasma volume/electrolytes. Treatments have focused on these particular areas with varied results. This review will focus on the clinical features of muscle cramps in patients with liver disease and review potential mechanisms and current therapies.
... the intestine. The liver acts as a “processing plant” in the body, taking what we ingest and breaking it down. It then sends some of that material to blood cells throughout the body. The rest is filtered out ...
Haghighatdoost, Fahimeh; Salehi-Abargouei, Amin; Surkan, Pamela J.; Azadbakht, Leila
Background: Although several observational and experimental studies have examined the effects of low carbohydrate diets (LCDs) on nonalcoholic fatty liver disease (NAFLD), there are considerable inconsistencies among studies. We summarized the effect of LCDs on liver function tests, including intrahepatic lipid content (IHLC), alanine transaminase (ALT), aspartate aminotransferases (AST), and gamma-glutamyl transferase (GGT) in patients with NAFLD. Materials and Methods: PubMed, ISI Web of Science, Scopus, and Google Scholar databases were searched for relevant publications until July 2014, resulting in ten relevant papers that were included in meta-analysis. Related articles were found by searching Medical Subject Heading terms of “NAFLD” in combination with “low carbohydrate”. For this meta-analysis, we used mean differences and standard errors of liver function biomarkers. Summary effect and corresponding confidence interval (CI) were estimated using random effect models. Heterogeneity between studies was assessed using Cochran's Q- and I-squared tests. Results: Our search led to ten eligible papers that evaluated serum ALT levels (n = 238), nine reported serum AST levels (n = 216), five reported serum GGT concentrations (n = 91), and four assessed IHLC (n = 50). LCD decreased IHLC by −11.53% (95% CI: −18.10, −4.96; I2 = 83.2%). However, the effect of LCD on liver enzymes was not significant. Mean differences for the effects of LCDs on ALT, AST, and GGT were −4.35 IU/L (95% CI: −12.91, 4.20; I2 = 87.9%), −1.44 IU/L (95% CI: −4.98, 2.10; I2 = 61.4%), and −7.85 IU/L (95% CI: −29.65, 13.96; I2 = 99.4%), respectively. Conclusion: LCD consumption in subjects with NAFLD led to a significant reduction in IHLC, but did not significantly affect the concentration of liver enzymes. PMID:27904598
Liao, Fadian; Ruan, Qiuyong; Lin, Juqiang; Lin, Jinyong; Zeng, Yongyi; Li, Ling; Huang, Zufang; Liu, Nenrong; Chen, Rong
Despite the introduction of high-technology methods of detection and diagnosis, screening of primary liver cancer (PLC) remains imperfect. To diagnosis PLC earlier, Surface-enhanced Raman spectroscopy (SERS) coupled with cellulose-acetate membrane electrophoresis were introduced to separate human serum albumin and SERS spectra. Three groups (15 normal persons' samples, 17 hepatitis/cirrhosis samples, 15 cases of PLC) of serum albumin were tested. Silver colloid was used to obtain SERS spectra of human serum albumin. Principal component analysis (PCA) and linear discriminant analysis (LDA) were also employed for statistical analysis. The mean Raman spectra of three groups and the difference spectra of any two suggested that the albumin has changed in liver patients. Compared to normal groups, some Raman peaks have shifted or even disappeared in hepatitis/cirrhosis and PLCs groups. The sensitivity and specificity between PLCs and normal groups is 80% and 93.3%. Among hepatitis/cirrhosis and normal groups, the sensitivity is 88.2% and specificity is also 93.3%. Besides, the sensitivity and specificity between PLCs and hepatitis/cirrhosis groups is 86.7% and 76.5%. All the above data and results indicated that early screening of PLC is potential by SERS in different stages of liver disease before cancer occurs.
Madan, Shivank A; John, Febin; Pyrsopoulos, Nikolaos; Pitchumoni, Capecomorin S
Observational studies suggest that nonalcoholic fatty liver disease (NAFLD) is associated with increased carotid intimal medial thickness (C-IMT) and carotid plaques in both children and adults. We carried out a meta-analysis to evaluate the relationship between NAFLD and carotid atherosclerosis measured as C-IMT and carotid plaque prevalence. Medline (Ovid), PubMed, Web of Science, and CINAHL databases were searched from 1946 to September 2014, complemented with a manual review of references of the published articles for studies that compared C-IMT or carotid plaque prevalence in adults and children. Results were pooled using both fixed and random effects models. Of the studies identified, 20 were suitable for testing the effect of NAFLD on C-IMT in adults, 13 for testing the effect of NAFLD on carotid plaque prevalence in adults, and five for testing the effect of NAFLD on C-IMT in the pediatric population. The pooled data from 20 studies (19,274 adult participants: NAFLD=8652, controls=10,622) showed significantly increased C-IMT in patients with NAFLD, compared with controls without NAFLD, according to both fixed [standardized mean difference (SMD)=0.251, 95% confidence interval (CI): 0.220-0.282, P<0.001] and random effects models (SMD=0.944, 95% CI: 0.728-1.160, P<0.001). NAFLD was also found to be associated with a higher carotid artery plaque prevalence when compared with controls, according to both fixed (OR=1.273, 95% CI=1.162-1.394, P<0.001) and random effects models (OR=1.769, 95% CI: 1.213-2.581, P=0.003), on pooling of 13 studies (14,445 adult participants: NAFLD=5399 and controls=9046). Analysis of pooled data from five studies in the pediatric population (1121 pediatric participants: NAFLD=312 and controls=809) also found NAFLD to be associated with significantly increased C-IMT according to fixed (SMD=0.995, 95% CI: 0.840-1.150, P<0.001) and random effects models (1.083, 95% CI: 0.457-1.709, P=0.001). NAFLD is associated with increased C-IMT in
Wijarnpreecha, K; Thongprayoon, C; Panjawatanan, P; Ungprasert, P
This sudy aims to investigate the association between insomnia or excessive daytime sleepiness (EDS) and risk of nonalcoholic fatty liver disease (NAFLD). We searched published studies indexed in MEDLINE and EMBASE database from inception to December 2015. Studies that reported odds ratios (ORs), risk ratios, hazard ratios or standardized incidence ratio with 95% confidence intervals (CI) comparing the risk of NAFLD among participants who had insomnia or EDS versus those without insomnia or EDS were included. Pooled ORs and 95% CI were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Cochran's Q test and I2 statistic were used to determine the between-study heterogeneity. Our search strategy yielded 2117 potentially relevant articles (781 articles from MEDLINE and 1336 articles from EMBASE). After comprehensive review, seven studies (three cross-sectional studies and four case-control studies) were found to be eligible and were included in the meta-analysis. The risk of NAFLD in participants who had insomnia was significantly higher with the pooled OR of 1.13 (95% CI, 1.00-1.27). The statistical heterogeneity was moderate with an I2 of 62%. Elevated risk of NAFLD was also observed among participants with EDS even though the 95% CI was wider and did not reach statistical significance (pooled OR 2.21; 95% CI, 0.84-5.82). The statistical heterogeneity was moderate with an I2 of 62%. Our study demonstrated an increased risk of NAFLD among participants who had insomnia or EDS. Whether this association is causal needs further investigations.
Phisalprapa, Pochamana; Supakankunti, Siripen; Charatcharoenwitthaya, Phunchai; Apisarnthanarak, Piyaporn; Charoensak, Aphinya; Washirasaksiri, Chaiwat; Srivanichakorn, Weerachai; Chaiyakunapruk, Nathorn
Abstract Background: Nonalcoholic fatty liver disease (NAFLD) can be diagnosed early by noninvasive ultrasonography; however, the cost-effectiveness of ultrasonography screening with intensive weight reduction program in metabolic syndrome patients is not clear. This study aims to estimate economic and clinical outcomes of ultrasonography in Thailand. Methods: Cost-effectiveness analysis used decision tree and Markov models to estimate lifetime costs and health benefits from societal perspective, based on a cohort of 509 metabolic syndrome patients in Thailand. Data were obtained from published literatures and Thai database. Results were reported as incremental cost-effectiveness ratios (ICERs) in 2014 US dollars (USD) per quality-adjusted life year (QALY) gained with discount rate of 3%. Sensitivity analyses were performed to assess the influence of parameter uncertainty on the results. Results: The ICER of ultrasonography screening of 50-year-old metabolic syndrome patients with intensive weight reduction program was 958 USD/QALY gained when compared with no screening. The probability of being cost-effective was 67% using willingness-to-pay threshold in Thailand (4848 USD/QALY gained). Screening before 45 years was cost saving while screening at 45 to 64 years was cost-effective. Conclusions: For patients with metabolic syndromes, ultrasonography screening for NAFLD with intensive weight reduction program is a cost-effective program in Thailand. Study can be used as part of evidence-informed decision making. Translational Impacts: Findings could contribute to changes of NAFLD diagnosis practice in settings where economic evidence is used as part of decision-making process. Furthermore, study design, model structure, and input parameters could also be used for future research addressing similar questions. PMID:28445256
Phisalprapa, Pochamana; Supakankunti, Siripen; Charatcharoenwitthaya, Phunchai; Apisarnthanarak, Piyaporn; Charoensak, Aphinya; Washirasaksiri, Chaiwat; Srivanichakorn, Weerachai; Chaiyakunapruk, Nathorn
Nonalcoholic fatty liver disease (NAFLD) can be diagnosed early by noninvasive ultrasonography; however, the cost-effectiveness of ultrasonography screening with intensive weight reduction program in metabolic syndrome patients is not clear. This study aims to estimate economic and clinical outcomes of ultrasonography in Thailand. Cost-effectiveness analysis used decision tree and Markov models to estimate lifetime costs and health benefits from societal perspective, based on a cohort of 509 metabolic syndrome patients in Thailand. Data were obtained from published literatures and Thai database. Results were reported as incremental cost-effectiveness ratios (ICERs) in 2014 US dollars (USD) per quality-adjusted life year (QALY) gained with discount rate of 3%. Sensitivity analyses were performed to assess the influence of parameter uncertainty on the results. The ICER of ultrasonography screening of 50-year-old metabolic syndrome patients with intensive weight reduction program was 958 USD/QALY gained when compared with no screening. The probability of being cost-effective was 67% using willingness-to-pay threshold in Thailand (4848 USD/QALY gained). Screening before 45 years was cost saving while screening at 45 to 64 years was cost-effective. For patients with metabolic syndromes, ultrasonography screening for NAFLD with intensive weight reduction program is a cost-effective program in Thailand. Study can be used as part of evidence-informed decision making. Findings could contribute to changes of NAFLD diagnosis practice in settings where economic evidence is used as part of decision-making process. Furthermore, study design, model structure, and input parameters could also be used for future research addressing similar questions.
The liver plays a key role in hemostasis as the site of synthesis of many of the proteins involved in the coagulation, antithrombotic and fibrinolytic systems that interact to both establish hemostasis, and preventing thrombosis. The common laboratory tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT), evolved from studies of plasma clotting in test tubes. Such studies laid the basis for the coagulation cascade model of hemostasis. However, thought has evolved to place a greater emphasis on the active roles of cells in localizing and regulating hemostasis. The PT and aPTT do not reflect the roles of cellular elements in hemostasis, nor do they reflect the crucial roles of antithrombotic and fibrinolytic systems. Thus, though the PT may indeed reflect the synthetic capacity of the liver, it does not accurately reflect the risk of bleeding or thrombosis in patients with liver failure.
Wei, Xiaoyun; Wang, Chunyan; Hao, Shijun; Song, Haiyan
Aim. To assess the efficacy of berberine in the treatment of nonalcoholic fatty liver disease through meta-analysis. Method. We searched Embase, Pubmed, Cochrane Library, and so forth, until March 2016 for randomized controlled trials using berberine to treat NAFLD. Result. Six randomized controlled trials involving 501 patients were included in this study. The results showed that the efficacy of reducing TC, LDL, ALT, 2hPG, and HbA1c in NAFLD patients of the berberine group were significantly higher than that of control group. The subgroup analyses on TG, AST, and FBG indicated that treatment combined with berberine decreased TG level in NAFLD patients significantly. Compared with other drugs, berberine alone decreased TG level in NAFLD patients significantly. We also conducted a descriptive analysis on insulin resistance and radiography results that berberine can improve NAFLD patients' insulin resistance and fatty liver. Conclusion. According to analysis result, berberine has positive efficacy on blood lipids, blood glucose, liver function, insulin resistance, and fatty liver condition of NAFLD patients. However, due to the limitation of number and quality of trials included, more clinical randomized controlled trials with high quality are needed for further verification of the efficacy of berberine on NAFLD patients. PMID:27446224
Wei, Xiaoyun; Wang, Chunyan; Hao, Shijun; Song, Haiyan; Yang, Lili
Aim. To assess the efficacy of berberine in the treatment of nonalcoholic fatty liver disease through meta-analysis. Method. We searched Embase, Pubmed, Cochrane Library, and so forth, until March 2016 for randomized controlled trials using berberine to treat NAFLD. Result. Six randomized controlled trials involving 501 patients were included in this study. The results showed that the efficacy of reducing TC, LDL, ALT, 2hPG, and HbA1c in NAFLD patients of the berberine group were significantly higher than that of control group. The subgroup analyses on TG, AST, and FBG indicated that treatment combined with berberine decreased TG level in NAFLD patients significantly. Compared with other drugs, berberine alone decreased TG level in NAFLD patients significantly. We also conducted a descriptive analysis on insulin resistance and radiography results that berberine can improve NAFLD patients' insulin resistance and fatty liver. Conclusion. According to analysis result, berberine has positive efficacy on blood lipids, blood glucose, liver function, insulin resistance, and fatty liver condition of NAFLD patients. However, due to the limitation of number and quality of trials included, more clinical randomized controlled trials with high quality are needed for further verification of the efficacy of berberine on NAFLD patients.
Schwimmer, Jeffrey B.; Celedon, Manuel A.; Lavine, Joel E.; Salem, Rany; Campbell, Nzali; Schork, Nicholas J.; Shiehmorteza, Masoud; Yokoo, Takeshi; Chavez, Alyssa; Middleton, Michael S.; Sirlin, Claude B.
Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The etiology is believed to be multi-factorial with a substantial genetic component; however, the heritability of NAFLD is undetermined. Therefore, a familial aggregation study was performed to test the hypothesis that NAFLD is highly heritable. Methods Overweight children with biopsy-proven NAFLD and overweight children without NAFLD served as probands. Family members were studied including magnetic resonance imaging to quantify liver fat fraction. Fatty liver was defined as a liver fat fraction ≥ 5%. Etiologies for fatty liver other than NAFLD were excluded. Narrow-sense heritability estimates for fatty liver (dichotomous) and fat fraction (continuous) were calculated using variance components analysis adjusted for covariate effects. Results Fatty liver was present in 17% of siblings and 37% of parents of overweight children without NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Liver fat fraction was correlated with body mass index (BMI), although the correlation was significantly stronger for families of children with NAFLD than those without NAFLD. Adjusted for age, sex, race, and BMI, heritability of fatty liver was 1.000 and of liver fat fraction 0.386. Conclusion Family members of children with NAFLD should be considered at high risk for NAFLD. These data suggest that familial factors are a major determinant of whether an individual has NAFLD. Studies examining the complex relations between genes and environment in the development and progression of NAFLD are warranted. PMID:19208353
The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations
Musso, Giovanni; Gambino, Roberto; Tabibian, James H.; Ekstedt, Mattias; Kechagias, Stergios; Hamaguchi, Masahide; Hultcrantz, Rolf; Hagström, Hannes; Yoon, Seung Kew; Charatcharoenwitthaya, Phunchai; George, Jacob; Barrera, Francisco; Hafliðadóttir, Svanhildur; Björnsson, Einar Stefan; Armstrong, Matthew J.; Hopkins, Laurence J.; Gao, Xin; Francque, Sven; Verrijken, An; Yilmaz, Yusuf; Lindor, Keith D.; Charlton, Michael; Haring, Robin; Lerch, Markus M.; Rettig, Rainer; Völzke, Henry; Ryu, Seungho; Li, Guolin; Wong, Linda L.; Machado, Mariana; Cortez-Pinto, Helena; Yasui, Kohichiroh; Cassader, Maurizio
Background Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. Methods and Findings English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8
Medici, Valentina; Halsted, Charles H
Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of ALD with particular focus on ethanol-induced alterations in methionine metabolism, which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of ALD based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Ambrosino, Pasquale; Lupoli, Roberta; Spadarella, Gaia; Tarantino, Paolo; Di Minno, Alessandro; Tarantino, Luciano; Di Minno, Matteo Nicola Dario
Several studies reported an association between autoimmune liver diseases (AiLD) and antiphospholipid antibodies (aPL) positivity. We performed a meta-analysis of studies evaluating the association of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) with aPL positivity and with aPL-related thrombotic events. Studies evaluating the association of AiLD with aPL (anticardiolipin [aCL], anti-β2 glycoprotein-I [anti-β2GPI], lupus anticoagulant [LA] antibodies) and with aPL-related thrombotic complications were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. A total of 10 studies (750 patients with AiLD and 1,244 healthy controls) were included in the analysis on the prevalence of aPL and showed that AiLD are significantly associated with the presence of aCL and anti-β2GPI. The association with aCL positivity was consistently confirmed in PBC (OR: 13.93, 95%CI: 4.69-41.38), AIH (OR: 23.50, 95%CI: 4.28-129.13), and PSC (OR: 18.21, 95%CI: 7.05-47.08). Similarly, anti-β2GPI were found more frequently in PBC (OR: 25.10, 95%CI: 4.77-132.11), AIH (OR: 48.57, 95%CI: 11.07-213.09), and PSC (OR: 36.30, 95%CI: 6.55-201.31). These findings are confirmed when separately analyzing IgM, IgG, and IgA directed against phospholipids. Two of the 10 included articles and 1 further study (67 cases and 75 controls) showed a trend - not achieving statistical significance - towards a higher prevalence of thrombotic complications in AIH patients with aPL as compared to those with only AIH (OR: 1.67, 95%CI: 0.46-6.05). PBC, AIH, and PSC are significantly associated with aPL positivity. The association with aPL-related thrombotic complications should be further studied.
Arriazu, Elena; Ruiz de Galarreta, Marina; Cubero, Francisco Javier; Varela-Rey, Marta; Pérez de Obanos, María Pilar; Leung, Tung Ming; Lopategi, Aritz; Benedicto, Aitor; Abraham-Enachescu, Ioana
Abstract Significance: The extracellular matrix (ECM) is a dynamic microenvironment that undergoes continuous remodeling, particularly during injury and wound healing. Chronic liver injury of many different etiologies such as viral hepatitis, alcohol abuse, drug-induced liver injury, obesity and insulin resistance, metabolic disorders, and autoimmune disease is characterized by excessive deposition of ECM proteins in response to persistent liver damage. Critical Issues: This review describes the main collagenous and noncollagenous components from the ECM that play a significant role in pathological matrix deposition during liver disease. We define how increased myofibroblasts (MF) from different origins are at the forefront of liver fibrosis and how liver cell-specific regulation of the complex scarring process occurs. Recent Advances: Particular attention is paid to the role of cytokines, growth factors, reactive oxygen species, and newly identified matricellular proteins in the regulation of fibrillar type I collagen, a field to which our laboratory has significantly contributed over the years. We compile data from recent literature on the potential mechanisms driving fibrosis resolution such as MF’ apoptosis, senescence, and reversal to quiescence. Future Directions: We conclude with a brief description of how epigenetics, an evolving field, can regulate the behavior of MF and of how new “omics” tools may advance our understanding of the mechanisms by which the fibrogenic response to liver injury occurs. Antioxid. Redox Signal. 21, 1078–1097. PMID:24219114
Assessment of liver function in chronic liver diseases and regional function of irradiated liver by means of 99mTc-galactosyl-human serum albumin liver scintigraphy and quantitative spectral analysis.
Fukui, A; Murase, K; Tsuda, T; Fujii, T; Ikezoe, J
Scintigraphy with 99mTc-diethylenetriamine pentaacetic acid galactosyl human serum albumin (99mTc-GSA) was performed on 102 patients, then the hepatic extraction fraction (HEF), the rate constant for liver uptake of the tracer from the blood (K1) and the hepatic blood flow index (HBFI) were determined by spectral analysis. The HEF, K1 and HBFI values correlated moderately or closely with various indices of hepatic function, and the HEF and K1 values decreased according to the stage of liver dysfunction. The HEF and K1 values linearly and nonlinearly correlated with HH15 and LHL15, respectively. The HEF, K1 and HBFI values for the irradiated portion of 20 patients before and alter irradiation were compared. The HEF value in patients with a cirrhotic liver significantly (p < 0.002) decreased compared with that in patients with a normal liver at a dose of less than 40 Gy, whereas the HBFI value in patients with a normal liver significantly (p < 0.05) decreased compared with that in patients with a cirrhotic liver at a dose of 40 Gy or greater. This method appears to be a simple, non-invasive and useful tool with which to quantitatively evaluate liver function and it also helps clarify changes in regional function of the irradiated liver.
Bang, Chang Seok; Shin, In Soo; Lee, Sung Wha; Kim, Jin Bong; Baik, Gwang Ho; Suk, Ki Tae; Yoon, Jai Hoon; Kim, Yeon Soo; Kim, Dong Joon
To evaluate the association between alcoholic liver disease (ALD) and bone fractures or osteoporosis. Non-randomized studies were identified from databases (PubMed, EMBASE, and the Cochrane Library). The search was conducted using Boolean operators and keywords, which included "alcoholic liver diseases", "osteoporosis", or "bone fractures". The prevalence of any fractures or osteoporosis, and bone mineral density (BMD) were extracted and analyzed using risk ratios and standardized mean difference (SMD). A random effects model was applied. In total, 15 studies were identified and analyzed. Overall, ALD demonstrated a RR of 1.944 (95%CI: 1.354-2.791) for the development of bone fractures. However, ALD showed a RR of 0.849 (95%CI: 0.523-1.380) for the development of osteoporosis. BMD was not significantly different between the ALD and control groups, although there was a trend toward lower BMD in patients with ALD (SMD in femur-BMD: -0.172, 95%CI: -0.453-0.110; SMD in spine-BMD: -0.169, 95%CI: -0.476-0.138). Sensitivity analyses showed consistent results. Current publications indicate significant associations between bone fractures and ALD, independent of BMD or the presence of osteoporosis.
Elfeki, Mohamed A; Pungpapong, Surakit; Genco, Petrina V; Nakhleh, Raouf E; Nguyen, Justin H; Harnois, Denise M
Graft-versus-host disease (GVHD) is a rare, fatal complication following orthotopic liver transplantation (OLT). To date, several risk factors have been proposed, but reports on these factors have been inconclusive. This is a retrospective, case-control study of prospectively collected data from 2775 OLTs performed at our institution. Eight cases of GVHD after OLT were diagnosed on the basis of the patient's clinical characteristics, and the findings were confirmed with skin and colonic biopsies. Each case was matched to three controls based on the diagnosis of liver disease, recipient's age, and blood group. Univariate and multivariate analyses were performed to identify risk factors associated with the development of GVHD after OLT. The univariate and multivariate analyses identified two main risk factors associated with development of GVHD in OLT recipients, a difference between recipient and donor age of >20 yr, and any human leukocyte antigen class I matches. Taking these two risk factors into consideration while matching prospective donors and recipients may reduce further incidence of GVHD in OLT patients. However, further studies are recommended to validate these findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Muriel, Pablo; Arauz, Jonathan
Coffee consumption is worldwide spread with few side effects. Interestingly, coffee intake has been inversely related to the serum enzyme activities gamma-glutamyltransferase, and alanine aminotransferase in studies performed in various countries. In addition, epidemiological results, taken together, indicate that coffee consumption is inversely related with hepatic cirrhosis; however, they cannot demonstrate a causative role of coffee with prevention of liver injury. Animal models and cell culture studies indicate that kahweol, diterpenes and cafestol (some coffee compounds) can function as blocking agents by modulating multiple enzymes involved in carcinogenic detoxification; these molecules also alter the xenotoxic metabolism by inducing the enzymes glutathione-S-transferase and inhibiting N-acetyltransferase. Drinking coffee has been associated with reduced risk of hepatic injury and cirrhosis, a major pathogenic step in the process of hepatocarcinogenesis, thus, the benefit that produces coffee consumption on hepatic cancer may be attributed to its inverse relation with cirrhosis, although allowance for clinical history of cirrhosis did not completely account for the inverse association. Therefore, it seems to be a continuum of the beneficial effect of coffee consumption on liver enzymes, cirrhosis and hepatocellular carcinoma. At present, it seems reasonable to propose experiments with animal models of liver damage and to test the effect of coffee, and/or isolated compounds of this beverage, not only to evaluate the possible causative role of coffee but also its action mechanism. Clinical prospective double blind studies are also needed. Copyright 2009 Elsevier B.V. All rights reserved.
Testino, Gianni; Patussi, Valentino; Scafato, Emanuele
Alcoholic liver disease (ALD) is the second most common diagnosis among patients undergoing liver transplantation (LT) in Europe and in the United States. The outcome of patients transplanted for ALD is at least as good as that for most other diagnoses and better than that for hepatitis C virus. In case of severe acute alcoholic hepatitis (AAH) non-responders to medical therapy, the reason for denying LT is that it requires abstinence from alcohol for six months before consideration for a transplant. A strict application of a period of abstinence as a policy for transplant eligibility is unfair to non-responder patients, as most of them will have died prior to the end of the six-month sober period. In our opinion, in severe AAH subjects with a good social support, with the frequency of self-help groups (alcoholics anonymous or association of clubs of alcoholics in treatment), with the frequency of Alcohol Unit and without severe psychotic or personality disorders, the lack of pre-LT abstinence alone should not be a barrier against being listed.
Park, Hyun Jeong; Jang, Kyung Mi; Kang, Tae Wook; Song, Kyoung Doo; Kim, Seong Hyun; Kim, Young Kon; Cha, Dong Ik; Kim, Joungyoun; Goo, Juna
To identify predictors for the discrimination of intrahepatic cholangiocarcinoma (IMCC) and combined hepatocellular-cholangiocarcinoma (CHC) from hepatocellular carcinoma (HCC) for primary liver cancers on gadoxetic acid-enhanced MRI among high-risk chronic liver disease (CLD) patients using classification tree analysis (CTA). A total of 152 patients with histopathologically proven IMCC (n = 40), CHC (n = 24) and HCC (n = 91) were enrolled. Tumour marker and MRI variables including morphologic features, signal intensity, and enhancement pattern were used to identify tumours suspicious for IMCC and CHC using CTA. On CTA, arterial rim enhancement (ARE) was the initial splitting predictor for assessing the probability of tumours being IMCC or CHC. Of 43 tumours that were classified in a subgroup on CTA based on the presence of ARE, non-intralesional fat, and non-globular shape, 41 (95.3 %) were IMCCs (n = 29) or CHCs (n = 12). All 24 tumours showing fat on MRI were HCCs. The CTA model demonstrated sensitivity of 84.4 %, specificity of 97.8 %, and accuracy of 92.3 % for discriminating IMCCs and CHCs from HCCs. We established a simple CTA model for classifying a high-risk group of CLD patients with IMCC and CHC. This model may be useful for guiding diagnosis for primary liver cancers in patients with CLD. • Arterial rim enhancement was the initial splitting predictor on CTA. • CTA model achieved high sensitivity, specificity, and accuracy for discrimination of tumours. • This model may be useful for guiding diagnosis of primary liver cancers.
Mikolasevic, Ivana; Milic, Sandra; Turk Wensveen, Tamara; Grgic, Ivana; Jakopcic, Ivan; Stimac, Davor; Wensveen, Felix; Orlic, Lidija
Non-alcoholic fatty liver disease (NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome (MetS). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of MetS. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease (CVD), diabetes mellitus type 2 (T2DM) and chronic kidney disease (CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with MetS, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both (sub-) specialists and primary care physicians. PMID:27920470
Beckmann, Mingo; Paslakis, Georgios; Böttcher, Michael; Helander, Anders; Erim, Yesim
A large proportion of liver transplants (LTXs) are performed due to alcoholic liver disease (ALD) in the final stage of organ insufficiency. In order to list patients for LTX, transplant centers commonly require 6 months abstinence from alcohol. However, significant differences have been reported between alcohol intake as indicated by self-report and biochemical markers of alcohol. In the present study, the usefulness of ethyl glucuronide analysis in hair (hETG) was examined during the evaluation procedure before listing patients with ALD for an LTX. Cross-sectional survey. Psychosomatic evaluation. Seventy patients with ALD prior to listing for an LTX. According to clinical assessment before listing patients with ALD (n = 233) for an LTX, hETG analysis was only performed in the patients who were assumed to deny or underreport their alcohol consumption (n = 70). The analysis of hETG by liquid chromatography-mass spectrometry, clinical interview. By hETG analyses, 27 (38.6%) of the 70 patients tested positive for ongoing alcohol consumption. Selective use of hETG based on the clinical interview rather than widespread screening is a possible way to detect excessive alcohol consumption in patients with ALD in the transplant setting. The primary evaluation of a patient's situation in its entirety should remain the superordinate standard procedure. An interdisciplinary approach to transplant candidates with an ALD is asked for. © 2016, NATCO.
Liu, Xia; Zhong, Fang; Tang, Xu-long; Lian, Fu-lin; Zhou, Qiao; Guo, Shan-mai; Liu, Jia-fu; Sun, Peng; Hao, Xu; Lu, Ying; Wang, Wei-ming; Chen, Nan; Zhang, Nai-xia
Aim: To test the hypothesis that the traditional Chinese medicine Cordyceps sinensis could improve the metabolic function of extrarenal organs to achieve its anti-chronic kidney disease (CKD) effects. Methods: Male SD rats were divided into CKD rats (with 5/6-nephrectomy), CKD rats treated with Cordyceps sinensis (4 mg•kg-1•d-1, po), and sham-operated rats. After an 8-week treatment, metabolites were extracted from the hearts and livers of the rats, and then subjected to 1H-NMR-based metabolomic analysis. Results: Oxidative stress, energy metabolism, amino acid and protein metabolism and choline metabolism were considered as links between CKD and extrarenal organ dysfunction. Within the experimental period of 8 weeks, the metabolic disorders in the liver were more pronounced than in the heart, suggesting that CKD-related extrarenal organ dysfunctions occurred sequentially rather than simultaneously. Oral administration of Cordyceps sinensis exerted statistically significant rescue effects on the liver and heart by reversely regulating levels of those metabolites that are typically perturbed in CKD. Conclusion: Oral administration of Cordyceps sinensis significantly attenuates the liver and heart injuries in CKD rats. The 1H NMR-based metabolomic approach has provided a systematic view for understanding of CKD and the drug treatment, which can also be used to elucidate the mechanisms of action of other traditional Chinese medicines. PMID:24632844
Liu, Xia; Zhong, Fang; Tang, Xu-long; Lian, Fu-lin; Zhou, Qiao; Guo, Shan-mai; Liu, Jia-fu; Sun, Peng; Hao, Xu; Lu, Ying; Wang, Wei-ming; Chen, Nan; Zhang, Nai-xia
To test the hypothesis that the traditional Chinese medicine Cordyceps sinensis could improve the metabolic function of extrarenal organs to achieve its anti-chronic kidney disease (CKD) effects. Male SD rats were divided into CKD rats (with 5/6-nephrectomy), CKD rats treated with Cordyceps sinensis (4 mg•kg-1•d-1, po), and sham-operated rats. After an 8-week treatment, metabolites were extracted from the hearts and livers of the rats, and then subjected to (1)H-NMR-based metabolomic analysis. Oxidative stress, energy metabolism, amino acid and protein metabolism and choline metabolism were considered as links between CKD and extrarenal organ dysfunction. Within the experimental period of 8 weeks, the metabolic disorders in the liver were more pronounced than in the heart, suggesting that CKD-related extrarenal organ dysfunctions occurred sequentially rather than simultaneously. Oral administration of Cordyceps sinensis exerted statistically significant rescue effects on the liver and heart by reversely regulating levels of those metabolites that are typically perturbed in CKD. Oral administration of Cordyceps sinensis significantly attenuates the liver and heart injuries in CKD rats. The (1)H NMR-based metabolomic approach has provided a systematic view for understanding of CKD and the drug treatment, which can also be used to elucidate the mechanisms of action of other traditional Chinese medicines.
Bang, Chang Seok; Shin, In Soo; Lee, Sung Wha; Kim, Jin Bong; Baik, Gwang Ho; Suk, Ki Tae; Yoon, Jai Hoon; Kim, Yeon Soo; Kim, Dong Joon
AIM: To evaluate the association between alcoholic liver disease (ALD) and bone fractures or osteoporosis. METHODS: Non-randomized studies were identified from databases (PubMed, EMBASE, and the Cochrane Library). The search was conducted using Boolean operators and keywords, which included “alcoholic liver diseases”, “osteoporosis”, or “bone fractures”. The prevalence of any fractures or osteoporosis, and bone mineral density (BMD) were extracted and analyzed using risk ratios and standardized mean difference (SMD). A random effects model was applied. RESULTS: In total, 15 studies were identified and analyzed. Overall, ALD demonstrated a RR of 1.944 (95%CI: 1.354-2.791) for the development of bone fractures. However, ALD showed a RR of 0.849 (95%CI: 0.523-1.380) for the development of osteoporosis. BMD was not significantly different between the ALD and control groups, although there was a trend toward lower BMD in patients with ALD (SMD in femur-BMD: -0.172, 95%CI: -0.453-0.110; SMD in spine-BMD: -0.169, 95%CI: -0.476-0.138). Sensitivity analyses showed consistent results. CONCLUSION: Current publications indicate significant associations between bone fractures and ALD, independent of BMD or the presence of osteoporosis. PMID:25852292
Hartmann, Phillipp; Seebauer, Caroline T.; Schnabl, Bernd
Alcoholic liver disease is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with alcoholic liver disease have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier or preventing cellular responses to microbial products protect from experimental alcoholic liver disease. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of alcoholic liver disease. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship and consequences for alcoholic liver disease. We also discuss how the liver affects the intestinal microbiota. PMID:25872593
With prevalence of 10–20% in adults in developed countries, gallstone disease (GSD) is one of the most prevalent and costly gastrointestinal tract disorders in the world. In addition to gallstone disease, chronic liver disease (CLD) is also an important global public health problem. The reported frequency of gallstone in chronic liver disease tends to be higher. The prevalence of gallstone disease might be related to age, gender, etiology, and severity of liver disease in patients with chronic liver disease. In this review, the aim was to identify the epidemiology, mechanisms, and treatment strategies of gallstone disease in chronic liver disease patients. PMID:28251162
Dulai, Parambir S; Singh, Siddharth; Patel, Janki; Soni, Meera; Prokop, Larry J; Younossi, Zobair; Sebastiani, Giada; Ekstedt, Mattias; Hagstrom, Hannes; Nasr, Patrik; Stal, Per; Wong, Vincent Wai-Sun; Kechagias, Stergios; Hultcrantz, Rolf; Loomba, Rohit
Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD. Through a systematic review and meta-analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage-specific mortality (0-4). Using fibrosis stage 0 as a reference population, fibrosis stage-specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all-cause and liver-related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow-up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19-2.11); stage 2, MRR = 2.52 (95% CI 1.85-3.42); stage 3, MRR = 3.48 (95% CI 2.51-4.83); and stage 4, MRR = 6.40 (95% CI 4.11-9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17-11.95); stage 2, MRR = 9.57 (95% CI 1.67-54.93); stage 3, MRR = 16.69 (95% CI 2.92-95.36); and stage 4, MRR = 42.30 (95% CI 3.51-510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. The risk of liver-related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis
Catana, Andreea M; Medici, Valentina
The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options may include hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD. PMID:22312450
Bojórquez-Ramos, María del Carmen
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of liver disease in children and adolescents in the United States of America (USA) and probably in the entire western hemisphere, due to the increase in the prevalence of overweight and obesity. Steatosis can progress to inflammation, fibrosis and even cirrhosis, which increases the morbidity and mortality associated to liver disease. In every overweight and obese child a thorough analysis should be performed including liver function tests and liver ultrasound, in order to establish a timely diagnosis. The liver biopsy is the most specific study to rule out other potentially treatable entities. It is necessary to count on non-invasive methods to detect children with NAFLD and identify those in risk of progression. Biomarkers related to inflammation, oxidative stress, apoptosis and fibrosis have been reported. The main goal of the treatment is to modify the life style, starting with a healthy diet and an increase of physical activity. Regarding pharmacological treatment, there is evidence of histological improvement with vitamin E use, as opposed to metformin, but more conclusive studies regarding this subject are needed.
Koretz, Ronald L; Avenell, Alison; Lipman, Timothy O
treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi(2) test and I(2) statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in
Beier, Juliane I.; Arteel, Gavin E.
Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration–approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD. PMID:21088999
Mottershead, Marcus; Neuberger, James
Liver transplantation remains an effective treatment for those with end-stage disease and with intractable liver-related symptoms. The shortage of organs for transplantation has resulted in the need for rationing. A variety of approaches to selection and allocation have been developed and vary from country to country. The shortage of donors has meant that new approaches have to be adopted to make maximal use of the available organs; these include splitting grafts, use of extended criteria livers, livers from non-heart-beating donors and from living donors. Post transplantation, most patients will need life-long immunosuppression, although a small proportion can have immunosuppression successfully withdrawn. Newer immunosuppressive drugs and different strategies may allow a more targeted approach with a reduction in side-effects and so improve the patient and graft survival. For autoimmune diseases, transplantation is associated with significant improvement in the quality and length of life. Disease may recur after transplantation and may affect patient and graft survival. PMID:18528936
Segura Grau, A; Valero López, I; Díaz Rodríguez, N; Segura Cabral, J M
Liver ultrasound is frequently used as a first-line technique for the detection and characterization of the most common liver lesions, especially those incidentally found focal liver lesions, and for monitoring of chronic liver diseases. Ultrasound is not only used in the Bmode, but also with Doppler and, more recently, contrast-enhanced ultrasound. It is mainly used in the diagnosis of diffuse liver diseases, such as steatosis or cirrhosis. This article presents a practical approach for diagnosis workup, in which the different characteristics of the main focal liver lesions and diffuse liver diseases are reviewed.
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Jiang, Heng; Livingston, Michael; Room, Robin; Dietze, Paul; Norström, Thor; Kerr, William C.
Aims: The aim of the study was to examine for Australia whether the link between population alcohol consumption and liver disease mortality varies over time, using 71 years of data. Methods: Overall and gender-specific rates of liver disease mortality were analysed in relation to total alcohol consumption as well as for different beverage types by using autoregressive integrated moving average (ARIMA) time series methods. Separate models were developed for the entire time period and for two sub-periods (1935–1975, 1976–2006). Results: A 1-l increase in adult per capita consumption of pure alcohol led to a rise of ∼10% in overall liver disease mortality rates and a 11 and 9% increase in female and male liver disease mortality, respectively. The strength of the relationship between per capita consumption and liver disease mortality diminished over time. Spirits consumption was found to be the main driving factor in liver mortality rates between 1935 and 1975, while beer consumption was found to be the most significant predictor in liver diseases in the last three decades. In a comparative perspective, the effect of per capita alcohol consumption on liver disease in Australia is similar to the USA, Southern and Eastern Europe countries, but weaker than in Canada and western European countries. Conclusion: An increase in per capita alcohol consumption in Australia is likely to lead to an increase in liver disease. Changes in the most important beverage over the study period suggest substantial shifts in drinking patterns and preferences among the heaviest Australian drinkers. PMID:24052533
Torruellas, Cara; French, Samuel W; Medici, Valentina
Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease (ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean corpuscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential.
Torruellas, Cara; French, Samuel W; Medici, Valentina
Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease (ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean corpuscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential. PMID:25206273
Li, Xiaozhou; Yang, Tianyue; Yu, Ting; Sun, Ruomin; Li, Siqi
In this paper, 514.5nm argon ion laser induced human serum Raman and auto-fluorescence spectra of normal, liver cirrhosis and liver cancer were measured and analyzed. The spectral differences between these three types of serums were observed and given brief explanations. Three parameters α, φ and Δλ were introduced to describe characteristics of each type of spectrum. Experimental results showed that these parameters might be applicable for discrimination of normal, liver cirrhosis and liver cancer, which will provide some reference values to explore the method of laser spectral diagnosis of cancer.
Wijarnpreecha, Karn; Thongprayoon, Charat; Panjawatanan, Panadeekarn; Ungprasert, Patompong
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. Several studies have suggested that short sleep duration could be a risk factor for NAFLD. However, results of those reports are inconsistent. This meta-analysis was conducted with an attempt to summarize all available data. A comprehensive literature review was performed using MEDLINE and EMBASE database. Studies that reported relative risks, odd ratios or hazard ratios comparing the risk of NAFLD among participants who had short sleep duration versus those with longer sleep duration were included. Pooled risk ratios and 95% confidence interval were calculated using a random-effect, generic inverse variance method. Six studies met the eligibility criteria and were included in the meta-analysis. The risk of NAFLD in participants who had short sleep duration was significantly higher than participants with longer sleep duration with pooled risk ratios of 1.19 (95% confidence interval, 1.04-1.36, I(2) = 0%). Our study demonstrated a small but significantly increased risk of NAFLD among participants who had short sleep duration. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Darmawan, Guntur; Hamijoyo, Laniyati; Hasan, Irsan
non-alcoholic fatty liver disease (NAFLD) is known to be associated with some metabolic disorders. Recent studies suggested the role of uric acid in NAFLD through oxidative stress and inflammatory process. This study is aimed to evaluate the association between serum uric acid and NAFLD. a systematic literature review was conducted using Pubmed and Cochrane library. The quality of all studies was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). All data were analyzed using REVIEW MANAGER 5.3. eleven studies from America and Asia involving 100,275 subjects were included. The pooled adjusted OR for NAFLD was 1.92 (95% CI: 1.66-2.23; p<0.00001). Subgroup analyses were done based on study design, gender, non-diabetic subjects, non-obese subjects. All subgroup analyses showed statistically significant adjusted OR and most of which having low to moderate heterogeneity. Two studies revealed relationship between increased serum uric acid levels and severity of NAFLD. No publication bias was observed. our study demonstrated association between serum uric acid level and NAFLD. This finding brings a new insight of uric acid in clinical practice. Increased in serum uric acid levels might serve as a trigger for physician to screen for NAFLD.
Jaurigue, Maryconi M; Cappell, Mitchell S
Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function ≥ 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and
Bissonnette, Julien; Durand, François; de Raucourt, Emmanuelle; Ceccaldi, Pierre-François; Plessier, Aurélie; Valla, Dominique; Rautou, Pierre-Emmanuel
Vascular disorders of the liver frequently affect women of childbearing age. Pregnancy and the postpartum are prothrombotic states. Pregnancy seems to be a trigger for Budd–Chiari syndrome in patients with an underlying prothrombotic disorder. Whether pregnancy is a risk factor for other vascular liver disorders is unknown. In women with a known vascular liver disorder and a desire for pregnancy, stabilisation of the liver disease, including the use of a portal decompressive procedure when indicated, should be reached prior to conception. The presence of esophageal varices should be screened and adequate prophylaxis of bleeding applied in a manner similar to what is recommended for patients with cirrhosis. Most women likely benefit from anticoagulation during pregnancy and the postpartum. Labor and delivery are best managed by a multidisciplinary team with experience in this situation. Assisted vaginal delivery is the preferred mode of delivery. Although the risk of miscarriage and premature birth is heightened, current management of these diseases makes it very likely to see the birth of a live baby when pregnancy reaches 20 weeks of gestation. PMID:25941432
Savale, Laurent; Sattler, Caroline; Sitbon, Olivier
Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary hypertension (mPAP ≥ 25 mmHg, PCWP < 15 mmHg and PVR > 3 Wood units). PoPH is characterised by pathobiological mechanisms that are similar to other forms of pulmonary arterial hypertension. Prevalence of PoPH is estimated at 0.5-5% among patients with portal hypertension with or without cirrhosis. Treatment strategies most commonly employed for PoPH patients are based on recommendations for idiopathic PAH management. Indeed, the choice of specific PAH treatment must take account the severity of the underlying liver disease. Prognosis of PoPH patients is dependent on both the severity of PAH and of the underlying liver disease. PoPH may be a contraindication for orthotopic liver transplantation (OLT) if mean pulmonary arterial pressure is > 35 mmHg associated with severe right ventricular dysfunction or high level of pulmonary vascular resistance (> 3-4 Wood units). Bridge therapy with specific PAH therapies should be considered in those patients in an attempt to improve pulmonary hemodynamic and thereby allow OLT with acceptable risk. Recent data suggest that stabilize, improve or cure PoPH seems to be possible by combining specific PAH therapies and liver transplantation in selected patients. Clinical and experimental evidences suggest that IFN therapy may be a possible risk factor for PAH.
Li, Xiaozhou; Jia, Chunde; Lin, Junxiu; Kang, Youping
In this paper, laser induced human serum Raman spectra of liver cancer are measured. The spectra differences in serum from normal people and liver cancer patients are analyzed. For the typical spectrum of normal serum, there are three sharp Raman peaks and relative intensity of Raman peaks excited by 514.5 nm is higher than that excited by 488.0 nm. However, for the Raman spectrum of liver cancer serum there are no peaks or very weak Raman peaks at the same positions. Results from more than two hundred case measurements show that clinical diagnostic accuracy is 92.86%. And then, the liver fibrosis and liver cirrhosis are studied applying the technology of LIF. To liver cirrhosis, the shape of Raman peak is similar to normal and fluorescence spectrum is similar to that of liver cancer from statistic data. The experiment indicates that there is notable fluorescence difference between the abnormal and normal liver tissue and have blue shift in fluorescence peak. These results have important reference values to explore the method of laser spectrum diagnosis.
McClain, Craig J.; Barve, Shirish S.; Barve, Ashutosh; Marsano, Luis
Malnutrition, both protein energy malnutrition (PEM) and deficiencies in individual nutrients, is a frequent complication of alcoholic liver disease (ALD). Severity of malnutrition correlates with severity of ALD. Malnutrition also occurs in patients with cirrhosis due to etiologies other than alcohol. The mechanisms for malnutrition are multifactorial, and malnutrition frequently worsens in the hospital due to fasting for procedures and metabolic complications of liver disease, such as hepatic encephalopathy. Aggressive nutritional support is indicated in inpatients with ALD, and patients often need to be fed through an enteral feeding tube to achieve protein and calorie goals. Enteral nutritional support clearly improves nutrition status and may improve clinical outcome. Moreover, late-night snacks in outpatient cirrhotics improve nutritional status and lean body mass. Thus, with no FDA-approved therapy for ALD, careful nutritional intervention should be considered as frontline therapy. PMID:21284673
Yadav, Anitha; Carey, Elizabeth J
Osteoporosis is a common skeletal complication seen in patients with chronic liver disease. Osteoporosis is usually asymptomatic and, if untreated, can result in fractures and impaired quality of life. For this review, we performed a systematic search of the PubMed database, and all recent peer-reviewed articles regarding the prevalence, pathophysiology, diagnosis, and management of osteoporosis in chronic liver disease were included. The prevalence of osteoporosis varies between 11% and 58% in patients with chronic liver disease and in transplant recipients. The etiology of osteoporosis is multifactorial and only partially understood. Various factors linked to the pathogenesis of bone loss are vitamin D, calcium, insulin growth factor-1, receptor activation of nuclear factor-κB ligand (RANKL), bilirubin, fibronectin, leptin, proinflammatory cytokines, and genetic polymorphisms. Management of osteoporosis involves early diagnosis, identifying and minimizing risk factors, general supportive care, nutrition therapy, and pharmacotherapy. Osteoporosis is diagnosed based on the bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry scan. Measurement of BMD should be considered in all patients with advanced liver disease and in transplant recipients. Vitamin D and calcium supplementation is recommended for all patients with osteoporosis. Specific agents used for treatment of osteoporosis include bisphosphonates, calcitonin, hormonal therapy, and raloxifene. Bisphosphonates have become the mainstay of therapy for osteoporosis prevention and treatment. Prolonged suppression of bone remodeling resulting in atypical fractures has emerged as a significant complication with long-term use of bisphosphonates. Newer treatment agents and better fracture prevention strategies are necessary to prevent and treat osteoporosis.
Zhang, Tong-Shuo; Qin, Hua-Lei; Wang, Tong; Li, Hai-Tao; Li, Hai; Xia, Shi-Hai; Xiang, Xiao-Hui
AIM To identify and assess the research situation of top 100 cited articles in nonalcoholic fatty liver disease (NAFLD). METHODS The global scientific research articles in the Science Citation Index-Expanded relevant to NAFLD were retrieved and listed according to their citation times from the most to the least. The 100 most frequently cited original articles were selected to systematically evaluate their bibliometric parameters including times cited, publication year, journals, subject categories, and the highly related concepts of NAFLD, which reflected the history and current situation, publication distribution of leading countries and institutes as well as the research hotspots of NAFLD. RESULTS Top 100 cited articles in NAFLD were published from 1965 to 2015 with a citation ranging of 227 to 2151 times since publication, in which the United States was the most predominant country and Mayo Clin was the most productive institution. The majority of the top 100 cited articles were concentrated in SCI subject category of Gastroenterology and Hepatology. Hepatology and Gastroenterology is the top journal that published over half 100 top-cited articles. The significant peak of top cited articles present in the first half of the 2000s while the highest mean number of citation presents in first half of the 1980s. In addition, concepts related to pathology characteristics, epidemiology and medicalization, metabolic syndrome and its combination of symptoms including insulin resistance, biomarkers of lipid metabolism and obesity are listed as the highly related concepts. CONCLUSION The 100 top-cited articles marked with the leading countries, institutions, journals, hotspots and development trend in NAFLD field that could provide the foundation for further investigations. PMID:27957247
Zhang, Tong-Shuo; Qin, Hua-Lei; Wang, Tong; Li, Hai-Tao; Li, Hai; Xia, Shi-Hai; Xiang, Xiao-Hui
To identify and assess the research situation of top 100 cited articles in nonalcoholic fatty liver disease (NAFLD). The global scientific research articles in the Science Citation Index-Expanded relevant to NAFLD were retrieved and listed according to their citation times from the most to the least. The 100 most frequently cited original articles were selected to systematically evaluate their bibliometric parameters including times cited, publication year, journals, subject categories, and the highly related concepts of NAFLD, which reflected the history and current situation, publication distribution of leading countries and institutes as well as the research hotspots of NAFLD. Top 100 cited articles in NAFLD were published from 1965 to 2015 with a citation ranging of 227 to 2151 times since publication, in which the United States was the most predominant country and Mayo Clin was the most productive institution. The majority of the top 100 cited articles were concentrated in SCI subject category of Gastroenterology and Hepatology. Hepatology and Gastroenterology is the top journal that published over half 100 top-cited articles. The significant peak of top cited articles present in the first half of the 2000s while the highest mean number of citation presents in first half of the 1980s. In addition, concepts related to pathology characteristics, epidemiology and medicalization, metabolic syndrome and its combination of symptoms including insulin resistance, biomarkers of lipid metabolism and obesity are listed as the highly related concepts. The 100 top-cited articles marked with the leading countries, institutions, journals, hotspots and development trend in NAFLD field that could provide the foundation for further investigations.
Yang, Bing-Bing; Chen, Yuan-Hua; Zhang, Cheng; Shi, Chang-E; Hu, Kai-Feng; Zhou, Ju; Xu, De-Xiang; Chen, Xi
Several studies explored the association between vitamin D status and nonalcoholic fatty liver disease with contradictory results. We aimed to investigate the association between vitamin D status, inflammatory cytokines and liver fibrosis in nonalcoholic fatty liver disease patients. Two hundred nineteen nonalcoholic fatty liver disease patients and 166 age- and gender- matched healthy controls were recruited for this study. Serum 25(OH)D was measured by radioimmunoassay. Serum interleukin-8 and transforming growth factor-β1 were measured using ELISA. Serum 25(OH)D was only marginally decreased in nonalcoholic fatty liver disease patients. Interestingly, serum 25(OH)D was markedly reduced in nonalcoholic fatty liver disease patients with advanced liver fibrosis compared to nonalcoholic fatty liver disease patients with indeterminate liver fibrosis and no advanced fibrosis. Logistic regression analysis showed that there was an inverse association between serum 25(OH)D and severity of liver fibrosis in nonalcoholic fatty liver disease patients. Further analysis showed that serum interleukin-8 was elevated in nonalcoholic fatty liver disease patients, the highest interleukin-8 in patients with advanced fibrosis. An inverse correlation between serum 25(OH)D and interleukin-8 was observed in nonalcoholic fatty liver disease patients with and without liver fibrosis. Although serum transforming growth factor-β1 was slightly elevated in nonalcoholic fatty liver disease patients, serum transforming growth factor-β1 was reduced in nonalcoholic fatty liver disease patients with advanced fibrosis. Unexpectedly, a positive correlation between serum 25(OH)D and transforming growth factor-β1 was observed in nonalcoholic fatty liver disease patients with advanced fibrosis. In conclusion, low vitamin D status is associated with advanced liver fibrosis in nonalcoholic fatty liver disease patients. Interleukin-8 may be an important mediator for hepatic fibrosis in nonalcoholic
Since liver function is changed by chronic liver diseases, chronic liver disease can lead to different hemorheological alterations during the course of the progression. This study aims to compare alterations in whole blood viscosity in patients with chronic liver disease, focusing on the gender effect. Chronic liver diseases were classified into three categories by patient’s history, serologic markers, and radiologic findings: nonalcoholic fatty liver disease (NAFLD) (n = 63), chronic viral hepatitis B and C (n = 50), and liver cirrhosis (LC) (n = 35). Whole blood viscosity was measured by automated scanning capillary tube viscometer, while liver stiffness was measured by transient elastography using FibroScan®. Both systolic and diastolic whole blood viscosities were significantly lower in patients with LC than NAFLD and chronic viral hepatitis (P < 0.001) in male patients, but not in female patients. In correlation analysis, there were inverse relationships between both systolic and diastolic whole blood viscosity and liver stiffness (systolic: r = −0.25, diastolic: r = −0.22). Whole blood viscosity was significantly lower in male patients with LC than NAFLD or chronic viral hepatitis. Our data suggest that whole blood viscosity test can become a useful tool for classifying chronic liver disease and determining the prognosis for different types of chronic liver diseases. PMID:27822933
Jang, Bohyun; Han, Ji Won; Sung, Pil Soo; Jang, Jeong Won; Bae, Si Hyun; Choi, Jong Young; Cho, Young I; Yoon, Seung Kew
Since liver function is changed by chronic liver diseases, chronic liver disease can lead to different hemorheological alterations during the course of the progression. This study aims to compare alterations in whole blood viscosity in patients with chronic liver disease, focusing on the gender effect. Chronic liver diseases were classified into three categories by patient's history, serologic markers, and radiologic findings: nonalcoholic fatty liver disease (NAFLD) (n = 63), chronic viral hepatitis B and C (n = 50), and liver cirrhosis (LC) (n = 35). Whole blood viscosity was measured by automated scanning capillary tube viscometer, while liver stiffness was measured by transient elastography using FibroScan®. Both systolic and diastolic whole blood viscosities were significantly lower in patients with LC than NAFLD and chronic viral hepatitis (P < 0.001) in male patients, but not in female patients. In correlation analysis, there were inverse relationships between both systolic and diastolic whole blood viscosity and liver stiffness (systolic: r = -0.25, diastolic: r = -0.22). Whole blood viscosity was significantly lower in male patients with LC than NAFLD or chronic viral hepatitis. Our data suggest that whole blood viscosity test can become a useful tool for classifying chronic liver disease and determining the prognosis for different types of chronic liver diseases.
Rocco, Alba; Compare, Debora; Angrisani, Debora; Sanduzzi Zamparelli, Marco; Nardone, Gerardo
The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world’s third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the “necrosis-fibrosis” sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract. PMID:25356028
Rocco, Alba; Compare, Debora; Angrisani, Debora; Sanduzzi Zamparelli, Marco; Nardone, Gerardo
The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world's third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the "necrosis-fibrosis" sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract.
Wilkins, Thad; Tadkod, Altaf; Hepburn, Iryna; Schade, Robert R
Nonalcoholic fatty liver disease is characterized by excessive fat accumulation in the liver (hepatic steatosis). Nonalcoholic steatohepatitis is characterized by steatosis, liver cell injury, and inflammation. The mechanism of nonalcoholic fatty liver disease is unknown but involves the development of insulin resistance, steatosis, inflammatory cytokines, and oxidative stress. Nonalcoholic fatty liver disease is associated with physical inactivity, obesity, and metabolic syndrome. Screening is not recommended in the general population. The diagnosis is usually made after an incidental discovery of unexplained elevation of liver enzyme levels or when steatosis is noted on imaging (e.g., ultrasonography). Patients are often asymptomatic and the physical examination is often unremarkable. No single laboratory test is diagnostic, but tests of liver function, tests for metabolic syndrome, and tests to exclude other causes of abnormal liver enzyme levels are routinely performed. Imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging, can assess hepatic fat, measure liver and spleen size, and exclude other diseases. Liver biopsy remains the criterion standard for the diagnosis of nonalcoholic steatohepatitis. Noninvasive tests are available and may reduce the need for liver biopsy. A healthy diet, weight loss, and exercise are first-line therapeutic measures to reduce insulin resistance. There is insufficient evidence to support bariatric surgery, metformin, thiazolidinediones, bile acids, or antioxidant supplements for the treatment of nonalcoholic fatty liver disease. The long-term prognosis is not associated with an increased risk of all-cause mortality, cardiovascular disease, cancer, or liver disease.
Chung, Mei; Ma, Jiantao; Patel, Kamal; Berger, Samantha; Lau, Joseph; Lichtenstein, Alice H
Background: Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States. Objective: We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans. Design: We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision. Results: Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD. Conclusions: On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust
Chung, Mei; Ma, Jiantao; Patel, Kamal; Berger, Samantha; Lau, Joseph; Lichtenstein, Alice H
Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States. We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans. We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision. Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD. On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose
Acar, S; Gencdal, G; Tokac, M; Eren, E; Alkara, U; Tellioglu, G; Dinckan, A; Akyildiz, M
Polycystic liver disease is characterized by multiple cystic lesions on the liver. It is an uncommon autosomal dominant disease. The cysts' diameters range from 20 to 30 cm to small microscopic nodules. Generally, more than half of the liver parenchyma is covered. The mass effect of the liver created by the large cysts can cause life-threatening symptoms such as weight loss, reduction of oral intake, and malnutrition. Liver transplantation is the best treatment option in symptomatic patients. We present a patient who had polycystic liver and kidney disease, and we performed liver transplantation because of his life-threatening symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.
Kawaguchi, Takumi; Suetsugu, Takuro; Ogata, Shyou; Imanaga, Minami; Ishii, Kumiko; Esaki, Nao; Sugimoto, Masako; Otsuyama, Jyuri; Nagamatsu, Ayu; Taniguchi, Eitaro; Itou, Minoru; Oriishi, Tetsuharu; Iwasaki, Shoko; Miura, Hiroko; Torimura, Takuji
The incidence of traffic accidents in patients with chronic liver disease (CLD) is high in the USA. However, the characteristics of patients, including dietary habits, differ between Japan and the USA. The present study investigated the incidence of traffic accidents in CLD patients and the clinical profiles associated with traffic accidents in Japan using a data-mining analysis. A cross-sectional study was performed and 256 subjects [148 CLD patients (CLD group) and 106 patients with other digestive diseases (disease control group)] were enrolled; 2 patients were excluded. The incidence of traffic accidents was compared between the two groups. Independent factors for traffic accidents were analyzed using logistic regression and decision-tree analyses. The incidence of traffic accidents did not differ between the CLD and disease control groups (8.8 vs. 11.3%). The results of the logistic regression analysis showed that yoghurt consumption was the only independent risk factor for traffic accidents (odds ratio, 0.37; 95% confidence interval, 0.16-0.85; P=0.0197). Similarly, the results of the decision-tree analysis showed that yoghurt consumption was the initial divergence variable. In patients who consumed yoghurt habitually, the incidence of traffic accidents was 6.6%, while that in patients who did not consume yoghurt was 16.0%. CLD was not identified as an independent factor in the logistic regression and decision-tree analyses. In conclusion, the difference in the incidence of traffic accidents in Japan between the CLD and disease control groups was insignificant. Furthermore, yoghurt consumption was an independent negative risk factor for traffic accidents in patients with digestive diseases, including CLD.
KAWAGUCHI, TAKUMI; SUETSUGU, TAKURO; OGATA, SHYOU; IMANAGA, MINAMI; ISHII, KUMIKO; ESAKI, NAO; SUGIMOTO, MASAKO; OTSUYAMA, JYURI; NAGAMATSU, AYU; TANIGUCHI, EITARO; ITOU, MINORU; ORIISHI, TETSUHARU; IWASAKI, SHOKO; MIURA, HIROKO; TORIMURA, TAKUJI
The incidence of traffic accidents in patients with chronic liver disease (CLD) is high in the USA. However, the characteristics of patients, including dietary habits, differ between Japan and the USA. The present study investigated the incidence of traffic accidents in CLD patients and the clinical profiles associated with traffic accidents in Japan using a data-mining analysis. A cross-sectional study was performed and 256 subjects [148 CLD patients (CLD group) and 106 patients with other digestive diseases (disease control group)] were enrolled; 2 patients were excluded. The incidence of traffic accidents was compared between the two groups. Independent factors for traffic accidents were analyzed using logistic regression and decision-tree analyses. The incidence of traffic accidents did not differ between the CLD and disease control groups (8.8 vs. 11.3%). The results of the logistic regression analysis showed that yoghurt consumption was the only independent risk factor for traffic accidents (odds ratio, 0.37; 95% confidence interval, 0.16–0.85; P=0.0197). Similarly, the results of the decision-tree analysis showed that yoghurt consumption was the initial divergence variable. In patients who consumed yoghurt habitually, the incidence of traffic accidents was 6.6%, while that in patients who did not consume yoghurt was 16.0%. CLD was not identified as an independent factor in the logistic regression and decision-tree analyses. In conclusion, the difference in the incidence of traffic accidents in Japan between the CLD and disease control groups was insignificant. Furthermore, yoghurt consumption was an independent negative risk factor for traffic accidents in patients with digestive diseases, including CLD. PMID:27123257
Peces, R; González, P; Venegas, J L
Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.
Temmerman, F; Gevers, T; Ho, T A; Vanslembrouck, R; Coudyzer, W; van Pelt, J; Bammens, B; Pirson, Y; Drenth, J P; Nevens, F
Long-acting lanreotide (LAN) 120 mg every 4 weeks reduces liver volume (LV) in patients with polycystic liver diseases (PCLD). Animal studies demonstrated that the inhibition of hepatic and renal cystogenesis is dose dependent. To investigate the safety and efficacy of two different LAN doses in PCLD patients. The 6-month results of the LOCKCYST I trial, its extension study and the LOCKCYST II trial were pooled. LV at baseline and month 6 was measured by CT-scan and blindly re-analysed by two independent radiologists. The study population [132 treatment periods, age 49 years (IQR: 45-55), 114 women] consisted of three groups. Each received treatment every 4 weeks during 6 months: placebo (n = 26); LAN 90 mg (n = 55) or LAN 120 mg (n = 51). The inter-observer variability and agreement in the calculation of LV were excellent. Severe side effects occurred with placebo, LAN 90 mg and LAN 120 mg in respectively 0%, 7% and 16%. Change in LV's after 6 months in these three groups were respectively: increase of +36 mL [(-45)-(+138)]; decrease of -82 mL [(-285)-(+92)] and decrease of -123 mL [(-312)-(+4)] (Kruskal-Wallis One Way anova on Ranks; P = 0.002). Based on ROC analysis, a reduction of ≥120 mL in LV has a positive predictive value of 64% for improving symptoms (ROC analysis AUC: 0.729; sensitivity 73%, specificity 69%, P < 0.0001). Both LAN 90 mg and LAN 120 mg reduce liver volume. LAN 90 mg has less side effects. This suggests that in case of intolerance to LAN 120 mg, a dose reduction to LAN 90 mg is meaningful. © 2013 John Wiley & Sons Ltd.
Zheng, Wei; Wang, Lu; Su, Xiao; Hu, Xiao-Fang
Microsomal transfer protein (MTP), a lipid transfer protein localized in the endoplasmic reticulum of hepatocytes and enterocytes, plays an important role in the development of nonalcoholic fatty liver disease (NAFLD). Many existing studies have demonstrated that a common polymorphism (-493G>T, rs1800591 G>T) in the MTP gene may be implicated in the development and progression of NAFLD, but individually published results are inconclusive. This meta-analysis aimed to investigate whether MTP -493G>T polymorphism may be a potential risk factor for NAFLD. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through October 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Eleven clinical case-control studies with a total of 636 NAFLD cases and 918 healthy controls met the inclusion criteria. Our meta-analysis results revealed that MTP -493G>T polymorphism was strongly correlated with an increased risk of NAFLD. Subgroup analysis by ethnicity suggested that MTP -493G>T polymorphism might increase individuals' susceptibility to NAFLD among both Caucasian and non-Caucasian populations. No publication bias was observed in this meta-analysis. In short, the present meta-analysis indicates that MTP -493G>T polymorphisms may contribute to individuals' susceptibility to NAFLD. Thus, MTP -493G>T polymorphism may be a valuable and practical biomarker for early detection of NAFLD.
During inflammation, the inflammasomes representing a group of multi-protein complexes trigger the biological maturation of pro-inflammatory cytokines such as interleukin-1β and interleukin-18 by proteolytic activation of caspase-1 from its inactive proforms. The individual genes encoding components of the inflammasome machinery are regulated at transcriptional and post-transcriptional levels. Once activated, they drive a wide variety of cellular responses that are necessary to mediate host defense against microbial pathogens and to guarantee tissue homeostasis. In the present work, we have studied the expression of the different inflammasomes in various primary hepatic cell subpopulations, in models of acute inflammation and during experimental liver fibrogenesis. We demonstrate that NLRP-1, NLRP-3 and AIM2 are prominently expressed in Kupffer cells and liver sinusoidal endothelial cells, moderately expressed in periportal myofibroblasts and hepatic stellate cells, and virtually absent in primary cultured hepatocytes. We found that the challenge with the lipopolysaccharides results in a time- and concentration-dependent expression of the NOD-like receptor family members NLRP-1, NLRP-3 and NLRC4/NALP4 in cultured hepatic stellate cells and a strong transcriptional activation of NLRP-3 in hepatocytes. Moreover, we detect a diverse regulatory network of the different inflammasomes in the chosen experimental models of acute and chronic liver insult suggesting that the various inflammasomes might contribute simultaneously to the outcome of inflammatory and fibrotic liver insult, irrespectively of the underlying inflammatory stimulus. PMID:23192004
Boaru, Sorina Georgiana; Borkham-Kamphorst, Erawan; Tihaa, Lidia; Haas, Ute; Weiskirchen, Ralf
During inflammation, the inflammasomes representing a group of multi-protein complexes trigger the biological maturation of pro-inflammatory cytokines such as interleukin-1β and interleukin-18 by proteolytic activation of caspase-1 from its inactive proforms. The individual genes encoding components of the inflammasome machinery are regulated at transcriptional and post-transcriptional levels. Once activated, they drive a wide variety of cellular responses that are necessary to mediate host defense against microbial pathogens and to guarantee tissue homeostasis. In the present work, we have studied the expression of the different inflammasomes in various primary hepatic cell subpopulations, in models of acute inflammation and during experimental liver fibrogenesis. We demonstrate that NLRP-1, NLRP-3 and AIM2 are prominently expressed in Kupffer cells and liver sinusoidal endothelial cells, moderately expressed in periportal myofibroblasts and hepatic stellate cells, and virtually absent in primary cultured hepatocytes. We found that the challenge with the lipopolysaccharides results in a time- and concentration-dependent expression of the NOD-like receptor family members NLRP-1, NLRP-3 and NLRC4/NALP4 in cultured hepatic stellate cells and a strong transcriptional activation of NLRP-3 in hepatocytes. Moreover, we detect a diverse regulatory network of the different inflammasomes in the chosen experimental models of acute and chronic liver insult suggesting that the various inflammasomes might contribute simultaneously to the outcome of inflammatory and fibrotic liver insult, irrespectively of the underlying inflammatory stimulus.
Ioannou, George N
Cholelithiasis and fatty liver disease share some important risk factors, such as central obesity, insulin resistance, and diabetes. We sought to determine whether persons with cholelithiasis or a history of cholecystectomy were more likely to have elevated serum liver enzymes or to develop cirrhosis. We used cohort data from the first National Health and Nutrition Examination Survey (NHANES), to determine whether persons with a self-reported history of cholecystectomy at baseline (n=466) had a higher incidence of hospitalization or death due to cirrhosis than persons without a history of cholecystectomy (n=8,691) during up to 21 years of follow-up. We also used cross-sectional data from the third NHANES conducted between the years 1988 and 1994 to determine whether persons with cholelithiasis (n=833) or previous cholecystectomy (n=709), as determined by ultrasonography, were more likely to have elevated serum alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) than persons without cholecystectomy or cholelithiasis (n=8,027). Persons with previous cholecystectomy were two times more likely to be hospitalized for or die of cirrhosis (adjusted hazard ratio 2.1, 95% confidence interval (CI) 1.1-4.0) and were more likely to have elevated serum ALT (adjusted odds ratio 1.8, 95% CI 1.3-2.5) or GGT (adjusted odds ratio 1.7, 95% CI 1.1-2.6) than persons without cholecystectomy. We did not identify an independent association between cholelithiasis and serum ALT or GGT levels. Cholecystectomy is a predictor of the development cirrhosis and is associated with elevated serum liver enzymes. Cholelithiasis is not independently associated with serum liver enzyme levels; whether cholelithiasis is associated with the development of cirrhosis remains to be determined.
Hadzic, Nedim; Hierro, Loreto
Autoimmune liver disease is the second commonest cause of chronic liver disease in teenagers. There are several forms including autoimmune hepatitis, autoimmune sclerosing cholangitis, primary sclerosing cholangitis and various overlap syndromes, classified on the basis of different serum antibody profiles, histological features and appearances on cholangiography. Treatment with immunosupressants is usually effective, but often required medium to long-term, raising concerns about side effects and adherence to therapy. For a minority of children presenting in acute liver failure or with difficult-to-treat disease liver transplantation is a possible option, although risk of recurrence in the grafted liver remains lifelong.
Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases. PMID:28321390
Utiyama, Shirley R R; Zenatti, Katiane B; Nóbrega, Heloisa A J; Soares, Juliana Z C; Skare, Thelma L; Matsubara, Caroline; Muzzilo, Dominique A; Nisihara, Renato M
Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs. This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies. There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies. There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.
Elce, Ausilia; Amato, Felice
Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson's disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup. PMID:24222913
de Avelar, Camila Ribeiro; Pereira, Emile Miranda; de Farias Costa, Priscila Ribas; de Jesus, Rosângela Passos; de Oliveira, Lucivalda Pereira Magalhães
AIM To evaluate the effect of silymarin on the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (γGT) in patients with liver diseases. METHODS A systematic review with meta-analysis of ramdomized and controlled clinical trials was performed, evaluating the effects of sylimarin in patients with hepatic diseases, published by January 31, 2016. Clinical trials were sought on the basis of The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed/Medline, Scopus, Web of Science, Lilacs and Clinical Trials. The trials with adult and elderly patients of both sexes, with Liver Diseases who took oral silymarin supplementation, as extract or isolated, as well as Silymarin combined with other nutrients, were included. The trials should provide information about the intervention, such as dosages and detailing of the product used, besides the mean and standard deviation of serum levels of ALT, AST and γGT of the baseline and at the end of the intervention. RESULTS An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria. In this meta-analysis, the results indicated a reduction of 0.26 IU/mL (95%CI: -0.46-0.07, P = 0.007) at the level of ALT and 0.53 IU/mL (95%CI: -0.74-0.32, P = 0.000) at the serum levels of AST after using the silymarin, both, statistically significant, but with no clinical relevance. There was no significant change in the γGT levels. Subgroup analyzes were also performed for the biochemical markers in relation to the type of intervention, whether silymarin isolated or associated with other nutrients and the time of intervention (whether ≥ 6 mo or < 6 mo). Significant differences were not found. The evaluated studies presented a high degree of heterogeneity and low methodological quality in the carried out analysis. CONCLUSION Silymarin minimally
Dutkowski, Philipp; Oberkofler, Christian E; Béchir, Markus; Müllhaupt, Beat; Geier, Andreas; Raptis, Dimitri A; Clavien, Pierre-Alain
We analyzed the first 100 patients who underwent liver transplantation by Model for End-Stage Liver Disease (MELD) allocation, and compared the outcome of patients on the waiting list and after orthotopic liver transplantation with the last 100 patients who underwent transplantation prior to the introduction of the MELD system in July 2007. MELD allocation resulted in decreased waiting list mortality (386 versus 242 deaths per 1000 patient-years, P < 0.0001) and the transplantation of sicker recipients (uncorrected median MELD score 13.5 versus 20, P = 0.003). Recipient posttransplant morbidity was significantly higher, mainly caused by increased percentage of renal failure requiring renal replacement therapy (13 versus 46%, P < 0.0001). However, kidney function recovered in most cases within 6 months after OLT. Hospital mortality remained similar in both groups (6% versus 9%). Patient 1-year survival was 91% versus 83% (pre-MELD versus MELD era, P = 0.2154), graft 1-year survival was 88% versus 78% (P = 0.1013), respectively. Costs accumulated were significantly higher after introduction of the MELD policy (US $81,967 versus US $127,453, a 55% increase, P = 0.02) with a strong correlation with the individual MELD score (P < 0.0001). The MELD system addresses the goal of fairness well. However, the postoperative course appears more difficult in the MELD era with increased financial burden, but reasonable patient and graft survival. This is the inevitable price to balance justice and utility in liver graft allocation. Copyright © 2011 American Association for the Study of Liver Diseases.
Lang, Thomas; Feist, Stephen W; Stentiford, Grant D; Bignell, John P; Vethaak, A Dick; Wosniok, Werner
In the framework of the ICON project (Integrated Assessment of Contaminant Impacts on the North Sea), common dab (Limanda limanda) from seven offshore sampling areas in the North Sea, Icelandic waters and the western Baltic Sea were examined in 2008 for the presence of externally visible diseases and parasites (EVD), macroscopic liver neoplasms (tumours) (MLN) and histopathological liver lesions (LH). Methodologies applied followed standardised ICES and BEQUALM protocols. The EDV results revealed pronounced spatial variation, with dab from the central and northern North Sea sampling areas showing the highest disease prevalence. MLN were recorded only in North Sea dab from the German Bight, Firth of Forth and Ekofisk at a low prevalence. LH results revealed a dominant prevalence of non-specific, mostly inflammatory, lesions and a low prevalence of early toxicopathic non-neoplastic lesions, tumour pre-stages (foci of cellular alteration) and liver tumours. For the analysis and assessment of spatial variation of EVD, a Fish Disease Index (FDI) was calculated for individual dab, summarising data on the presence/absence of EDV, their severity grades, effects on the host and compensating for effects of length, sex and season. FDI data confirmed that the health status of North Sea dab from the offshore areas Dogger Bank, Ekofisk and Firth of Forth was significantly worse than in dab from the German Bight, Icelandic areas and the western Baltic Sea. An assessment of the disease data following ICES/OSPAR criteria was accomplished by applying established numeric background (BAC) and ecological assessment criteria (EAC) for EDV, MLN and LH. The combined assessment of the three disease categories indicated that health effects classified as unacceptable were rare and mainly affected dab from the North Sea. Based on the findings of the present study, it is recommended to monitor wild fish diseases in the context of assessing the impact of hazardous substances and other stressors
Essential facts Non-alcoholic fatty liver disease (NAFLD) is an excess of fat in the liver that is not the result of excessive alcohol consumption or other secondary causes, such as hepatitis C. According to the National Institute for Health and Care Excellence, fatty liver - steatosis - affects between 20% and 30% of the population and its prevalence is increasing.
Shi, Xue; Wei, Xiaoli; Koo, Imhoi; Schmidt, Robin H.; Yin, Xinmin; Kim, Seong Ho; Vaughn, Andrew; McClain, Craig J.; Arteel, Gavin E.
Arsenic is a widely-distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet-environment interaction via a high throughput metabolomics approach. GC×GC-TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice, and they point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease. PMID:24328084
Shi, Xue; Wei, Xiaoli; Koo, Imhoi; Schmidt, Robin H; Yin, Xinmin; Kim, Seong Ho; Vaughn, Andrew; McClain, Craig J; Arteel, Gavin E; Zhang, Xiang; Watson, Walter H
Arsenic is a widely distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet-environment interaction via a high-throughput metabolomics approach. GC×GC-TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice and point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease.
Chassaing, Benoit; Etienne-Mesmin, Lucie; Gewirtz, Andrew T.
Accumulating evidence indicates that the gut microbiota, long appreciated to be a key determinant of intestinal inflammation, is also playing a key role in chronic inflammatory disease of the liver. Such studies have yielded a general central hypothesis whereby microbiota products activate the innate immune system to drive pro-inflammatory gene expression thus promoting chronic inflammatory disease of the liver. This article reviews the background supporting this hypothesis, outlines how it can potentially explain classic and newly emerging epidemiological chronic inflammatory liver disease, and discusses potential therapeutic means to manipulate the microbiota so as to prevent and/or treat liver disease. PMID:23703735
Neuman, Manuela G; Cohen, Lawrence B; Nanau, Radu M
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers. AIM: To review the biomarkers used to diagnose and define the severity of NAFLD and NASH. METHODS: A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed. RESULTS: Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity. CONCLUSIONS: The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical
Clark, Virginia C.; Dhanasekaran, Renumathy; Brantly, Mark; Rouhani, Farshid; Schreck, Pamela; Nelson, David R.
BACKGROUND & AIMS Liver disease is a significant cause of mortality among adults with α-1 antitrypsin (AAT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test AAT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with AAT deficiency, to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease. METHODS We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross-section of AAT-deficient adults (n=647) with and without liver disease; individuals without AAT-deficiency were used as controls (n=152). Results from ALT tests were compared between groups. RESULTS The prevalence of liver disease among individuals with ATT-deficiency was 7.9%; an increased level of ALT was observed in 7.8% of ATT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only γ- glutamyl transpeptidase was significantly higher in the AAT-deficient group than in controls (43 vs 30 IU/ml; P<.003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis. CONCLUSIONS An increased level of ALT does not identify adults with AAT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk. PMID:22835581
Clark, Virginia C; Dhanasekaran, Renumathy; Brantly, Mark; Rouhani, Farshid; Schreck, Pamela; Nelson, David R
Liver disease is a significant cause of death among adults with α(1)-antitrypsin (A-AT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test A-AT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with A-AT deficiency to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease. We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross section of A-AT-deficient adults (n = 647) with and without liver disease; individuals without A-AT deficiency were used as controls (n = 152). Results from ALT tests were compared between groups. The prevalence of liver disease among individuals with A-AT deficiency was 7.9%; an increased level of ALT was observed in 7.8% of A-AT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only γ-glutamyl transpeptidase was significantly higher in the A-AT-deficient group than in controls (43 vs 30 IU/mL; P < .003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis. An increased level of ALT does not identify adults with A-AT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Targher, Giovanni; Chonchol, Michel B; Byrne, Christopher D
The possible link between nonalcoholic fatty liver disease and chronic kidney disease (CKD) recently has attracted considerable scientific interest. Accumulating clinical evidence indicates that the presence and severity of nonalcoholic fatty liver disease is associated significantly with CKD (defined as decreased estimated glomerular filtration rate and/or proteinuria) and that nonalcoholic fatty liver disease predicts the development and progression of CKD, independently of traditional cardiorenal risk factors. Experimental evidence also suggests that nonalcoholic fatty liver disease itself may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory, procoagulant, pro-oxidant, and profibrogenic mediators that play important roles in the development and progression of CKD. However, despite the growing evidence linking nonalcoholic fatty liver disease with CKD, it has not been definitively established whether a causal association exists. The clinical implication for these findings is that patients with nonalcoholic fatty liver disease may benefit from more intensive surveillance or early treatment interventions to decrease the risk of CKD. In this review, we discuss the evidence linking nonalcoholic fatty liver disease with CKD and the putative mechanisms by which nonalcoholic fatty liver disease contributes to kidney damage. We also briefly discuss current treatment options for this increasingly prevalent disease that is likely to have an important future impact on the global burden of disease.
Bhatia, Sangeeta N; Underhill, Gregory H; Zaret, Kenneth S; Fox, Ira J
Despite the tremendous hurdles presented by the complexity of the liver's structure and function, advances in liver physiology, stem cell biology and reprogramming, and the engineering of tissues and devices are accelerating the development of cell-based therapies for treating liver disease and liver failure. This State of the Art Review discusses both the near- and long-term prospects for such cell-based therapies and the unique challenges for clinical translation.
Petta, Salvatore; Gastaldelli, Amalia; Rebelos, Eleni; Bugianesi, Elisabetta; Messa, Piergiorgio; Miele, Luca; Svegliati-Baroni, Gianluca; Valenti, Luca; Bonino, Ferruccio
The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.
Petta, Salvatore; Gastaldelli, Amalia; Rebelos, Eleni; Bugianesi, Elisabetta; Messa, Piergiorgio; Miele, Luca; Svegliati-Baroni, Gianluca; Valenti, Luca; Bonino, Ferruccio
The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation. PMID:27973438
Osna, Natalia A.; Donohue, Terrence M.; Kharbanda, Kusum K.
Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.
Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy. PMID:25132997
De Cruz, Sharon; Espiritu, Joseph Roland D; Zeidler, Michelle; Wang, Tisha S
Sleep-related complaints and disturbances are increasingly recognized in the setting of chronic liver disease and have recently been shown to be an important prognostic factor in patients with advanced chronic liver disease. This article reviews the literature surrounding sleep disturbances and disorders in a variety of types of chronic liver disease. This includes the association of sleep disturbances with hepatitis C and antiviral therapy, primary biliary cirrhosis, and Wilson disease as well as the circadian rhythm abnormalities present in cirrhosis and hepatic encephalopathy. The association between chronic liver disease, particularly nonalcoholic fatty liver disease, and sleep-disordered breathing is also reviewed in detail. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Leevy, Carroll M; Moroianu, Serban A
Development of ethanol-induced fatty liver, alcoholic hepatitis, and cirrhosis has been attributed in part to nutritional deficiencies for many years. Special attention must be focused on treating alcohol-induced liver disease while providing replacement of deficient amino acids, vitamins, minerals, and other nutrients. Avoidance of alcohol intake is required to eliminate progressive liver disease in alcoholics. This is best achieved by using educational and social programs to convince patients and their caretakers of the great necessity to eliminate alcohol intake.
Han, Pengyu; Sun, Dianxing; Yang, Jie
Periodontitis is an oral disease that is highly prevalent worldwide, with a prevalence of 30–50% of the population in developed countries, but only ~10% present with severe forms. It is also estimated that periodontitis results in worldwide productivity losses amounting to ~54 billion USD yearly. In addition to the damage it causes to oral health, periodontitis also affects other types of disease. Numerous studies have confirmed the association between periodontitis and systemic diseases, such as diabetes, respiratory disease, osteoporosis and cardiovascular disease. Increasing evidence also indicated that periodontitis may participate in the progression of liver diseases, such as non-alcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma, as well as affecting liver transplantation. However, to the best of our knowledge, there are currently no reviews elaborating upon the possible links between periodontitis and liver diseases. Therefore, the current review summarizes the human trials and animal experiments that have been conducted to investigate the correlation between periodontitis and liver diseases. Furthermore, in the present review, certain mechanisms that have been postulated to be responsible for the role of periodontitis in liver diseases (such as bacteria, pro-inflammatory mediators and oxidative stress) are considered. The aim of the review is to introduce the hypothesis that periodontitis may be important in the progression of liver disease, thus providing dentists and physicians with an improved understanding of this issue. PMID:27588170
Herrmann, Ulrike; Dockter, Gerd; Lammert, Frank
Liver disease is increasingly common in cystic fibrosis (CF). As new therapeutic options emerge, life expectancy increases and common hepatobiliary manifestations impact on quality of life and survival of CF patients. Hepatobiliary abnormalities in CF vary in nature and range from defects attributable to the underlying CFTR gene defect to those related to systemic disease and malnutrition. Today complications of liver disease represent the third most frequent cause of disease-related death in patients with CF. Here we review molecular and clinical genetics of CF, including genetic modifiers of CF-associated liver disease, and provide practical recommendations for genetic testing, diagnosis and treatment of hepatobiliary manifestations in CF.
Fukui, Aiko; Kawabe, Naoto; Hashimoto, Senju; Murao, Michihito; Nakano, Takuji; Shimazaki, Hiroaki; Kan, Toshiki; Nakaoka, Kazunori; Ohki, Masashi; Takagawa, Yuka; Takamura, Tomoki; Kamei, Hiroyuki; Yoshioka, Kentaro
AIM: To evaluate the efficacy of vitamin E treatment on liver stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-eight NAFLD patients were administered vitamin E for > 1 year. The doses of vitamin E were 150, 300, or 600 mg; three times per day after each meal. Responses were assessed by liver enzyme levels [aspartate aminotransferase (AST), alanine aminotranferease (ALT), and γ-glutamyl transpeptidase (γ-GTP)], noninvasive scoring systems of hepatic fibrosis-4 [FIB-4 index and aspartate aminotransferase-to-platelet index (APRI)], and liver stiffness [velocity of shear wave (Vs)] measured by acoustic radiation force impulse elastography. Vs measurements were performed at baseline and 12 mo after baseline. The patients were genotyped for the patatin-like phospholipase domain containing 3 (PNPLA3) polymorphisms and then divided into either the CC/CG or GG group to examine each group’s responses to vitamin E treatment. RESULTS: We found marked differences in the platelet count, serum albumin levels, alkaline phosphatase levels, FIB-4 index, APRI, and Vs at baseline depending on the PNPLA3 polymorphism. AST, ALT, and γ-GTP levels (all P < 0.001); FIB-4 index (P = 0.035); APRI (P < 0.001); and Vs (P < 0.001) significantly decreased from baseline to 12 mo in the analysis of all patients. In the subset analyses of PNPLA3 genotypes, AST levels (P = 0.011), ALT levels (P < 0.001), γ-GTP levels (P = 0.005), APRI (P = 0.036), and Vs (P = 0.029) in genotype GG patients significantly improved, and AST and ALT levels (both P < 0.001), γ-GTP levels (P = 0.003), FIB-4 index (P = 0.017), and APRI (P < 0.001) in genotype CC/CG patients. CONCLUSION: One year of vitamin E treatment improved noninvasive fibrosis scores and liver stiffness in NAFLD patients. The responses were similar between different PNPLA3 genotypes. PMID:26644818
Liberal, Rodrigo; Grant, Charlotte R
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids. PMID:27729952
Potze, Wilma; Porte, Robert J; Lisman, Ton
Liver disease is characterized by changes in all phases of hemostasis. These hemostatic alterations were long considered to predispose patients with liver disease towards a bleeding tendency, as they are associated with prolonged conventional coagulation tests. However, these patients may also suffer from thrombotic complications, and we now know that the hemostatic system in patient with liver disease is, in fact, in a rebalanced state. In this review we discuss the concept of rebalanced hemostasis and its implications for clinical management of patients with liver disease. For instance, there is no evidence that the use of prophylactic blood product transfusion prior to invasive procedures reduces bleeding risk. Clinicians should also be aware of the possibility of thrombosis occurring in patients with a liver disease, and regular thrombosis prophylaxis should not be withheld in these patients.
Zeman, Marilyn V; Hirschfield, Gideon M
Confirming whether a patient has autoimmune liver disease is challenging, given its varied presentation and complex definitions. In the continued absence of pathognomonic serum markers, diagnosis requires evaluation of laboratory investigations and, frequently, a liver biopsy - all of which need to be interpreted in the correct clinical context, with an emphasis on exclusion of viral infections, drug toxicity and metabolic disease. However, clear diagnosis is important for appropriate and timely therapy. Autoantibodies remain important tools for clinicians, and were the first proposed serological markers to aid in differentiating viral from chronic autoimmune hepatitis. Their presence is occasionally considered to be synonymous with autoimmune liver disease - a misinterpretation of their clinical significance. The present article summarizes the serum autoantibodies currently investigated in clinical and research practice, along with a description of their value in adult chronic liver diseases, with an emphasis on their appropriate use in the diagnosis and management of patients with autoimmune liver disease.
Chacko, Kristina R; Reinus, John
Nonalcoholic fatty liver disease (NAFLD) is an important cause of liver disease that is often associated with the metabolic syndrome. There is a growing awareness that extrahepatic complications occur in individuals with NAFLD, especially an increased risk of cardiovascular disease. Development of diabetes mellitus, chronic kidney disease, colorectal cancer, and endocrinopathies has been linked to NAFLD. This article reviews the extrahepatic complications affecting individuals with NAFLD and the pathogenesis underlying their development. Copyright © 2016 Elsevier Inc. All rights reserved.
Viglino, Damien; Jullian-Desayes, Ingrid; Minoves, Mélanie; Aron-Wisnewsky, Judith; Leroy, Vincent; Zarski, Jean-Pierre; Tamisier, Renaud; Joyeux-Faure, Marie; Pépin, Jean-Louis
Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities. Copyright ©ERS 2017.
Li, L; Wang, S J; Shi, K; Chen, D; Jia, H; Zhu, J
Several studies have found that microsomal transfer protein (MTP) may be important in the development and progression of non-alcoholic fatty liver disease (NAFLD). In this meta-analysis, we evaluated the relationships between a common polymorphism (-493G>T, rs1800591 G>T) in the MTP gene and NAFLD risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before October 1, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. Eleven case-control studies were included in this meta-analysis. A total of 636 NAFLD patients and 918 healthy control subjects were examined in this meta-analysis. Our results indicate that the MTP -493G/T polymorphism increases the risk of NAFLD (G allele vs T allele: OR = 1.39, 95%CI = 1.17-1.65, P < 0.001; GG + GT vs TT: OR = 1.46, 95%CI = 1.02-2.09, P = 0.038, respectively). Subgroup analyses indicated that the MTP -493G/T polymorphism was associated with an increased risk of NAFLD in population-based, hospital-based, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and large sample-size subgroups under the allele and dominant models (all P < 0.05). However, we found no association between non-PCR-RFLP polymorphism and small sample-size subgroups (all P > 0.05). Our findings indicate that the MTP -493G/ T polymorphism may contribute to the development of NAFLD. Thus, the MTP -493G/T polymorphism may be a biomarker for the early detection of NAFLD.
Sueyoshi, Shigeo; Sawai, Setsu; Satoh, Mamoru; Seimiya, Masanori; Sogawa, Kazuyuki; Fukumura, Atsushi; Tsutsumi, Mikihiro; Nomura, Fumio
AIM To assess how serum gamma-glutamyltransferase (GGT) fractions vary in patients with alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). METHODS Serum samples were obtained from 14 patients with biopsy-proven alcoholic liver diseases and 9 patients with biopsy proven non-alcoholic fatty liver disease. In addition to these biopsy-proven cases, 16 obese (body mass index > 25) patients without any history of alcohol consumption but with a fatty liver on ultrasound examination and with elevated GGT were included for an additional analysis. Serum GGT fractionation was conducted by high-performance gel filtration liquid chromatography and was separated into the four fractions, big-GGT, medium-GGT, small-GGT (s-GGT), and free-GGT (f-GGT). RESULTS The results were expressed as a ratio of each fraction including the total GGT (t-GGT). The s-GGT/t-GGT ratios were lowest for the control group and highest for the ALD group. The differences between the control and NAFLD groups and also between the NAFLD and ALD groups were statistically significant. In contrast, the f-GGT/t-GGT ratios were highest in the control group and lowest in the ALD group, with the differences being statistically significant. As a result, the s-GGT/f-GGT ratios were markedly increased in the NAFLD group as compared with the control group. The increase of the s-GGT/t-GGT ratios, the decrease of the f-GGT/t-GGT ratios, and the increase of s-GGT/F-GGT ratios as compared with the control group subjects were also found in obese patients with clinically diagnosed fatty change of the liver. CONCLUSION Serum GGT fractionation by high-performance gel filtration liquid chromatography is potentially useful for the differential diagnosis of ALD and NAFLD. PMID:28083083
Nalbantoglu, ILKe; Brunt, Elizabeth M
Nonalcoholic fatty liver disease (NAFLD), defined as abnormal accumulation (> 5%) of hepatic triglyceride without excess alcohol intake, is the most common form of chronic liver disease in adults and children in the United States. NAFLD encompasses a spectrum of histologic findings including uncomplicated steatosis, steatosis with inflammation and steatohepatitis [nonalcoholic steatohepatitis (NASH)]; the latter can advance to cirrhosis and hepatocellular carcinoma. NASH is currently accepted as the hepatic manifestation of the set of cardiovascular risk factors collectively known as metabolic syndrome. In 1999 a system for histologic grading and staging for NASH was proposed; this was revised by the NASH Clinical Research Network in 2005 for the entire spectrum of lesions in NAFLD, including the lesions and patterns of pediatric NAFLD, and for application in clinical research trials. Diagnosis remains distinct from grade and stage. A recent European proposal separates steatosis from activity to derive a numeric diagnosis of NASH. Even though there have been promising advancements in non-invasive testing, these tests are not yet detailed enough to replace the full range of findings provided by liver biopsy evaluation. Limitations of biopsy are acknowledged, but liver biopsy remains the “gold standard” for diagnosis and determination of amounts of necroinflammatory activity, and location of fibrosis, as well as remodeling of the parenchyma in NASH. This review focuses on the specific histologic lesions of NAFLD and NASH, grading and staging, differential diagnoses to be considered, and the continuing role of the liver biopsy in this important liver disease. PMID:25083076
Feldstein, Ariel E; Patton-Ku, Dana; Boutelle, Kerri N
In this article, several aspects of childhood obesity are discussed, including epidemiology, associated metabolic complications, management strategies, and therapy with particular attention to the impact of obesity on the liver, resulting in nonalcoholic or metabolic fatty liver disease. The deleterious effects of obesity on the liver and health overall can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. The current evidence is summarized supporting pharmacologic, behavioral, and dietary interventions for the management of obesity and fatty liver disease in children.
Heath, Ryan D; Brahmbhatt, Mihir; Tahan, Asli C; Ibdah, Jamal A; Tahan, Veysel
Coffee has long been recognized as having hepatoprotective properties, however, the extent of any beneficial effect is still being elucidated. Coffee appears to reduce risk of hepatocellular carcinoma, reduce advancement of fibrotic disease in a variety of chronic liver diseases, and perhaps reduce ability of hepatitis C virus to replicate. This review aims to catalog the evidence for coffee as universally beneficial across a spectrum of chronic liver diseases, as well as spotlight opportunities for future investigation into coffee and liver disease. PMID:28596816
Montaño Loza, Aldo J; Angulo, Paul
Autoantibodies are a nonpathogenic manifestation of immune reactivity that may occur in acute and chronic liver diseases. Autoantibodies are the consequence rather than the cause of liver injury, and they can be used as diagnostic tools rather than etiologic markers. Conventional autoantibodies used in the categorization of liver disease are antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and perinuclear antineutrophil cytoplasmic antibodies. However, the final diagnosis and the treatment strategies do not depend solely on the serological markers. Autoantibodies titles vary overtime and their behavior does not correlate with disease activity. Over-interpretation is the major pitfall in the clinical application of the serological results. Recognition and characterization of new autoantibodies is expected to improve the diagnostic precision, provide diagnostic parameters, and elucidate target autoantigens for the management of liver diseases.
Rodriguez-Roisin, Roberto; Bartolome, Sonja D; Huchon, Gérard; Krowka, Michael J
This review is devoted to the distinct associations of inflammatory bowel diseases (IBD) and chronic liver disorders with chronic airway diseases, namely chronic obstructive pulmonary disease and bronchial asthma, and other chronic respiratory disorders in the adult population. While there is strong evidence for the association of chronic airway diseases with IBD, the data are much weaker for the interplay between lung and liver multimorbidities. The association of IBD, encompassing Crohn's disease and ulcerative colitis, with pulmonary disorders is underlined by their heterogeneous respiratory manifestations and impact on chronic airway diseases. The potential relationship between the two most prevalent liver-induced pulmonary vascular entities, i.e. portopulmonary hypertension and hepatopulmonary syndrome, and also between liver disease and other chronic respiratory diseases is also approached. Abnormal lung function tests in liver diseases are described and the role of increased serum bilirubin levels on chronic respiratory problems are considered. Copyright ©ERS 2016.
Wijarnpreecha, K; Thongprayoon, C; Edmonds, P J; Cheungpasitporn, W
Nonalcoholic fatty liver disease (NAFLD) is the major concern of public health worldwide. The risk of NAFLD in subjects who regularly drink soda is controversial. The aim of this study was to assess the association between consumption of sugar-sweetened soda and NAFLD. A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through June 2015. Studies that reported relative risks, odd ratios, or hazard ratios comparing the risk of NAFLD in patients consuming a significant amount of either sugar or artificially sweetened soda vs. those who did not consume soda were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Seven observational studies were included in our analysis to assess the association between consumption of sugar-sweetened soda and NAFLD. The pooled RR of NAFLD in patients consuming sugar-sweetened soda was 1.53 (95% CI: 1.34-1.75, I(2) = 0). When meta-analysis was limited only to studies with adjusted analysis, the pooled RR of NAFLD was 1.55 (95% CI: 1.36-1.78, I(2) = 0). The data on association between consumption of artificially sweetened soda and NAFLD were limited; one observational study reported no significant increased risk of NAFLD in artificially sweetened soda consumption. Our study demonstrates statistically significant association between sugar-sweetened soda consumption and NAFLD. This finding may impact clinical management and primary prevention of NAFLD. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Loomba, Rohit; Sirlin, Claude B.; Schwimmer, Jeffrey B.; Lavine, Joel E.
Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in children and adolescents in the United States. A two- to three-fold rise in the rates of obesity and overweight in children over the last 2 decades is probably responsible for the epidemic of NAFLD. Emerging data suggest that children with NASH progress to cirrhosis which may ultimately increase liver-related mortality. More worrisome is the recognition that cardiovascular risk and morbidity in children and adolescents is associated with fatty liver. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults. Liver biopsy remains the gold standard for diagnosis of NASH. Non-invasive biomarkers are needed to identify individuals with progressive liver injury. Targeted therapies to improve liver histology and metabolic abnormalities associated with fatty liver are needed. Currently, randomized-controlled trials are underway in the pediatric population to define pharmacologic therapy for NAFLD. Public health awareness and intervention are needed to promote healthy diet, exercise, and lifestyle modifications to prevent and reduce the burden of disease in the community. PMID:19637286
Wruck, Wasco; Adjaye, James
AIM To compare transcriptomes of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) in a meta-analysis of liver biopsies. METHODS Employing transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD. RESULTS We observed predominating commonalities at the transcriptome level between ALD and NAFLD, most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction, phagosome and lysosome. However some pathways were regulated in opposite directions in ALD and NAFLD, for example, glycolysis was down-regulated in ALD and up-regulated in NAFLD. Interestingly, we found rate-limiting genes such as HMGCR, SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD (down-regulated) and NAFLD (up-regulated). We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE. Additionally, we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD. CONCLUSION Our finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile. Thus, it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile - also as possible drug targets. The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD. PMID:28357032
Lucero, Catherine; Brown, Robert S.
Determining the degree of fibrosis is an important step in the assessment of disease severity in patients with chronic liver disease. Liver biopsy has been the gold standard for estimating the extent of inflammation and fibrosis, although the procedure has limitations such as sampling error and variability. Noninvasive testing has been shown to be equally predictive in ruling out fibrosis or ruling in advanced fibrosis. Serum biomarkers and imaging-based tests have more limited predictive ability when classifying intermediate stages, but these tools can help identify which patients should receive antiviral treatment sooner and require ongoing cancer surveillance without the need for biopsy. Using a combination of serum markers and imaging tests may also be helpful in providing functional assessment of portal hypertension in patients with chronic liver disease. PMID:27330502
Fernández Fernández, Nereida; Linares Torres, Pedro; Joáo Matias, Diana; Jorquera Plaza, Francisco; Olcoz Goñi, Jose Luis
Vitamin D (VD) is known to have multiple extra-skeletal health functions. There is emerging interest in exploring the relationship between vitamin D and chronic liver disease (CLD). To determine the prevalence of VD deficiency in patients with CLD in our setting and to assess whether VD supplementation influences plasma levels and is associated with improved liver function. We conducted a study in 2 phases. First, we analysed clinical and epidemiological characteristics in 94 patients with CLD; second, different doses of calcifediol (25-OH-VD) were administered to patients with VD deficiency (<20ng/mL) and insufficiency (20-30ng/mL). Plasma concentrations and liver function (Child-Pugh and MELD) at the end of treatment were compared with baseline data. Deficient or insufficient VD levels were found in 87% of the patients, with an average concentration of 18.8ng/mL. Levels were lower in patients with cirrhosis (15.9ng/mL) (P=.002) and in alcoholic liver disease. VD levels were inversely proportional to the degree of liver function: Child A (16.52ng/mL) vs C (7.75ng/mL). After VD supplementation, optimal serum levels were achieved in 94% of patients and significant improvements were observed in platelet count, albumin levels (P<.05) and functional status assessed by the Child-Pugh scale (P<.05). Given the high prevalence of VD deficiency or insufficiency, the need for screening should be considered in the population with CLD. VD supplementation could be safe and effective. Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.
Beben, Tomasz; Rifkin, Dena E.
It is important to accurately assess the glomerular filtration rate (GFR) of patients with liver disease in order to deliver care and allocate organs for transplantation in a way that improves outcomes. The most commonly used methods to estimate GFR in this population are based on creatinine, which is biased by these patients’ low creatinine production and potentially by elevated serum bilirubin and decreased albumin levels. None of the creatinine based estimated GFR (eGFR) equations have been specifically modified for a population with liver disease, and even measurement of a 24 hour creatinine clearance has limitations. In liver disease, all creatinine based estimates of GFR overestimate gold standard measured GFR (mGFR), and the degree of overestimation is highest at lower mGFR values and in more severe liver disease. Cystatin C based eGFR has shown promise in general population studies by demonstrating less bias than creatinine based eGFR and improved association with clinically important outcomes, but results in the liver disease population have been mixed and further studies are necessary. Ultimately, specific eGFR equations for liver disease or novel methods for estimating GFR may be necessary. However, for now, the limitations of currently available methods need to be appreciated to understand renal function in liver disease. PMID:26311594
Dogra, Sunil; Jindal, Rashmi
Skin functions as a window to our overall health and a number of systemic diseases result in various cutaneous changes. Knowledge of these manifestations helps in suspecting an underlying systemic illness. Cutaneous abnormalities are quite common in patients with liver diseases and this article aims to focus on these dermatoses. Cutaneous manifestations seen in patients with liver disease though common are nonspecific. They can also be seen in patients without liver diseases and generally do not indicate about a specific underlying hepatic disorder. The presence of a constellation of signs and symptoms is more useful in pointing toward an underlying hepatobiliary condition. The commonest symptom in patients with liver disease is pruritus which is often protracted and disabling. Other common features include spider angiomas, palmar erythema, paper money skin, xanthelasmas, pigmentary changes, and nutritional deficiencies. In this article, first the common cutaneous manifestations that may be associated with liver disorders are discussed and then common liver diseases with their specific cutaneous findings are discussed. Cutaneous abnormalities may be the first clue to the underlying liver disease. Identifying them is crucial for early diagnosis and better management. PMID:25755383
Gevers, Tom J G; Drenth, Joost P H
Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years.
Sarsby, Joscelyn; Martin, Nicholas J.; Lalor, Patricia F.; Bunch, Josephine; Cooper, Helen J.
Liquid extraction surface analysis mass spectrometry (LESA MS) has the potential to become a useful tool in the spatially-resolved profiling of proteins in substrates. Here, the approach has been applied to the analysis of thin tissue sections from human liver. The aim was to determine whether LESA MS was a suitable approach for the detection of protein biomarkers of nonalcoholic liver disease (nonalcoholic steatohepatitis, NASH), with a view to the eventual development of LESA MS for imaging NASH pathology. Two approaches were considered. In the first, endogenous proteins were extracted from liver tissue sections by LESA, subjected to automated trypsin digestion, and the resulting peptide mixture was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) (bottom-up approach). In the second (top-down approach), endogenous proteins were extracted by LESA, and analyzed intact. Selected protein ions were subjected to collision-induced dissociation (CID) and/or electron transfer dissociation (ETD) mass spectrometry. The bottom-up approach resulted in the identification of over 500 proteins; however identification of key protein biomarkers, liver fatty acid binding protein (FABP1), and its variant (Thr→Ala, position 94), was unreliable and irreproducible. Top-down LESA MS analysis of healthy and diseased liver tissue revealed peaks corresponding to multiple (~15-25) proteins. MS/MS of four of these proteins identified them as FABP1, its variant, α-hemoglobin, and 10 kDa heat shock protein. The reliable identification of FABP1 and its variant by top-down LESA MS suggests that the approach may be suitable for imaging NASH pathology in sections from liver biopsies.
Bhatia, Sangeeta N.; Underhill, Gregory H.; Zaret, Kenneth S.; Fox, Ira J.
Despite the tremendous hurdles presented by the complexity of the liver’s structure and function, advances in liver physiology, stem cell biology and reprogramming, and the engineering of tissues and devices are accelerating the development of cell-based therapies for treating liver disease and liver failure. This State of the Art Review discusses both the near and long-term prospects for such cell-based therapies and the unique challenges for clinical translation. PMID:25031271
Alcoholic liver disease (ALD) has been amongst the leading causes of liver cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation suggesting a role for gut-derived “toxins” in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that is increasingly recognized as a major factor in ALD. Bacterial endotoxin, LPS, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4 (TLR4). Recent studies also demonstrated that alcohol consumption is associated with alterations in the gut microbiome and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut-liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut-liver axis relevant to ALD. PMID:25447847
Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719
Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Carr, J Jeffrey; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Kao, W H Linda; Hirschhorn, Joel N; Borecki, Ingrid B
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.
Fabregat, Isabel; Moreno-Càceres, Joaquim; Sánchez, Aránzazu; Dooley, Steven; Dewidar, Bedair; Giannelli, Gianluigi; Ten Dijke, Peter
The transforming growth factor-beta (TGF-β) family signalling pathways play essential roles in the regulation of different cellular processes, including proliferation, differentiation, migration or cell death, which are essential for the homeostasis of tissues and organs. Because of the diverse and pleiotropic TGF-β functions, deregulation of its pathways contributes to human disease. In the case of the liver, TGF-β signalling participates in all stages of disease progression, from initial liver injury through inflammation and fibrosis, to cirrhosis and cancer. TGF-β has cytostatic and apoptotic effects in hepatocytes, promoting liver differentiation during embryogenesis and physiological liver regeneration. However, high levels of TGF-β, as a consequence of chronic liver damage, result in activation of stellate cells to myofibroblasts and massive hepatocyte cell death, which contributes to the promotion of liver fibrosis and later cirrhosis. During liver tumorigenesis, TGF-β may behave as a suppressor factor at early stages; however, there is strong evidence that overactivation of TGF-β signalling might contribute to later tumour progression, once cells escape from its cytostatic effects. For these reasons, targeting the TGF-β signalling pathway is being explored to counteract liver disease progression. In this review, we aim to shed light on the state-of-the-art in the signalling pathways induced by TGF-β that are involved in different stages of liver physiology and pathology.
Jung, E M; Wiggermann, P; Stroszczynski, C; Reiser, M F; Clevert, D-A
The current improvements in modern high resolution ultrasound technology, like Tissue Harmonic Imaging (THI), Speckle Reduction Imaging (SRI), partial color coding of B-mode (Color Coded Imaging), and also the advent of ultrasound based elastography as well as contrast-enhanced ultrasound (CEUS) offer fundamentally new ways to characterize diffuse alterations of the liver parenchyma. Besides metabolic disease, disorders of liver fat distribution, infectious and malignant diseases can cause diffuse alterations of the liver parenchyma. In case of liver fibrosis, only a combination of different ultrasound techniques including CEUS, allows the differentiation between benign dysplastic and malignant lesions. Ultrasound elastography allows assessing the extent of the fibrosis. This article focuses on the different ultrasound based diagnostic possibilities in case of diffuse liver disease.
Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy
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
Uppal, Vikas; Mansoor, Sana; Furuya, Katryn N
Childhood obesity has reached epidemic proportions, and by 2012, more than one third of American children were overweight or obese. As a result, increasingly, children are developing complications of obesity including liver disease. In fact, non-alcoholic fatty liver disease is the most common form of chronic liver disease seen in children today. Recently, there has been a burgeoning literature examining the pathogenesis, genetic markers, and role of the microbiome in this disease. On the clinical front, new modalities of diagnosing hepatic steatosis and hepatic fibrosis are being developed to provide non-invasive methods of surveillance in children. Lastly, the mainstay of treatment of pediatric non-alcoholic fatty liver disease (NAFLD) has been largely through lifestyle interventions, namely, dieting and exercise. Currently, there are a number of clinical trials examining novel lifestyle and drug therapies for NAFLD that are registered with the US National Institutes of Health ClinicalTrials.gov website.
Neuschwander-Tetri, Brent A
Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. As the burden of hepatitis C abates over the next decade, non-alcoholic fatty liver disease will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation. This overview briefly summarizes the most recent data on the pathophysiology, diagnosis, and treatment of non-alcoholic fatty liver disease. Ongoing clinical trials are focused on an array of disease mechanisms and reviewed here are how these treatments fit into the current paradigm of substrate overload lipotoxic liver injury. Many of the approaches are directed at downstream events such as inflammation, injury and fibrogenesis. Addressing more proximal processes such as dysfunctional satiety mechanisms and inappropriately parsimonious energy dissipation are potential therapeutic opportunities that if successfully understood and exploited would not only address fatty liver disease but also the other components of the metabolic syndrome such as obesity, diabetes and dyslipidemia.
Parajuli, Sandesh; Foley, David; Djamali, Arjang; Mandelbrot, Didier
Kidney injury is associated with increased morbidity and mortality in liver transplant recipients. Since the introduction of the model for end-stage liver disease for the allocation of organs for liver transplantation in 2002, the heavy weighting of serum creatinine in the model for end-stage liver disease score has significantly increased the incidence of renal dysfunction seen among patients undergoing liver transplantation. As a result, the frequency of simultaneous liver-kidney (SLK) transplantation compared to liver transplantation alone (LTA) has also increased. The decision to perform SLK rather than LTA is an important one because the benefits to the liver transplant recipient receiving a kidney transplant must be balanced with the benefits of using that organ for a patient with end-stage renal disease. However, predicting whether or not a patient with liver failure has reversible kidney disease, and therefore does not also need a kidney transplant, is difficult. The severity and duration of pretransplant renal dysfunction, hepatitis c, diabetes, and other risk factors for kidney disease are associated with an increased risk of posttransplant end-stage renal disease. However, there are currently no clinical findings that accurately predict renal recovery post liver transplant. As a result, the rate of SLK versus LTA differs significantly between transplant centers. To increase consistency across centers, multiple guidelines have been proposed to guide the decision between SLK and LTA, but their poor predictive value has limited their uniform adoption. Nevertheless, adoption of uniform rules for the allocation of kidneys would reduce the variability between centers in rates of SLK transplant.
Hartmann, Phillipp; Seebauer, Caroline T; Schnabl, Bernd
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota.
Our view on liver macrophages in the context of health and disease has been reformed by the recognition of a remarkable heterogeneity of phagocytes in the liver. Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Kupffer cells are self-renewing, resident and principally non-migratory phagocytes, serving as sentinels for liver homeostasis. Liver injury triggers Kupffer cell activation, leading to inflammatory cytokine and chemokine release. This fosters the infiltration of monocytes into the liver, which give rise to large numbers of inflammatory monocyte-derived macrophages. Liver macrophages are very plastic and adapt their phenotype according to signals derived from the hepatic microenvironment (e.g. danger signals, fatty acids, phagocytosis of cellular debris), which explains their manifold and even opposing functions during disease. These central functions include the perpetuation of inflammation and hepatocyte injury, activation of hepatic stellate cells with subsequent fibrogenesis, and support of tumor development by angiogenesis and T cell suppression. If liver injury ceases, specific molecular signals trigger hepatic macrophages to switch their phenotype towards reparative phagocytes that promote tissue repair and regression of fibrosis. Novel strategies to treat liver disease aim at targeting macrophages. These interventions modulate Kupffer cell activation (e.g. via gut-liver axis or inflammasome formation), monocyte recruitment (e.g. via inhibiting chemokine pathways like CCR2 or CCL2) or macrophage polarization and differentiation (e.g. by nanoparticles). Evidence from mouse models and early clinical studies in patients with non-alcoholic steatohepatitis and fibrosis support the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with liver disease. Macrophages (Greek for "big eaters") are a frequent non-parenchymal cell
VanWagner, Lisa B; Rinella, Mary E
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with an increased prevalence of metabolic, macro- and microvascular complications. The primary causes of mortality in NAFLD are cardiovascular disease (CVD), malignancy and liver disease. NAFLD is a multisystem disease that affects a variety of extra-hepatic organ systems. The main focus of this review is to summarize the reported extra-hepatic associations, which include CVD, chronic kidney disease, obstructive sleep apnea, osteoporosis, psoriasis, colorectal cancer, iron overload and various endocrinopathies (e.g. type 2 diabetes mellitus, thyroid dysfunction, and polycystic ovarian syndrome). Due to the systemic manifestations of NAFLD patients require a multidisciplinary assessment and may benefit from more rigorous surveillance and early treatment interventions to decrease mortality related to malignancy or cardiometabolic diseases.
Seki, Ekihiro; Brenner, David A.; Friedman, Scott; Cohen, Jessica I.; Nagy, Laura; Szabo, Gyongyi; Zakhari, Samir
Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease. PMID:21252049
Most of primary and secondary parasitic liver diseases, at present can be property treated with drugs. Venezuelan pharmaceutic market has some peculiarities that have determined the disappearance from the market of many drugs such as emetine, thiabendazole, quinacrine and niclosamide. Diloxanide never appeared. Venezuela has no commercial international treatises that protect international patents in the pharmaceutical area. In addition, government regulation of cost of drugs is very strict. This is particularly true with old drugs (such as emetine or quinacrine) which had such a low price that is non-commercial for the maker of the drug, usually a large transnational, and is withdrawn from the market. Flexibility of prices is quite easy for new antibiotics which are very expensive. Frequently small national companies import the drug from Italy and Japan which sell the drug independently from international treats. Such companies frequently produce the drug for the government social system, but are unreliable and also frequently they withdraw the drug a variable period of time. The government, through the Ministry of Public Health administer free treatment with drugs for malaria, tuberculosis and leprosy. The severe economic crisis of the country has severely impaired the preventive programs and there is an increase of malaria due to gold mining in the south of the country and falciparum chloroquine resistance and an increase of schistosomiasis in a previous free area. Also administration of drugs for malaria has been severely impaired, mainly for economic reasons. The establishment of a National Government Laboratory is an old (as far as 1946) political goal, but has remained in the political intention.(ABSTRACT TRUNCATED AT 250 WORDS)
Anderson, Emma L; Howe, Laura D; Jones, Hayley E; Higgins, Julian P T; Lawlor, Debbie A; Fraser, Abigail
Narrative reviews of paediatric NAFLD quote prevalences in the general population that range from 9% to 37%; however, no systematic review of the prevalence of NAFLD in children/adolescents has been conducted. We aimed to estimate prevalence of non-alcoholic fatty liver disease (NAFLD) in young people and to determine whether this varies by BMI category, gender, age, diagnostic method, geographical region and study sample size. We conducted a systematic review and meta-analysis of all studies reporting a prevalence of NAFLD based on any diagnostic method in participants 1-19 years old, regardless of whether assessing NAFLD prevalence was the main aim of the study. The pooled mean prevalence of NAFLD in children from general population studies was 7.6% (95%CI: 5.5% to 10.3%) and 34.2% (95% CI: 27.8% to 41.2%) in studies based on child obesity clinics. In both populations there was marked heterogeneity between studies (I2 = 98%). There was evidence that prevalence was generally higher in males compared with females and increased incrementally with greater BMI. There was evidence for differences between regions in clinical population studies, with estimated prevalence being highest in Asia. There was no evidence that prevalence changed over time. Prevalence estimates in studies of children/adolescents attending obesity clinics and in obese children/adolescents from the general population were substantially lower when elevated alanine aminotransferase (ALT) was used to assess NAFLD compared with biopsies, ultrasound scan (USS) or magnetic resonance imaging (MRI). Our review suggests the prevalence of NAFLD in young people is high, particularly in those who are obese and in males.
Anderson, Emma L.; Howe, Laura D.; Jones, Hayley E.; Higgins, Julian P. T.; Lawlor, Debbie A.; Fraser, Abigail
Background & Aims Narrative reviews of paediatric NAFLD quote prevalences in the general population that range from 9% to 37%; however, no systematic review of the prevalence of NAFLD in children/adolescents has been conducted. We aimed to estimate prevalence of non-alcoholic fatty liver disease (NAFLD) in young people and to determine whether this varies by BMI category, gender, age, diagnostic method, geographical region and study sample size. Methods We conducted a systematic review and meta-analysis of all studies reporting a prevalence of NAFLD based on any diagnostic method in participants 1–19 years old, regardless of whether assessing NAFLD prevalence was the main aim of the study. Results The pooled mean prevalence of NAFLD in children from general population studies was 7.6% (95%CI: 5.5% to 10.3%) and 34.2% (95% CI: 27.8% to 41.2%) in studies based on child obesity clinics. In both populations there was marked heterogeneity between studies (I2 = 98%). There was evidence that prevalence was generally higher in males compared with females and increased incrementally with greater BMI. There was evidence for differences between regions in clinical population studies, with estimated prevalence being highest in Asia. There was no evidence that prevalence changed over time. Prevalence estimates in studies of children/adolescents attending obesity clinics and in obese children/adolescents from the general population were substantially lower when elevated alanine aminotransferase (ALT) was used to assess NAFLD compared with biopsies, ultrasound scan (USS) or magnetic resonance imaging (MRI). Conclusions Our review suggests the prevalence of NAFLD in young people is high, particularly in those who are obese and in males. PMID:26512983
Duncan, Martin; Zong, Wenjing; Biank, Vincent F; Hageman, Joseph R
A 16-year-old Hispanic girl with an elevated body mass index in an otherwise normal state of health presented for her well-child examination. She had signs of metabolic syndrome and insulin resistance including increased waist circumference and acanthosis nigricans. Laboratory results revealed elevated transaminases with otherwise normal hepatic function. Based on the physical examination and laboratory results, she was diagnosed with nonalcoholic fatty liver disease (NAFLD). After further evaluation, she eventually underwent a liver biopsy. The biopsy revealed nonalcoholic steatohepatitis (NASH) with stage 2 fibrosis. This article reviews the definition of NAFLD and NASH, an increasingly prevalent cause of pediatric chronic liver disease associated with obesity and metabolic syndrome. The article also outlines the epidemiology, risk factors, and natural history of NAFLD, which may help identify and prevent high-risk pediatric patients from progressing to irreversible liver disease. Understanding the diagnostic and treatment options offers the best chance at preventing and reversing the early stages of this disease.
Iruzubieta, Paula; Terán, Álvaro; Crespo, Javier; Fábrega, Emilio
Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.
Iruzubieta, Paula; Terán, Álvaro; Crespo, Javier; Fábrega, Emilio
Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti-inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required. PMID:25544877
Feldstein, Ariel E.; Patton-Ku, Dana; Boutelle, Kerri N.
Synopsis The prevalence of childhood obesity has reached epidemic proportions in the US and many other parts of the world. With obesity comes a variety of adverse health outcomes and metabolic complications. The liver in particular seems to be significantly impacted by fat deposition in the presence of obesity. In this article we discuss several aspects of childhood obesity from epidemiology and associated metabolic complications, to management strategies and therapy with particular attention to the impact of obesity on the liver resulting in non-alcoholic or metabolic fatty liver disease. The deleterious effects of obesity on the liver and health overall can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. Here we summarize the current evidence supporting pharmacologic, behavioral and dietary interventions for the management of obesity and fatty liver disease in children. PMID:24274876
Hashemi, Seyed-Abbas; Alavian, Seyed-Moayed; Gholami-Fesharaki, Mohammad
Background: Transient elastography (TE) is a new modality for the diagnosis of liver fibrosis caused by various etiologies. This study was conducted to determine the accuracy of TE in detecting the different stages of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) patients. Methods: MEDLINE/PubMed, Embase, Ovid, Cochrane Library, American College of Physicians (ACP) Journal Club, Google Scholar, Database of Abstracts of Reviews of Effects, and Web of Science that evaluated the liver stiffness by means of TE and liver biopsy were enrolled in this systematic review and meta-analysis. Published articles were extracted from 2002 to March 2015. Results: A total of 7 articles from 114 papers were included which consisted of 698 patients. The results indicated that when F ≥3, the outcomes were 93.7% (95% confidence interval (CI): 92-95.5), 91.1% (95% CI: 89-93.2), 82.4% (95% CI: 79.9-84.9), and 95.9% (95% CI: 94.4-97.4) for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), respectively. With fibrosis stage ≥4, it has reached the sensitivity of 96.2 % (95% CI: 94.5-97.8), a specificity of 92.2% (95% CI: 89.9-94.6), a PPV of 5.5% (95% CI: 51.2-59.8) and NPV of 98.5% (95% CI: 97.4-99.5). Conclusion: We concluded that as the pathological fibrosis increases, the sensitivity, specificity and NPV of TE in the diagnosis of fibrosis improves in NAFLD patients. TE can be considered as a unique alternative instead of liver biopsy in NAFLD patients and it has an important role in the exclusion of liver cirrhosis. More studies are required to confirm the results. PMID:27999641
Rinella, Mary E
Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. PubMed was queried for published articles through February 28, 2015, using the search terms NAFLD and cirrhosis, mortality, biomarkers, and treatment. A total of 88 references were selected, including 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses. Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The
Purpose of review Interactions of the gut microbiome with the host are important in health and disease. Microbial translocation releases bacterial products that play a key role in progression of chronic liver disease by promoting hepatic injury and inflammation. Although this has long been recognized, we are just beginning to understand the circumstances under which the gut becomes leaky and to discover bacterial metabolites that promote liver disease. In this review we will summarize recent findings from the last two years. Recent findings Chronic liver disease is associated with an altered microbiome with both qualitative (dysbiosis) and quantitative (overgrowth) differences. This can be viewed as a loss of the symbiotic relationship between the microflora and the host. An imbalanced intestinal homeostasis results in a breach of the gut barrier and subsequent microbial translocation. However, the contribution of the intestinal microflora is beyond simple microbial translocation as pathogenic factor. Bacterial metabolites resulting from an imbalanced homeostasis and dysbiosis play also a crucial role in liver disease. Summary A combination between an initiating liver insult and a disturbance of the gut – host symbiosis synergize in progression of liver disease. PMID:23493073
Freire, Maristela Pinheiro; Soares Oshiro, Isabel C V; Bonazzi, Patricia Rodrigues; Guimarães, Thais; Ramos Figueira, Estela Regina; Bacchella, Telésforo; Costa, Silvia Figueiredo; Carneiro D'Albuquerque, Luiz Augusto; Abdala, Edson
In recipients of liver transplantation (LT), surgical site infection (SSIs) are among the most common types of infection occurring in the first 60 days after LT. In 2007, the Model for End-Stage Liver Disease (MELD) scoring system was adopted as the basis for prioritizing organ allocation. Patients with higher MELD scores are at higher risk for developing SSIs as well as other health care-associated infections. However, there have been no studies comparing the incidence of SSIs in the pre-MELD era with the incidence in the period since its adoption. Therefore, the objectives of this study were to evaluate the incidence, etiology, epidemiology, and outcomes of post-LT SSIs in those 2 periods and to identify risk factors for SSIs. We evaluated all patients who underwent LT over a 10-year period (2002-2011). SSI cases were identified through active surveillance. The primary outcome measure was an SSI during the first 60 days after LT. Risk factors were analyzed via logistic regression, and 60-day survival rates were evaluated via Cox regression. We evaluated 543 patients who underwent LT 597 times. The SSI rates in the 2002-2006 and 2007-2011 periods were 30% and 24%, respectively (P = 0.21). We identified the following risk factors for SSIs: retransplantation, the transfusion of more than 2 U of blood during LT, dialysis, cold ischemia for >400 minutes, and a cytomegalovirus infection. The overall 60-day survival rate was 79%. Risk factors for 60-day mortality were retransplantation, dialysis, and a longer surgical time. The use of the MELD score modified the incidence and epidemiology of SSIs only during the first year after its adoption. Risks for SSIs were related more to intraoperative conditions and intercurrences after LT than to a patient's status before LT.
Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito
Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin.
Hartmann, Christina; Schuchmann, Marcus; Zimmermann, Tim
Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-α and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed.
Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito
Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin. PMID:27563875
Vogl, T J; Steiner, S; Hammerstingl, R; Schwarz, S; Kraft, E; Weinzierl, M; Felix, R
To show that Wilson's disease is one likely cause of multiple low-intensity nodules of the liver we obtained MR images in 16 patients with clinically and histopathologically confirmed Wilson's disease. Corresponding to morphological changes MRI enabled the subdivision of the patients into two groups. Using a T2-weighted spin-echo sequence (TR/TE = 2000/45-90) liver parenchyma showed multiple tiny low-intensity-nodules surrounded by high-intensity septa in 10 out of 16 patients. 5 patients had also low-intensity nodules in T1-weighted images (TR/TE = 600/20). In patients of this group histopathology revealed liver cirrhosis (n = 7) and fibrosis (n = 2). Common feature of this patient group was marked inflammatory cell infiltration into fibrous septa, increase of copper concentration in liver parenchyma and distinct pathological changes of laboratory data. In the remaining 6 patients no pathological change of liver morphology was demonstrated by MRI corresponding to slight histopathological changes of parenchyma and normal laboratory data. As low-intensity nodules surrounded by high intensity septa can be demonstrated in patients with marked inflammatory infiltration of liver parenchyma MRI may help to define Wilson patients with poorer prognosis. In patients with low-intensity nodules of the liver and unknown cause of liver cirrhosis laboratory data and histopathology should be checked when searching for disorders of copper metabolism.
Close, John M.; Eghtesad, Bijan
Sialadenosis (sialosis) has been associated most often with alcoholic liver disease and alcoholic cirrhosis, but a number of nutritional deficiencies, diabetes, and bulimia have also been reported to result in sialadenosis. The aim of this study was to determine the prevalence of sialadenosis in patients with advanced liver disease. Patients in the study group consisted of 300 candidates for liver transplantation. Types of liver disease in subjects with clinical evidence of sialadenosis were compared with diagnoses in cases who had no manifestations of sialadenosis. The data were analyzed for significant association. Sialadenosis was found in 28 of the 300 subjects (9.3%). Among these 28 cases, 11 (39.3%) had alcoholic cirrhosis. The remaining 17 (60.7%) had eight other types of liver disease. There was no significant association between sialadenosis and alcoholic cirrhosis (P = 0.389). These findings suggest that both alcoholic and non-alcoholic cirrhosis may lead to the development of sialadenosis. Advanced liver disease is accompanied by multiple nutritional deficiencies which may be exacerbated by alcohol. Similar metabolic abnormalities may occur in patients with diabetes or bulimia. Malnutrition has been associated with autonomic neuropathy, the pathogenic mechanism that has been proposed for sialadenosis. PMID:19644542
Guggenheimer, James; Close, John M; Eghtesad, Bijan
Sialadenosis (sialosis) has been associated most often with alcoholic liver disease and alcoholic cirrhosis, but a number of nutritional deficiencies, diabetes, and bulimia have also been reported to result in sialadenosis. The aim of this study was to determine the prevalence of sialadenosis in patients with advanced liver disease. Patients in the study group consisted of 300 candidates for liver transplantation. Types of liver disease in subjects with clinical evidence of sialadenosis were compared with diagnoses in cases who had no manifestations of sialadenosis. The data were analyzed for significant association. Sialadenosis was found in 28 of the 300 subjects (9.3%). Among these 28 cases, 11 (39.3%) had alcoholic cirrhosis. The remaining 17 (60.7%) had eight other types of liver disease. There was no significant association between sialadenosis and alcoholic cirrhosis (P = 0.389). These findings suggest that both alcoholic and non-alcoholic cirrhosis may lead to the development of sialadenosis. Advanced liver disease is accompanied by multiple nutritional deficiencies which may be exacerbated by alcohol. Similar metabolic abnormalities may occur in patients with diabetes or bulimia. Malnutrition has been associated with autonomic neuropathy, the pathogenic mechanism that has been proposed for sialadenosis.
Sun, Man-Yi; Zhang, Li; Shi, Song-Li; Lin, Jing-Na
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
Sun, Man-Yi; Zhang, Li; Shi, Song-Li; Lin, Jing-Na
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. 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. 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. 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.
Fotbolcu, Hakan; Zorlu, Elçin
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases.
Gudowska, Monika; Gruszewska, Ewa; Panasiuk, Anatol; Cylwik, Bogdan; Flisiak, Robert; Świderska, Magdalena; Szmitkowski, Maciej; Chrostek, Lech
The aim of this study was to evaluate the effect of liver diseases of different etiologies and clinical severity of liver cirrhosis on the serum level of hyaluronic acid. The results were compared with noninvasive markers of liver fibrosis: APRI, GAPRI, HAPRI, FIB-4 and Forn's index. Serum samples were obtained from 20 healthy volunteers and patients suffering from alcoholic cirrhosis (AC)-57 patients, non-alcoholic cirrhosis (NAC)-30 and toxic hepatitis (HT)-22. Cirrhotic patients were classified according to Child-Pugh score. Hyaluronic acid concentration was measured by the immunochemical method. Non-patented indicators were calculated using special formulas. The mean serum hyaluronic acid concentration was significantly higher in AC, NAC and HT group in comparison with the control group. There were significant differences in the serum hyaluronic acid levels between liver diseases, and in AC they were significantly higher than those in NAC and HT group. The serum hyaluronic acid level differs significantly due to the severity of cirrhosis and was the highest in Child-Pugh class C. The sensitivity, specificity, accuracy, positive and negative predictive values and the area under the ROC curve for hyaluronic acid and all non-patented algorithms were high and similar to each other. We conclude that the concentration of hyaluronic acid changes in liver diseases and is affected by the severity of liver cirrhosis. Serum hyaluronic acid should be considered as a good marker for noninvasive diagnosis of liver damage, but the combination of markers is more useful.
Marin, Jose J G; Bujanda, Luis; Banales, Jesus M
To highlight the increasing evidence supporting the concept that microRNAs (miRNAs) are involved in the cause and pathogenesis of cholestatic liver disorders. miRNAs play a key role in maintaining bile acid homeostasis and modulating pathological processes associated to liver cholestasis, such as proliferation, apoptosis, fibrosis and cancer. Changes in the expression level of specific miRNAs have been reported in serum, peripheral blood mononuclear cells or liver tissue from patients suffering from chronic cholestatic liver diseases, such as primary biliary cirrhosis. Although our understanding regarding the role of miRNAs in the development and progression of cholestatic liver diseases is still limited, in the present review, we have revised and discussed the recent information that has emerged on the role of miRNAs in the secretory function of the liver under physiological and pathological conditions. This has led to suggest their potential usefulness as biomarkers for the diagnosis and monitoring of cholestatic liver diseases, as well as tools for the development of novel therapeutic strategies.
French, Samuel W.
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD. PMID:24313165
French, Samuel W
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.
Llorente, Cristina; Schnabl, Bernd
The leaky gut hypothesis links translocating microbial products with the onset and progression of liver disease, and for a long time was considered one of its major contributors. However, a more detailed picture of the intestinal microbiota contributing to liver disease started to evolve. The gut is colonized by trillions of microbes that aid in digestion, modulate immune response, and generate a variety of products that result from microbial metabolic activities. These products together with host-bacteria interactions influence both normal physiology and disease susceptibility. A disruption of the symbiosis between microbiota and host is known as dysbiosis and can have profound effects on health. Qualitative changes such as increased proportions of harmful bacteria and reduced levels of beneficial bacteria, and also quantitative changes in the total amount of bacteria (overgrowth) have been associated with liver disease. Understanding the link between the pathophysiology of liver diseases and compositional and functional changes of the microbiota will help in the design of innovative therapies. In this review, we focus on factors resulting in dysbiosis, and discuss how dysbiosis can disrupt intestinal homeostasis and contribute to liver disease.
Rau, Monika; Weiss, Johannes; Geier, Andreas
Non-alcoholic fatty liver disease is the most common chronic liver disease in Europe and in the USA with rising prevalence. Patients with a metabolic syndrome (diabetes mellitus, obesity, dyslipidemia) are patients at risk with the highest prevalence for NAFLD. Progression from a non-alcoholic fatty liver (NAFL) to a non-alcoholic steatohepatitis (NASH) occurs in 5-20% of patients with the potential to develop a liver fibrosis/cirrhosis. NASH patients and NAFLD patients with higher fibrosis should be identified because they are at risk of a higher mortality. A specific treatment for NASH is not available at the moment. Therefore, the treatment of risk factors and metabolic syndrome has high priority.
Juakiem, Wassem; Torres, Dawn M; Harrison, Stephen A
Nutrition has not been a primary focus of many medical conditions despite its importance in the development and the severity of these diseases. This is certainly the case with nutrition and end-stage liver disease despite the well-established association of nutritional deficiencies and increased rates of complications and mortality in cirrhosis. This review provides an overview of nutrition in chronic liver disease with an emphasis on its pathogenesis as well as ways to assess nutritional status and intervene in an effort to improve nutrition.
Brumbaugh, David E; Friedman, Jacob E
Obese pregnant women may transmit their metabolic phenotype to offspring, leading to a cycle of obesity and diabetes over generations. Early childhood obesity predicts nonalcoholic fatty liver disease (NAFLD), the most common chronic human liver disease. The fetus may be vulnerable to steatosis because immature fetal adipose depots are not available to buffer the excess transplacental lipid delivery in maternal obesity. In animal models, in utero high-fat diet exposure results in an increase in the accumulation of liver triglycerides in offspring and increased hepatic oxidative stress and apoptosis, perhaps priming the liver for later development of NAFLD. Innate immune dysfunction and necroinflammatory changes have been observed in postnatal offspring liver of animals born to high-fat-fed dams. Postweaning, livers of offspring exposed to maternal high-fat feeding in utero share pathophysiologic features with human NAFLD, including increased de novo lipogenesis and decreased free fatty acid oxidation. Human studies using magnetic resonance imaging have shown that maternal BMI predicts infant intrahepatocellular lipid storage, as seen in animal models. The generational transfer of NAFLD may occur via epigenetic changes in offspring liver. Transmission of microbiota from mother to infant may impact energy retention and immune function that contribute to a predisposition to NAFLD.
Ben Ari, Ziv
In the recent decade the subject of general hepatology has undergone significant upgrading. Several breakthrough discoveries have lead to substantial improvement in the antiviral treatment of viral hepatitis, the therapy of hepatocellular carcinoma and the development of noninvasive diagnosis of the severity of liver disease. Nonalcoholic fatty liver disease (NAFLD] is now established as one of the most common causes of chronic liver disease in the Western world. NAFLD can progress to cirrhosis and its associated complications. This issue of "Harefuah" is dedicated to the current knowledge and challenges in liver disease and transplantation and to novel discoveries in this field. Two new important guidelines of the Israeli Association for the Study of the Liver are published in this issue, the first deals with the management of ascites and its complications and the second relates to the innovative antiviral treatment of chronic hepatitis C virus infection. An extensive review on this latter subject is also included, summarizing the major breakthroughs in this field: the development of the new direct acting antiviraL agents and the role of IL28B polymorphism in the response to treatment. One article argues the concept of the high hepatitis B virus (HBV) vertical transmission in an Arab cohort in Israel, while another paper provides data on a significantly improved response rate to antiviral therapy in HIV-HCV co-infected patients. Increased serum level of lipoprotein-associated phospholipase A2 level, an independent predictor of coronary heart disease, was detected in patients with nonalcohoLic fatty liver disease [NAFLD] in another article. The issue also provides encouraging data showing that following two decades of liver transplantation in Israel, the survival rate has improved. Several additional articles in the issue shed further light on recent discoveries in the field of hepatology.
Andringa, Kelly K.; King, Adrienne L.; Eccleston, Heather B.; Mantena, Sudheer K.; Landar, Aimee; Jhala, Nirag C.; Dickinson, Dale A.; Squadrito, Giuseppe L.
S-adenosylmethionine (SAM) minimizes alcohol hepatotoxicity; however, the molecular mechanisms responsible for SAM hepatoprotection remain unknown. Herein, we use proteomics to determine whether the hepatoprotective action of SAM against early-stage alcoholic liver disease is linked to alterations in the mitochondrial proteome. For this, male rats were fed control or ethanol-containing liquid diets ± SAM and liver mitochondria were prepared for proteomic analysis. Two-dimensional isoelectric focusing (2D IEF/SDS-PAGE) and blue native gel electrophoresis (BN-PAGE) were used to determine changes in matrix and oxidative phosphorylation (OxPhos) proteins, respectively. SAM coadministration minimized alcohol-dependent inflammation and preserved mitochondrial respiration. SAM supplementation preserved liver SAM levels in ethanol-fed rats; however, mitochondrial SAM levels were increased by ethanol and SAM treatments. With use of 2D IEF/SDS-PAGE, 30 proteins showed significant changes in abundance in response to ethanol, SAM, or both. Classes of proteins affected by ethanol and SAM treatments were chaperones, beta oxidation proteins, sulfur metabolism proteins, and dehydrogenase enzymes involved in methionine, glycine, and choline metabolism. BN-PAGE revealed novel changes in the levels of 19 OxPhos proteins in response to ethanol, SAM, or both. Ethanol- and SAM-dependent alterations in the proteome were not linked to corresponding changes in gene expression. In conclusion, ethanol and SAM treatment led to multiple changes in the liver mitochondrial proteome. The protective effects of SAM against alcohol toxicity are mediated, in part, through maintenance of proteins involved in key mitochondrial energy conserving and biosynthetic pathways. This study demonstrates that SAM may be a promising candidate for treatment of alcoholic liver disease. PMID:20150243
Andringa, Kelly K; King, Adrienne L; Eccleston, Heather B; Mantena, Sudheer K; Landar, Aimee; Jhala, Nirag C; Dickinson, Dale A; Squadrito, Giuseppe L; Bailey, Shannon M
S-adenosylmethionine (SAM) minimizes alcohol hepatotoxicity; however, the molecular mechanisms responsible for SAM hepatoprotection remain unknown. Herein, we use proteomics to determine whether the hepatoprotective action of SAM against early-stage alcoholic liver disease is linked to alterations in the mitochondrial proteome. For this, male rats were fed control or ethanol-containing liquid diets +/- SAM and liver mitochondria were prepared for proteomic analysis. Two-dimensional isoelectric focusing (2D IEF/SDS-PAGE) and blue native gel electrophoresis (BN-PAGE) were used to determine changes in matrix and oxidative phosphorylation (OxPhos) proteins, respectively. SAM coadministration minimized alcohol-dependent inflammation and preserved mitochondrial respiration. SAM supplementation preserved liver SAM levels in ethanol-fed rats; however, mitochondrial SAM levels were increased by ethanol and SAM treatments. With use of 2D IEF/SDS-PAGE, 30 proteins showed significant changes in abundance in response to ethanol, SAM, or both. Classes of proteins affected by ethanol and SAM treatments were chaperones, beta oxidation proteins, sulfur metabolism proteins, and dehydrogenase enzymes involved in methionine, glycine, and choline metabolism. BN-PAGE revealed novel changes in the levels of 19 OxPhos proteins in response to ethanol, SAM, or both. Ethanol- and SAM-dependent alterations in the proteome were not linked to corresponding changes in gene expression. In conclusion, ethanol and SAM treatment led to multiple changes in the liver mitochondrial proteome. The protective effects of SAM against alcohol toxicity are mediated, in part, through maintenance of proteins involved in key mitochondrial energy conserving and biosynthetic pathways. This study demonstrates that SAM may be a promising candidate for treatment of alcoholic liver disease.
Mackavey, Carole L; Hanks, Robert
Coagulopathy-related bleeding events are a major concern in the management of acute and chronic liver disease. The liver attempts to maintain a balance between procoagulant and anticoagulant factors, and providers struggle with poor prognostic indicators to manage bleeding and critical complications. Subtle changes in patient presentation that may require extensive provider-directed interventions, such as blood transfusions, intravenous fluid management, mitigating possible sepsis, and evaluating appropriate pharmacologic treatment, are discussed.
Kochan, Kamila; Maslak, Edyta; Krafft, Christoph; Kostogrys, Renata; Chlopicki, Stefan; Baranska, Malgorzata
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common liver disorder, characterized by an excessive lipids deposition within the hepatic tissue. Due to the lack of clear-cut symptoms and optimal diagnostic method, the actual prevalence of NAFLD and its pathogenesis remains unclear, especially in the early stages of progression. In the presented work confocal Raman microspectroscopy was used to investigate alterations in the chemical composition of the NAFLD-affected liver. We have investigated two NAFLD models, representative for macrovesicular and microvesicular steatosis, induced by High Fat Diet (60 kcal %) and Low Carbohydrate High Protein Diet (LCHP), respectively. In both models we confirmed the development of NAFLD, manifested by the presence of lipid droplets (LDs), but of different sizes. Model of macrovesicular steatosis was characterized by large LDs, whereas in the microvesicular steatosis model small droplets were found. In both models, however, we observed a significant decrease in the degree of unsaturation of lipids, in comparison to the control. In addition, for both models, the impact of medical treatment with selected drugs (perindopril and nicotinic acid, respectively) was tested, indicating a significant influence of medicine not only on the occurrence and size of the droplets, but also on their composition. In both cases the drug treatment resulted in an increase of the degree of unsaturation of lipids forming droplets. Confocal Raman microspectroscopy was proven to be a powerful tool providing detailed insight into selected areas of hepatic tissue, following the NAFLD pathogenesis and diagnostic potential of the applied drugs. © 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.
Bush, Haley; Golabi, Pegah; Younossi, Zobair M.
With the increase in the prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become among the leading causes of chronic liver disease in the pediatric age group. Once believed to be a “two-hit process”, it is now clear that the actual pathophysiology of NAFLD is complex and involves multiple pathways. Moreover, NAFLD is not always benign, and patients with non-alcoholic steatohepatitis (NASH) are at increased risk of developing advanced stages of liver disease. It has also been shown that NAFLD is not only a liver disease, but is also associated with multiple extrahepatic manifestations, including cardiovascular diseases, type 2 diabetes, and low bone mineral density. Although the data is scarce in the pediatric population, some studies have suggested that long-term mortality and the requirement of liver transplantation will continue to increase in patients with NAFLD. More studies are needed to better understand the natural history of NAFLD, especially in the pediatric age group. PMID:28598410
Goldberg, David S.; Fallon, Michael B.
Patients with chronic liver disease are at risk of extra-hepatic complications related to cirrhosis and portal hypertension, as well organ-specific complications of certain liver diseases. These complications can compromise quality-of-life, while also increasing morbidity and mortality pre- and post-liver transplantation. Patients with chronic liver disease are at risk for pulmonary complications of hepaotpulmonary syndrome and portopulmonary syndrome; the major cardiac complication falls under the general concept of the cirrhotic cardiomyopathy, which can affect systolic and diastolic function, as well as cardiac conduction. In addition, patients with certain diseases are at risk of lung and/or cardiac complications that are specific to the primary disease (i.e., emphysema in alpha-1-antitrypsin deficiency) or occur with increased incidence in certain conditions (i.e., ischemic heart disease associated with non-alcoholic steatohepatitis. This section will focus on the epidemiology, clinical presentation, pathogenesis, treatment options, and role of transplantation for lung and heart diseases secondary to liver disease, while also highlighting select liver diseases that directly affect the lungs and hearts. PMID:25934564
Chen, Lian-Hui; Wang, Yong-Fen; Xu, Qing-Hong; Chen, Shan-Shan
The most typical chronic liver disease in children and adolescents is non-alcoholic fatty liver disease (NAFLD). The dietary addition of ω-3 polyunsaturated fatty acids (PUFAs) provides a promising therapy for children with NAFLD due to its convenience and safety; however, several studies suggested contradictory results for PUFA supplementation in children. Hence, we performed a systematic review and meta-analysis to evaluate the effectiveness of PUFA supplementation in children with NAFLD. Published randomized controlled trials (RCTs) that evaluated the effectiveness of the dietary addition of PUFA in children with NAFLD were considered. The primary result was the alteration in hepatic steatosis grade on ultrasound after treatment. The secondary outcomes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP) and components of metabolic syndrome. Predefined sensitivity analysis was also performed to explore possible explanations for heterogeneity in the evaluations. In total, 4 studies with 263 subjects were identified. PUFA supplementation was associated with significantly improved hepatic steatosis grade on ultrasound (risk difference: 25%, 95% CI: 12-38%), without heterogeneity (P = 0.27, I(2) = 24%). Sensitivity analysis confirmed the robustness of our findings. PUFA supplementation could decrease AST levels after 6 months, but could only reduce ALT levels after 12 months. PUFA did not have a significant effect on most components of metabolic syndrome and the CRP level. ω-3 PUFA supplementation can improve liver steatosis and liver functions, and it is a potential food supplementation to treat NAFLD in children. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Mota, Vitor Gomes; Markman Filho, Brivaldo
Doppler echocardiography (Echo) is a non-invasive method of excellent accuracy to screen portopulmonary hypertension (PPH) and to assess intrapulmonary shunts (IPS) in chronic liver disease (CLD). In the past decade, Echo proved to play a fundamental role in the diagnosis of cirrhotic cardiomyopathy (CCM). To perform a systematic review of relevant articles on the subject 'Echo in CLD'. In November 2011, a systematic review was performed in the PubMed, LILACS and SciELO databases, and the characteristics of the studies selected were reported. The search based on descriptors and free terms obtained 204 articles (179 in Pubmed, 21 in LILACS, and 1 in SciELO). Of those 204 articles, 22 were selected for systematic review. A meta-analysis could not be performed because of the heterogeneity of the articles. Echo should be part of CLD stratification for screening PPH, IPS and CCM, because, most of the time, such complications are diagnosed only when patients are already waiting for a liver transplant.
Neuman, Manuela G; Nanau, Radu M; Cohen, Lawrence B
Unhealthy diet and lack of physical exercise are responsible for fat accumulation in the liver, which may lead to liver disease. Histologically, the severity of the disease has two stages: nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NAFLD is defined by the presence of steatosis with no evidence of cellular injury such as hepatocyte ballooning. NASH is a distinct entity from NAFLD, and is characterized by the presence of inflammation with hepatocytes damage, with or without fibrosis. While several therapeutic strategies have been proposed to improve this condition, the present review aims to discuss nonmedicinal interventions used to reduce liver involvement or to prevent the disease altogether. The authors investigated dietary patterns and vitamin deficiencies associated with NAFLD, and their role in enhancing disease severity. Additionally, they reviewed the role of exercise and the use of interventions, such as as intragastric balloon and bariatric surgery, for improving disease progression. The authors propose monitoring disease progression or repair by following changes in cytoadipokine levels. PMID:26076224
Tovikkai, Chutwichai; Charman, Susan C; Praseedom, Raaj K; Gimson, Alexander E; van der Meulen, Jan
AIM To explore the effect of primary liver disease and comorbidities on transplant length of stay (TLOS) and LOS in later admissions in the first two years after liver transplantation (LLOS). METHODS A linked United Kingdom Liver Transplant Audit - Hospital Episode Statistics database of patients who received a first adult liver transplant between 1997 and 2010 in England was analysed. Patients who died within the first two years were excluded from the primary analysis, but a sensitivity analysis was also performed including all patients. Multivariable linear regression was used to evaluate the impact of primary liver disease and comorbidities on TLOS and LLOS. RESULTS In 3772 patients, the mean (95%CI) TLOS was 24.8 (24.2 to 25.5) d, and the mean LLOS was 24.2 (22.9 to 25.5) d. Compared to patients with cancer, we found that the largest difference in TLOS was seen for acute hepatic failure group (6.1 d; 2.8 to 9.4) and the largest increase in LLOS was seen for other liver disease group (14.8 d; 8.1 to 21.5). Patients with cardiovascular disease had 8.5 d (5.7 to 11.3) longer TLOS and 6.0 d (0.2 to 11.9) longer LLOS, compare to those without. Patients with congestive cardiac failure had 7.6 d longer TLOS than those without. Other comorbidities did not significantly increase TLOS nor LLOS. CONCLUSION The time patients spent in hospital varied according to their primary liver disease and some comorbidities. Time spent in hospital of patients with cancer was relatively short compared to most other indications. Cardiovascular disease and congestive cardiac failure were the comorbidities with a strong impact on increased LOS. PMID:28058226
Singal, Ashwani K; Chaha, Khushdeep S; Rasheed, Khalid; Anand, Bhupinderjit S
Alcoholic cirrhosis remains the second most common indication for liver transplantation. A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list. Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients. Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation (recidivism). These patients need to be identified and require alcohol rehabilitation treatment before transplantation. Recidivism to the level of harmful drinking is reported in about 15%-20% cases. Although, recurrent cirrhosis and graft loss from recidivism is rare, occurring in less than 5% of all alcoholic cirrhosis-related transplants, harmful drinking in the post-transplant period does impact the long-term outcome. The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease. Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome. The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids. Emerging data from retrospective and prospective studies has challenged the 6 mo rule, and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids. PMID:24106395
Telles-Correia, Diogo; Mega, Inês
In Europe, 30% to 50% of liver transplantations are currently due to alcoholic liver disease (ALD). In the United States, this percentage is 17.2%. Post-transplant survival and other predictors of clinical course do not differ significantly from those in other types of transplanted patients, as long as there is no relapse of drinking. However, 20%-25% of these patients lapse or relapse to heavy drinking post-operatively, which has been associated with an increased risk of liver damage and mortality. It is therefore crucial to design specific selection and follow-up strategies aimed at this particular type of patient. Several good and poor prognosis factors that could help to predict a relapse have been suggested, among them the duration of abstinence, social support, a family history of alcoholism, abuse diagnosis versus alcohol dependence, non-acceptance of diagnosis related to alcohol use, presence of severe mental illness, non-adherence in a broad sense, number of years of alcoholism, and daily quantity of alcohol consumption. In this article, we discuss these and other, more controversial factors in selecting ALD patients for liver transplantation. Abstinence should be the main goal after transplantation in an ALD patient. In this article, we review the several definitions of post-transplant relapse, its monitoring and the psychopharmacological and psychotherapeutic treatment. PMID:26494959
Drastich, Pavel; Honsová, Eva; Lodererová, Alena; Jarešová, Marcela; Pekáriková, Aneta; Hoffmanová, Iva; Tučková, Ludmila; Tlaskalová-Hogenová, Helena; Spičák, Julius; Sánchez, Daniel
To study the coincidence of celiac disease, we tested its serological markers in patients with various liver diseases. Large-scale screening of serum antibodies against tissue transglutaminase (tTG), and deamidated gliadin using enzyme-linked immunosorbent assay and serum antibodies against endomysium using immunohistochemistry, in patients with various liver diseases (n = 962) and patients who underwent liver transplantation (OLTx, n = 523) was performed. The expression of tTG in liver tissue samples of patients simultaneously suffering from celiac disease and from various liver diseases using immunohistochemistry was carried out. The final diagnosis of celiac disease was confirmed by histological analysis of small-intestinal biopsy. We found that 29 of 962 patients (3%) with liver diseases and 5 of 523 patients (0.8%) who underwent OLTx were seropositive for IgA and IgG anti-tTG antibodies. However, celiac disease was biopsy-diagnosed in 16 patients: 4 with autoimmune hepatitis type I, 3 with Wilson's disease, 3 with celiac hepatitis, 2 with primary sclerosing cholangitis, 1 with primary biliary cirrhosis, 1 with Budd-Chiari syndrome, 1 with toxic hepatitis, and 1 with non-alcoholic steatohepatitis. Unexpectedly, the highest prevalence of celiac disease was found in patients with Wilson's disease (9.7%), with which it is only rarely associated. On the other hand, no OLTx patients were diagnosed with celiac disease in our study. A pilot study of the expression of tTG in liver tissue using immunohistochemistry documented the overexpression of this molecule in endothelial cells and periportal hepatocytes of patients simultaneously suffering from celiac disease and toxic hepatitis, primary sclerosing cholangitis or autoimmune hepatitis type I. We suggest that screening for celiac disease may be beneficial not only in patients with associated liver diseases, but also in patients with Wilson's disease.
Munoz, L E; De Villiers, D; Markham, D; Whaley, K; Thomas, H C
Patients with HBsAg positive chronic active liver disease (CALD) and primary biliary cirrhosis (PBC) exhibit increased C3d concentrations and changes in the serum concentrations of the complement components consistent with activation of the classical and alternative pathways. In these patients the concentrations of the regulatory proteins, C3b inactivator (C3bINA) and beta IH globulin, are normal. Patients with HBsAg negative CALD and alcohol induced liver disease (ALD) exhibit no evidence of an increased level of complement system activation. In these patients diminished serum concentrations of complement components appear to be related to diminished hepatic synthetic function. C4 synthesis may be specifically reduced in autoimmune chronic active liver disease. PMID:7083631
Kesar, Vivek; Odin, Joseph A
Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Parisi, Giuseppe Fabio; Di Dio, Giovanna; Franzonello, Chiara; Gennaro, Alessia; Rotolo, Novella; Lionetti, Elena; Leonardi, Salvatore
Context Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emergedespecially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. Evidence Acquisition A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. Results CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause ofmortalityin CF (the third after pulmonary disease and transplant complications), only about the 33%ofCF patients presents clinically significant hepatobiliary disease. Conclusions Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed atdelaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of
de Caestecker, J S; Jazrawi, R P; Petroni, M L; Northfield, T C
The hydrophilic bile acid ursodeoxycholic acid has recently been shown to reduce biochemical markers of both cholestasis and hepatocellular damage in patients with chronic liver diseases. The most compelling evidence available is for chronic cholestatic liver diseases, in particular primary biliary cirrhosis, primary sclerosing cholangitis, and cholestasis associated with cystic fibrosis. The effects may be less beneficial in patients with advanced liver disease from these conditions. Data from placebo controlled trials are now available in support of earlier uncontrolled observations, but it is not yet clear whether short term benefit results in an improvement in longterm prognosis. The mechanism of action of the compound seems to reside in its displacement of toxic hydrophobic bile acids from both the bile acid pool and hepatocellular membranes. There may be an independent effect on bile flow, which could be of particular importance in cystic fibrosis, and possibly an effect on the immune system. Ursodeoxycholic acid should now be regarded as occupying a central place in the medical management of chronic cholestatic liver diseases, in particular primary biliary cirrhosis, because it improves cholestasis and reduces hepatocellular damage and it is not toxic. Research should now be targeted on whether treatment with ursodeoxycholic acid, initiated early in cholestatic liver conditions, improves the long-term outcome. PMID:1916492
Affronti, Marco; Affronti, Andrea; Soresi, Maurizio; Giannitrapani, Lydia; Campagna, Elisa; Tramuto, Fabio; Brunori, Giuseppe; Montalto, Giuseppe
The objective of this study was to evaluate the frequency of liver disease and its aetiology in a cohort of immigrants. We retrospectively examined the hospital discharge charts of all the immigrant patients presenting at our day hospital from July 2009 to June 2013, and after evaluating the anamnestic, clinical and laboratory data on these charts we identified subjects with liver disease and its various aetiologies. The total sample population consisted of 1218 patients, of whom 112 (9.2%) had a diagnosis of liver disease. More than two-thirds of the latter (67.8%) came from Africa, while 15.2% were from Asia and 17.0% from Eastern Europe. In most patients the disease was related to HBV (44.6%), followed by alcohol (25%) and then HCV or cryptogenic disease (both 15.2%). Forty-six patients had undergone liver biopsy, which showed eight cases of varying degrees of liver steatosis, 29 cases with a variable severity of chronic liver disease, eight cases with a definite picture of liver cirrhosis and one case of alcoholic hepatitis. These data show that a significant proportion of our immigrant population has liver disease and that the most frequent cause is hepatitis B infection.
Moy, Libia; Levine, Jeremiah
AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis.
Smyk, Daniel S; Orfanidou, Timoklia; Invernizzi, Pietro; Bogdanos, Dimitrios P; Lenzi, Marco
The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation.
Delvin, Edgard; Patey, Natasha; Dubois, Josée; Henderson, Melanie; Lévy, Émile
Summary The rapidly increasing prevalence of childhood obesity and its associated co-morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis. PMID:28356817
Golding, Peter L.
Renal tubular acidosis of the gradient or classic type, thought to be due to a disorder of the distal tubule, has been found to occur in 32% of 117 patients with chronic liver disease. Whilst the cause of this disorder is probably multifactorial, immunological mechanisms are considered to play a major role. The presence of this disorder might well be a cause, rather than the result of, the various electrolyte abnormalities seen in patients with chronic liver disease. ImagesFig. 1Fig. 6 PMID:1234340
Schmidt, S A; Juchems, M S
Perfusion computed tomography (CT) has its main application in the clinical routine diagnosis of neuroradiological problems. Polyphase multi-detector spiral computed tomography is primarily used in liver diagnostics. The use of perfusion CT is also possible for the diagnostics and differentiation of diffuse hepatic diseases. The differentiation between cirrhosis and cirrhosis-like parenchymal changes is possible. It also helps to detect early stages of malignant tumors. However, there are some negative aspects, particularly that of radiation exposure. This paper summarizes the technical basics and possible applications of perfusion CT in cases of diffuse liver disease and weighs up the advantages and disadvantages of the examinations.
Hepatorenal fibrocystic diseases (HRFCDs) are among the most common inherited human disorders. The discovery that proteins defective in the autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) localize to the primary cilia and the recognition of the role these organelles play in the pathogenesis of HRFCDs led to the term “ciliopathies.” While ADPKD and ARPKD are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet–Biedl, Meckel–Gruber, and oral–facial–digital syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD). Hepatocellular function remains relatively preserved in ciliopathy-associated liver diseases. The major morbidity associated with CHF is portal hypertension (PH), often leading to esophageal varices and hypersplenism. In addition, CD predisposes to recurrent cholangitis. PLD is not typically associated with PH, but may result in complications due to mass effects. The kidney pathology in ciliopathies ranges from non-functional cystic dysplastic kidneys to an isolated urinary concentration defect; the disorders contributing to this pathology, in addition to ADPKD and ARPKD, include nephronophithisis (NPHP), glomerulocystic kidney disease and medullary sponge kidneys. Decreased urinary concentration ability, resulting in polyuria and polydypsia, is the first and most common renal symptom in ciliopathies. While the majority of ADPKD, ARPKD, and NPHP patients require renal transplantation, the frequency and rate of progression to renal failure varies considerably in other ciliopathies. This review focuses on the kidney and liver disease found in the different ciliopathies. PMID:19876928
Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin
Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788
Berk, P D; Martin, J F; Young, R S; Creech, J; Selikoff, I J; Falk, H; Watanabe, P; Popper, H; Thomas, L
Although polyvinyl chloride has been produced from vinyl chlride monomer for more than 40 years, recognition of toxicity among vinyl chloride polymerization workers is more recent. In the mid 1960s, workers involved in cleaning polymerization tanks were found to have acro-osteolysis. In 1974, the same population of workers was found to be at risk for an unusual type of hepatic fibrosis and angiosarcoma of the liver. We describe two cases of vinyl chloride-associated liver injury, one of hepatic fibrosis and one of angiosarcoma. Histologic features of these lesions are similar to the hepatic fibrosis and angiosarcomas resulting from chronic exposure to inorganic arsenicals. Preliminary studies suggest that the toxicity of vinyl chloride may result from formation, during high-dose exposure, of active metabolites by mixed function oxidases of the liver. Epidemiologic studies indicate an increased incidence not only of liver disease, but also of cancers of the brain, lung, and possibly other organs.
Zhang, Jiao-Jiao; Meng, Xiao; Li, Ya; Zhou, Yue; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin
Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.
Wen, Yankai; Jeong, Seogsong; Xia, Qiang; Kong, Xiaoni
Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases. PMID:27570486
Singal, Ashwani K.; Kamath, Patrick S.
Model for end-stage liver disease (MELD) score, initially developed to predict survival following transjugular intrahepatic portosystemic shunt was subsequently found to be accurate predictor of mortality amongst patents with end-stage liver disease. Since 2002, MELD score using 3 objective variables (serum bilirubin, serum creatinine, and institutional normalized ratio) has been used worldwide for listing and transplanting patients with end-stage liver disease allowing transplanting sicker patients first irrespective of the wait time on the list. MELD score has also been shown to be accurate predictor of survival amongst patients with alcoholic hepatitis, following variceal hemorrhage, infections in cirrhosis, after surgery in patients with cirrhosis including liver resection, trauma, and hepatorenal syndrome (HRS). Although, MELD score is closest to the ideal score, there are some limitations including its inaccuracy in predicting survival in 15–20% cases. Over the last decade, many efforts have been made to further improve and refine MELD score. Until, a better score is developed, liver allocation would continue based on the currently used MELD score. PMID:25755471
Frith, James; Jones, David; Newton, Julia L
The prevalence of chronic liver disease is increasing in the elderly population. With a mostly asymptomatic or non-specific presentation, these diseases may easily go undiagnosed. Abnormal liver function tests of unknown cause are a common reason for referral to secondary care. Investigating the older person with abnormal liver function is important; even with mild abnormalities, the same vigilance should be applied to an older person as in a young person. Liver biopsy is safe but often overlooked in this age group and may provide useful information to diagnose, direct therapy and prognosticate. Treatment options are similar for all age groups, with a few subtle differences, although further evidence is frequently required for the older population. Morbidity and age-adjusted mortality are often more severe in older people, and therefore early diagnosis and intervention is important. Presented here are the most common chronic liver diseases that geriatricians are likely to encounter in clinical practise. Their epidemiology, clinical features, investigation, treatment and mortality are described with a particular focus on the elderly population.
Singal, Ashwani K.; Jampana, Sarat C.; Weinman, Steven A.
Oxidative stress is commonly associated with a number of liver diseases and is thought to play a role in the pathogenesis of chronic hepatitis C, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), hemochromatosis and Wilson’s disease. Antioxidant therapy has thus been considered to have the possibility of beneficial effects in the management of these liver diseases. In spite of this promise, antioxidants have produced mixed results in a number of clinical trials of efficacy. This review summarizes the results of clinical trials of antioxidants as sole or adjuvant therapy of chronic hepatitis C, alcoholic liver disease and NASH. Overall, the most promising results to date are for vitamin E therapy of NASH but some encouraging results have been obtained with antioxidant therapy of acute alcoholic hepatitis as well. In spite of evidence for small reductions of serum ALT, there is as yet no convincing evidence that antioxidant therapy itself is beneficial to patients with chronic hepatitis C. Problems such as small sample size, short follow up duration, inadequate end points, failure to demonstrate tissue delivery and antioxidant efficacy, and heterogeneous nature of the “antioxidant” compounds used have complicated interpretation of results of the clinical studies. These limitations and their implications for future trial design are discussed. PMID:22093324
Vascular radiology of the liver has increased in scope and function in recent years due mainly to the application of new techniques. It is now possible to examine not only the inferior vena cava and the portal venous system, but also the hepatic veins and the coeliac axis and superior mesenteric artery. Hepatic vein occlusion, portal vein patency and collateral veins, as well as space-occupying lesions, can now be diagnosed with a fair degree of accuracy. These techniques have also helped in the understanding of the altered haemodynamics of portal hypertension and can be used for treatment by intra-arterial perfusion of chemotherapeutic substances. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 14 PMID:5460928
Gaglio, Paul J; Gaglio, Paul J
Cirrhosis caused by alcohol-associated liver disease is a common indication for liver transplantation worldwide. Patients with alcohol-associated liver disease who undergo liver transplantation face multiple challenging comorbid medical issues that enhance the potential for perioperative and postoperative complications. Awareness of these issues and appropriate therapeutic intervention may minimize the negative effect of these complications on posttransplantation survival. This article reviews important posttransplantation problems in patients transplanted for alcohol-associated liver disease.
Buchman, Alan L; Naini, Bita V; Spilker, Bert
Intestinal failure-associated liver disease (IFALD), formerly known as parenteral nutrition-associated liver disease has often been listed in textbooks as an example of nonalcoholic fatty liver disease (NAFLD). However, the etiology, pathophysiology, epidemiology, histology, and progression differ substantially between the conditions defined as NAFLD and the disease, IFALD. Therefore, IFALD should not be defined or considered as a type or a cause of nonalcoholic fatty liver or nonalcoholic steatohepatitis, but rather as a distinct disease.
Della Corte, Claudia; Mazzotta, Anna Rita; Nobili, Valerio
The purpose of this short review is to summarize recent developments in the understanding of pediatric nonalcoholic fatty liver disease (NAFLD), focusing on novel findings in pathogenetic mechanisms and the therapeutic armamentarium. As a result of the increasing prevalence of pediatric obesity, NAFLD has rapidly become the most common cause of chronic hepatopathies in children. Lifestyle modification and diet remain the mainstay of treatment of pediatric obesity and NAFLD, but with disappointing results because of the difficulty in obtaining sustained long-term results. Considering the risk of progression of liver damage to cirrhosis and end-stage liver disease, in the last decades scientific research in this field has been directed to the identification of pathogenetic mechanisms and possible therapeutic strategies for NAFLD. We describe the therapeutic options for the management of pediatric NAFLD, focusing on emerging alternative strategies, including surgical approaches and new drugs directed against novel potential molecular targets.
Williams, C. N.; Sidorov, J. J.
Intestinal function was studied in 26 patients with seven types of acute and chronic liver disease, documented by liver biopsy. Steatorrhea, defined by a stool fat higher than 6 g. per day, was present in 18 of 23 consecutive patients studied, an incidence of 78.3%. Two patients with infectious hepatitis associated with steatorrhea studied previously were added and the 20 cases were analyzed. The malabsorption found was confined to fat and fat-soluble vitamins; stool excretion varied from 6.1 to 22 g. per day in the seven groups studied. No histological abnormality was seen on jejunal biopsy, serum vitamin B12, D-xylose and Schilling tests were normal, and no radiological findings associated with malabsorption were detected in the small bowel. It is concluded that steatorrhea is a common finding in a wide variety of acute and chronic liver diseases and cannot be attributed to a primary defect of the small bowel. PMID:5150072
Gangireddy, V G R; Kanneganti, P C; Sridhar, S; Talla, S; Coleman, T
Thrombocytopenia (defined as a platelet count <150×10(9)) is a well-known complication in patients with liver cirrhosis and has been observed in 76% to 85% of patients. Significant thrombocytopenia (platelet count <50×10(9) to 75×10(9)) occurs in approximately 13% of patients with cirrhosis. Thrombocytopenia can negatively impact the care of patients with severe liver disease by potentially interfering with diagnostic and therapeutic procedures. Multiple factors can contribute to the development of thrombocytopenia including splenic platelet sequestration, immunological processes, bone marrow suppression by chronic viral infection, and reduced levels or activity of the hematopoietic growth factor thrombopoietin. The present review focuses on the etiologies and management options for severe thrombocytopenia in the setting of advanced liver disease.
Carbone, Marco; Neuberger, James
End-stage liver disease due to hepatitis C (HCV) and cirrhosis from alcohol (ALD) are the commonest indications for liver transplantation in the western countries. Up to one third of HCV-infected transplant candidates have a history of significant alcohol intake prior to transplantation. However, there are few data available about the possible interaction between alcohol and HCV in the post-transplant setting. Patients with both HCV and alcohol are more likely to die on the waiting list than those with ALD and HCV alone. However, after transplantation, non-risk adjusted graft and patient survival of patients with HCV + ALD are comparable to those of patients with HCV cirrhosis or ALD cirrhosis alone. In the short and medium term HCV recurrence after transplant in patients with HCV + ALD cirrhosis does not seem more aggressive than that in patients with HCV cirrhosis alone. A relapse in alcohol consumption in patients with HCV + ALD cirrhosis does not have a major impact on graft survival. The evidence shows that, as is currently practiced, HCV + ALD as an appropriate indication for liver transplantation. However, these data are based on retrospective analyses with relatively short follow-up so the conclusions must be treated with caution. PMID:21209701
Ferrell, Jessica M.; Chiang, John Y.L.
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436
Ferrell, Jessica M; Chiang, John Y L
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.
Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are considered as putative autoimmune diseases of the liver. Whereas strong evidence that bacterial infection may trigger PBC exists, the etiologies for PSC and AIH remain unknown. Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases, their associations with environmental triggers and the subsequent implications have been difficult to elucidate. While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) have been suggested as genetic susceptibility factors for all three disorders, we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC, where Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, has recently been specifically associated with the pathogenesis of this devastating liver disease. Ultimately, the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers, establish infection and damage respective target organs. PMID:21307981
Sookoian, Silvia; Pirola, Carlos J.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed. PMID:28268262
Loddo, Italia; Romano, Claudio; Cutrupi, Maria Concetta; Sciveres, Marco; Riva, Silvia; Salpietro, Annamaria; Ferraù, Valeria; Gallizzi, Romina; Briuglia, Silvana
Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.
Rust, Christian; Beuers, Ulrich
The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardised definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC. The AIH-PBC overlap syndrome is the most common form, affecting almost 10% of adults with AIH or PBC. Single cases of AIH and autoimmune cholangitis (AMA-negative PBC) overlap syndrome have also been reported. The AIH-PSC overlap syndrome is predominantly found in children, adolescents and young adults with AIH or PSC. Interestingly, transitions from one autoimmune to another have also been reported in a minority of patients, especially transitions from PBC to AIH-PBC overlap syndrome. Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment. Therapy for overlap syndromes is empiric, since controlled trials are not available in these rare disorders. Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes. In end-stage disease, liver transplantation is the treatment of choice.
Rust, Christian; Beuers, Ulrich
The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardized definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC. The AIH-PBC overlap syndrome is the most common form, affecting almost 10% of adults with AIH or PBC. Single cases of AIH and autoimmune cholangitis (AMA-negative PBC) overlap syndrome have also been reported. The AIH-PSC overlap syndrome is predominantly found in children, adolescents and young adults with AIH or PSC. Interestingly, transitions from one autoimmune to another have also been reported in a minority of patients, especially transitions from PBC to AIH-PBC overlap syndrome. Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment. Therapy for overlap syndromes is empiric, since controlled trials are not available in these rare disorders. Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes. In end-stage disease, liver transplantation is the treatment of choice. PMID:18528934
Lee, Seung Soo; Park, Seong Ho
Nonalcoholic fatty liver disease (NAFLD) is a frequent cause of chronic liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH)-related liver cirrhosis. Although liver biopsy is still the gold standard for the diagnosis of NAFLD, especially for the diagnosis of NASH, imaging methods have been increasingly accepted as noninvasive alternatives to liver biopsy. Ultrasonography is a well-established and cost-effective imaging technique for the diagnosis of hepatic steatosis, especially for screening a large population at risk of NAFLD. Ultrasonography has a reasonable accuracy in detecting moderate-to-severe hepatic steatosis although it is less accurate for detecting mild hepatic steatosis, operator-dependent, and rather qualitative. Computed tomography is not appropriate for general population assessment of hepatic steatosis given its inaccuracy in detecting mild hepatic steatosis and potential radiation hazard. However, computed tomography may be effective in specific clinical situations, such as evaluation of donor candidates for hepatic transplantation. Magnetic resonance spectroscopy and magnetic resonance imaging are now regarded as the most accurate practical methods of measuring liver fat in clinical practice, especially for longitudinal follow-up of patients with NAFLD. Ultrasound elastography and magnetic resonance elastography are increasingly used to evaluate the degree of liver fibrosis in patients with NAFLD and to differentiate NASH from simple steatosis. This article will review current imaging methods used to evaluate hepatic steatosis, including the diagnostic accuracy, limitations, and practical applicability of each method. It will also briefly describe the potential role of elastography techniques in the evaluation of patients with NAFLD. PMID:24966609
Gao, Qiang; Shao, Dan; Pan, Aizhen; Gao, Mingyong; Liu, Zaiyi; Liang, Changhong
Transient elastography is a noninvasive and reliable method for the assessment of liver stiffness. This study aimed to assess liver stiffness of asymptomatic liver fluke disease patients by FibroScan and evaluate the factors influencing liver stiffness. Overall, 65 patients were prospectively recruited from The First People's Hospital of Foshan, Guangdong, China. All patients were diagnosed with liver fluke disease; their durations of ingested freshwater raw fish or shrimp were more than 10 years, and none of them had abnormal liver function and hepatitis B virus or hepatitis C virus infection, or clinical symptoms. All patients underwent FibroScan, blood biochemical examination, and BMI measurement on the same day. Liver stiffness measurement (LSM) values, sex, age, durations of ingested freshwater raw fish or shrimp, and BMI were recorded. LSM value greater than 7.4 kPa was defined as abnormal. A total of 27 patients (41.5%) had abnormal LSM values. On partial correlation analysis, duration of ingested freshwater raw fish or shrimp was the independent factor that showed a positive correlation with abnormal LSM values (r=0.502, P=0.012). An independent-samples t-test showed that the durations of patients with abnormal LSM values were significantly longer than the durations of patients with normal LSM values (P<0.001). Sex, age, and BMI were not significantly correlated with LSM values (P>0.05). A high proportion of asymptomatic liver fluke disease patients had abnormal LSM values. The durations of patients with abnormal LSM values were significantly longer than the durations of patients with normal LSM values and the durations of patients with abnormal LSM values were an independent factor that showed a positive correlation with abnormal LSM values.
Fang, Jianguo; Wang, Wenqing; He, Pei; Lei, Jiahui; Wang, Chunxu
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with rising prevalence. Increasing evidence has demonstrated that resveratrol, a dietary phytochemical, is capable of attenuating NAFLD development and progression; however, results from clinical studies are inconsistent and inconclusive. Here, we conducted a meta-analysis to evaluate the efficacy of resveratrol on NAFLD, using several parameters to provide new insights for clinical application. We systematically searched EMBASE, PubMed, Science Citation Index, Elsevier, and Cochrane Library databases for studies published up to date (July 2016), in English, to identify and screen eligible, relevant studies. Either a fixed-effect model or random model was used to estimate mean difference (MD) and 95% confidence intervals (CIs) for the effect of resveratrol on NAFLD. Four randomized, double-blinded, placebo-controlled trials involving 156 patients were included in the meta-analysis. Levels of low-density lipoprotein (MD = 0.47, 95% CI: 0.21, 0.74, P < 0.05) and total cholesterol (MD = 0.49, 95% CI: 0.18, 0.80, P < 0.05) were higher in the resveratrol treatment groups than in placebo control groups, whereas other parameters were not altered. Overall, this study indicates that resveratrol treatment has negligible effects on attenuating NAFLD, given the small improvement in NAFLD features. More high-quality clinical trials of resveratrol for NAFLD are required to confirm these results. PMID:27560482
Lake, April D.; Novak, Petr; Fisher, Craig D.; Jackson, Jonathan P.; Hardwick, Rhiannon N.; Billheimer, D. Dean; Klimecki, Walter T.
Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups—normal, steatosis, and NASH—was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes. PMID:21737566
Kim, Hyun-Jin; Lim, Chae-Wan; Lee, Jae hyuk; Park, Hyung-Bok; Suh, Yongsung; Cho, Yoon-Hyeong; Choi, Tae-Young; Hwang, Eui-Seok; Cho, Deok-Kyu; Kim, Hyun-Jin
Summary Background Carotid intima–media thickness (CIMT) is a surrogate of subclinical atherosclerosis. Fatty liver disease is also linked to increased risk of cardiovascular events. The aim of this study was to evaluate the association between fatty liver disease and CIMT according to gender. Methods Patients who had undergone carotid and abdominal ultrasound between June 2011 and December 2013 were retrospectively evaluated. The differences between the CIMT values measured in the common carotid artery and the prevalence of carotid plaque in patients with fatty liver disease and those with normal livers were investigated. Results Out of a total of 1 121 patients, the men had more fatty liver disease than the women. The mean CIMT of the men was significantly higher than that of the women, and the men had more plaque than the women. The women with fatty liver disease had a significantly higher mean CIMT value and more plaque than the women with normal livers. The differences between the men with fatty liver and those with normal livers in mean CIMT values and in the prevalence of plaque were not significant. In the women, multivariate analysis showed that fatty liver disease was independently associated with subclinical atherosclerosis [adjusted hazards ratio (HR) 1.65, 95% confidence interval (CI) 1.007–2.697, p = 0.047]. Conclusions The men had more fatty liver disease, carotid plaque and higher CIMT values than the women. Fatty liver disease was a useful predictor of atherosclerosis, especially for the female study patients. PMID:26972662
Arduini, Alessandro; Serviddio, Gaetano; Tormos, Ana M; Monsalve, Maria; Sastre, Juan
Cholestatic liver diseases are characterized by blockade of bile flow from the liver to the intestine, and accumulation of hydrophobic bile acids in the liver and plasma. As a consequence an inflammatory response evolves associated with increased apoptosis, oxidative stress, and eventually fibrosis. Cholestasis is associated with profound metabolic changes, alterations in the mitochondrial function, decreased fatty acid oxidation, and increased glycolisis. Mitochondria play a central role in the development of this liver disease because they mediate death receptor signaling - triggered by inflammatory cytokines or bile acids - and contribute to oxidative damage, metabolic disorder, and onset of fibrosis. During the pathogenesis of biliary cirrhosis mitochondria's need for renewal is hampered by a blunted mitochondrial biogenesis. Lack of stimulation of mitochondrial renewal helps to explain mitochondrial impairment in long-term cholestasis. The marked depletion of mitochondrial DNA and occurrence of mitochondrial DNA deletions are probably relevant contributors to the progression of this severe disease. All these findings certainly support the consideration of long-term cholestasis as a secondary mitochondrial hepatopathy.
Rastogi, Sanjeev; Rastogi, Ranjana
Ayurvedic medicines are often considered effective for treating chronic and lifestyle-related diseases only and have not been thoroughly evaluated for treating acute or terminal illnesses. A prospective evaluation of Ayurvedic intervention was proposed for a patient who had metastatic liver disease with abnormal liver functions. The reason given for this was that no other conventional therapies were feasible in this case, and the family and caregivers were not willing to opt for any other intervention. A diagnosed patient with metastatic liver disease that included abnormal liver functions and symptomatic presentation was treated with Ayurvedic therapies and was observed for 10 days for any possible changes. A substantial clinical and biochemical improvement was observed in this patient after 10 days of treatment. This improvement was noted to be consistent at a 1-week follow-up after the patient was discharged from the hospital. This case offers an opportunity to reconsider whether or not the toxic potentials of heavy metals used in Ayurvedic agents outweigh the possible benefits for treating patients with well-defined, incurable clinical conditions.
Bower, Guy; Athanasiou, Thanos; Isla, Alberto M; Harling, Leanne; Li, Jia V; Holmes, Elaine; Efthimiou, Evangelos; Darzi, Ara; Ashrafian, Hutan
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity-associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight-independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease.
Moreno Villares, J M
Parenteral nutrition associated liver disease (PNALD) is an important problem in patients who require longterm parenteral nutrition as well as in preterm infants. Prevalence varies according to different series. Clinical presentation is different in adults and infants. Although since its first descriptions several hypothesis have been elucidated, the aetiology is not quite clear. It is possible that different factors could be involved. PNALD risk factors can be classified in three groups: 1) those derived from the lack of enteral nutrition stimulus; 2) parenteral nutrition components acting as toxic or the lack of specific nutrients and 3) those due to the underlying disease. If PNALD appears in short-term PN and it presents only as a mild elevation of liver enzymes, there is no need to treat. On the contrary, when direct bilirubin is > 2 mg/dL and lasts longer, there is a need to consider different causes and to minimize risk factors. We review the different approaches to manage PNALD, including optimizing enteral nutrition, modify parenteral solutions, use of specific nutrients -taurine, choline, etc.- or the use of drugs (mainly ursodeoxicolic acid). If liver disease progresses to cirrhosis a liver transplant must be considered.
Protheroe, S M
Protein energy malnutrition leading to growth failure is an inevitable consequence of chronic liver disease in 60% of children. Malnutrition should be anticipated by serial anthropometric assessment and prevented by early intervention with nutritional support. Both morbidity and mortality postliver transplantation have been related to the degree of pretransplant malnutrition, and thus nutritional status is an important risk factor for survival postliver transplantation. As survival following pediatric liver transplantation improves, with most centers reporting 1 y survival rates of 90-95% and 5 y survival rates of 80-85%, attention has focused on achieving nutritional rehabilitation, normal psychosocial development, and normal quality of life. An understanding of the etiology of protein malnutrition in liver disease is essential when planning therapeutic strategies. Considerable research progress has been made exploring the pathophysiology of malnutrition, including long-chain fat malabsorption with essential fatty acid deficiency, abnormal energy metabolism, substrate utilization, and nitrogen metabolism in liver disease. Effective strategies are emerging and future advances include docosahexaenioc acid, branched chain amino acids, and structured lipids. The key to success is a multidisciplinary approach to nutritional intervention, including pediatric dietitian, liaison nurse, feeding psychologist, and clinician.
Sookoian, Silvia; Flichman, Diego; Scian, Romina; Rohr, Cristian; Dopazo, Hernán; Gianotti, Tomas Fernández; Martino, Julio San; Castaño, Gustavo O; Pirola, Carlos J
Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the 'missing heritability
Santos-Laso, A; Izquierdo-Sánchez, L; Lee-Law, P Y; Perugorria, M J; Marzioni, M; Marin, J J G; Bujanda, L; Banales, J M
Polycystic liver diseases (PLDs) include a heterogeneous group of congenital disorders inherited as dominant or recessive genetic traits; they are manifested alone or in association with polycystic kidney disease. Ductal plate malformation during embryogenesis and the loss of heterozygosity linked to second-hit mutations may promote the dilatation and/or development of a large number (> 20) of biliary cysts, which are the main cause of morbidity in these patients. Surgical procedures aimed to eliminate symptomatic cysts show short-term beneficial effects, but are not able to block the disease progression. Therefore, liver transplantation is the only curative option. Intense studies on the molecular mechanisms involved in the pathogenesis of PLDs have resulted in different clinical trials, some of them with promising outcomes. Here the authors summarize the key aspects of PLD etiology, pathogenesis, and therapy, highlighting the most recent advances and future research directions.
Marino, Laura; Jornayvaz, François R
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.
Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei
The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases. PMID:26549942
Marino, Laura; Jornayvaz, François R
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
The author discusses the role of “natural” hepatotoxic substances, derived from plants and fungi, in the etiology of liver disease, especially in tropical and subtropical countries. The hazards involved in even the occasional use of natural hepatotoxins and the difficulty in tracing the causative factors of chronic diseases are illustrated by the example of the pyrrolizidine (Senecio) alkaloids. The ingestion by rats of a single dose of these alkaloids can induce chronic liver lesions and even hepatoma which, however, may not become apparent for 1½-2½ years. It is suggested that, however varied the chemical structures of the various hepatocarcinogens, they may all affect an essential cell constituent (e.g., a “mitotic hormone”), possibly of a steroidal nature, each substance interfering with a particular stage of its biosynthesis. “Natural” toxic factors may also be responsible for some other chronic diseases, especially those which are mainly encountered in, or restricted to, certain pastoral communities. In view of the greater susceptibility of the suckling young and the foetus than of adults to hepatotoxins, it would appear more promising to attempt to trace the causative agents of liver disease in children than in adults, in whom disease takes much longer to develop. ImagesFIG. 1FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7FIG. 8FIG. 9FIG. 10 PMID:14107756
Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei
The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases.
Neuman, Manuela G.; Maor, Yaakov; Nanau, Radu M.; Melzer, Ehud; Mell, Haim; Opris, Mihai; Cohen, Lawrence; Malnick, Stephen
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed. PMID:26343741
Siebler, Juergen; Galle, Peter R
Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective. PMID:16610015
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations. PMID:25469013
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.
In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an 'infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients. © 2016 S. Karger AG, Basel.
Ju, Cynthia; Colgan, Sean P; Eltzschig, Holger K
Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.
Andersen, Henning; Aagaard, Niels K.; Jakobsen, Johannes; Dorup, Inge; Vilstrup, Hendrik
Patients with alcoholic liver disease often complain of restricted physical capacity, which could be due to decreased muscle endurance. The aim of this study was to assess the muscular endurance in patients with alcoholic liver disease. In a cross sectional study, 24 patients with alcoholic liver disease and 22 controls were evaluated using…
Andersen, Henning; Aagaard, Niels K.; Jakobsen, Johannes; Dorup, Inge; Vilstrup, Hendrik
Patients with alcoholic liver disease often complain of restricted physical capacity, which could be due to decreased muscle endurance. The aim of this study was to assess the muscular endurance in patients with alcoholic liver disease. In a cross sectional study, 24 patients with alcoholic liver disease and 22 controls were evaluated using…
Although nonalcoholic fatty liver disease (NAFLD) is not one of the defining criteria for metabolic syndrome, it is a common hepatic manifestation. NAFLD includes a spectrum of histologic findings ranging from simple steatosis, known as nonalcoholic fatty liver, to nonalcoholic steatohepatitis (NASH). To make the diagnosis of NAFLD, other etiologies of steatosis or hepatitis, such as hepatotoxic drugs, excessive alcohol intake, congenital errors of metabolism, or viral hepatitis, must be ruled out. After ruling out other conditions, the diagnosis of NAFLD often is made clinically, but a definitive diagnosis of NASH requires liver biopsy. As with other complications of metabolic syndrome, insulin resistance is thought to be an underlying etiology of NAFLD. Management strategies attempt to reverse or improve insulin resistance while minimizing liver damage. The strongest evidence supports lifestyle modifications with weight loss, but there is some evidence to support bariatric surgery, medical therapy with insulin-sensitizing agents, and/or pharmacotherapy to promote weight loss. Cardiovascular disease is the major cause of mortality in patients with NAFLD, so management must include modification of cardiovascular risk factors. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.
Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.
Carrascosa, J M; Bonanad, C; Dauden, E; Botella, R; Olveira-Martín, A
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver condition in the West. The prevalence and severity of NAFLD is higher and the prognosis worse in patients with psoriasis. The pathogenic link between psoriasis and NAFLD is chronic inflammation and peripheral insulin resistance, a common finding in diseases associated with psoriasis. NAFLD should therefore be ruled out during the initial evaluation of patients with psoriasis, in particular if they show signs of metabolic syndrome and require systemic treatment. Concomitant psoriasis and NAFLD and the likelihood of synergy between them place limitations on general recommendations and treatment for these patients given the potential for liver toxicity. As hepatotoxic risk is associated with some of the conventional drugs used in this setting (e.g., acitretin, methotrexate, and ciclosporin), patients prescribed these treatments should be monitored as appropriate. Anti-tumor necrosis factor agents hold the promise of potential benefits based on their effects on the inflammatory process and improving peripheral insulin resistance. However, cases of liver toxicity have also been reported in relation to these biologics. No evidence has emerged to suggest that anti-p40 or anti-interleukin 17 agents provide benefits or have adverse effects.
Kukuk, Guido M; Schaefer, Stephanie G; Fimmers, Rolf; Hadizadeh, Dariusch R; Ezziddin, Samer; Spengler, Ulrich; Schild, Hans H; Willinek, Winfried A
To evaluate hepatobiliary magnetic resonance imaging (MRI) using Gd-EOB-DTPA in relation to various liver function tests in patients with liver disorders. Fifty-one patients with liver disease underwent Gd-EOB-DTPA-enhanced liver MRI. Based on region-of-interest (ROI) analysis, liver signal intensity was calculated using the spleen as reference tissue. Liver-spleen contrast ratio (LSCR) and relative liver enhancement (RLE) were calculated. Serum levels of total bilirubin, gamma glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), serum albumin level (AL), prothrombin time (PT), creatinine (CR) as well as international normalised ratio (INR) and model for end-stage liver disease (MELD) score were tested for correlation with LSCR and RLE. Pre-contrast LSCR values correlated with total bilirubin (r = -0.39; p = 0.005), GGT (r = -0.37; p = 0.009), AST (r = -0.38; p = 0.013), ALT (r = -0.29; p = 0.046), PT (r = 0.52; p < 0.001), GLDH (r = -0.55; p = 0.044), INR (r = -0.42; p = 0.003), and MELD Score (r = -0.53; p < 0.001). After administration of Gd-EOB-DTPA bilirubin (r = -0.45; p = 0.001), GGT (r = -0.40; p = 0.004), PT (r = 0.54; p < 0.001), AST (r = -0.46; p = 0.002), ALT (r = -0.31; p = 0.030), INR (r = -0.45; p = 0.001) and MELD Score (r = -0.56; p < 0.001) significantly correlated with LSCR. RLE correlated with bilirubin (r = -0.40; p = 0.004), AST (r = -0.38; p = 0.013), PT (r = 0.42; p = 0.003), GGT (r = -0.33; p = 0.020), INR (r = -0.36; p = 0.011) and MELD Score (r = -0.43; p = 0.003). Liver-spleen contrast ratio and relative liver enhancement using Gd-EOB-DTPA correlate with a number of routinely used biochemical liver function tests, suggesting that hepatobiliary MRI may serve as a
Zhang, Yu-Jun; Hu, Ying; Li, Jing; Chi, Yu-Jing; Jiang, Wei-Wei; Zhang, Feng; Liu, Yu-Lan
The integrative analysis of microRNA and mRNA expression profiles can elucidate microRNA-targeted gene function. We used this technique to elucidate insights into the immunological pathology of non-alcoholic fatty liver disease (NAFLD). We analyzed differentially expressed microRNA and mRNA expression profiles of CD4+ T lymphocytes from the liver and mesenteric lymph nodes (MLNs) of mice with NAFLD using microarrays and RNA sequencing. Normal mice were used as controls. The target genes of microRNAs were predicted by TargetScan. Integrative analysis showed that the mRNAs were overlapped with microRNAs. Furthermore, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the key genes and pathways. Then, 16 microRNAs and 10 mRNAs were validated by qRT-PCR. Microarray analysis suggested that 170 microRNAs were significantly de-regulated in CD4+ T lymphocytes from the liver between the two groups. Eighty mRNAs corresponded with microRNA targeted genes. KEGG analysis indicated that the MAPK pathway was consistently augmented in the liver of NAFLD mice. miR-23b, let-7e, miR-128 and miR-130b possibly played significant parts in the MAPK pathways. Furthermore, between the two groups, 237 microRNAs were significantly de-regulated in CD4+ T lymphocytes from MLNs. 38 mRNAs coincided with microRNA target genes. The metabolic pathway was consistently enriched in the MLNs of NAFLD mice. miR-206-3p, miR-181a-5p, miR-29c-3p and miR-30d-5p likely play important roles in the regulation of metabolic pathways. The results of this study presented a new perspective on the application of integrative analysis to identify complex regulation means involved in the immunological pathogenesis of NAFLD.
Although alcohol feeding produces evident intestinal microbial changes in animals, only some alcoholics show evident intestinal dysbiosis, a decrease in Bacteroidetes and an increase in Proteobacteria. Gut dysbiosis is related to intestinal hyperpermeability and endotoxemia in alcoholic patients. Alcoholics further exhibit reduced numbers of the beneficial Lactobacillus and Bifidobacterium. Large amounts of endotoxins translocated from the gut strongly activate Toll-like receptor 4 in the liver and play an important role in the progression of alcoholic liver disease (ALD), especially in severe alcoholic liver injury. Gut microbiota and bacterial endotoxins are further involved in some of the mechanisms of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). There is experimental evidence that a high-fat diet causes characteristic dysbiosis of NAFLD, with a decrease in Bacteroidetes and increases in Firmicutes and Proteobacteria, and gut dysbiosis itself can induce hepatic steatosis and metabolic syndrome. Clinical data support the above dysbiosis, but the details are variable. Intestinal dysbiosis and endotoxemia greatly affect the cirrhotics in relation to major complications and prognosis. Metagenomic approaches to dysbiosis may be promising for the analysis of deranged host metabolism in NASH and cirrhosis. Management of dysbiosis may become a cornerstone for the future treatment of liver diseases. PMID:27682116
Israelite, Jill C
Pediatric parenteral nutrition-associated liver disease (PNALD) is typically defined as a decrease in bile flow that is independent of a mechanical obstruction and of any other underlying liver disease. It is most often seen in pediatric patients receiving parenteral nutrition support. Up to 50% to 66% of children receiving long-term parenteral nutrition are reported to be diagnosed with PNALD. The goal of treatment for PNALD is advancement to full enteral nutrition and elimination of dependence on parenteral nutrition support. Achieving this goal is not always possible, especially in patients with short bowel syndrome. The following review article highlights some of the current treatment strategies focused on prevention or correction of PNALD as noted in current American Society for Parenteral and Enteral Nutrition guidelines.
Zhang, Fang; Xu, Xiang; Zhang, Yi; Zhou, Ben; He, Zhishui; Zhai, Qiwei
Liver plays a key role in glucose metabolism and homeostasis, and impaired hepatic glucose metabolism contributes to the development of type 2 diabetes. However, the precise gene expression profile of diabetic liver and its association with diabetes and related diseases are yet to be further elucidated. In this study, we detected the gene expression profile by high-throughput sequencing in 9-week-old normal and type 2 diabetic db/db mouse liver. Totally 12132 genes were detected, and 2627 genes were significantly changed in diabetic mouse liver. Biological process analysis showed that the upregulated genes in diabetic mouse liver were mainly enriched in metabolic processes. Surprisingly, the downregulated genes in diabetic mouse liver were mainly enriched in immune-related processes, although all the altered genes were still mainly enriched in metabolic processes. Similarly, KEGG pathway analysis showed that metabolic pathways were the major pathways altered in diabetic mouse liver, and downregulated genes were enriched in immune and cancer pathways. Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased. In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes. Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases. PMID:23469233
Zhang, Fang; Xu, Xiang; Zhang, Yi; Zhou, Ben; He, Zhishui; Zhai, Qiwei
Liver plays a key role in glucose metabolism and homeostasis, and impaired hepatic glucose metabolism contributes to the development of type 2 diabetes. However, the precise gene expression profile of diabetic liver and its association with diabetes and related diseases are yet to be further elucidated. In this study, we detected the gene expression profile by high-throughput sequencing in 9-week-old normal and type 2 diabetic db/db mouse liver. Totally 12132 genes were detected, and 2627 genes were significantly changed in diabetic mouse liver. Biological process analysis showed that the upregulated genes in diabetic mouse liver were mainly enriched in metabolic processes. Surprisingly, the downregulated genes in diabetic mouse liver were mainly enriched in immune-related processes, although all the altered genes were still mainly enriched in metabolic processes. Similarly, KEGG pathway analysis showed that metabolic pathways were the major pathways altered in diabetic mouse liver, and downregulated genes were enriched in immune and cancer pathways. Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased. In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes. Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases.
Berlakovich, Gabriela A
Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist's assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient's pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key
Anand, Gobind; Zarrinpar, Amir; Loomba, Rohit
The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets.
Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A
Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic
Kerr, Thomas A.; Korenblat, Kevin M.; Davidson, Nicholas O.
Post-transcriptional regulation of gene expression is now recognized as an important contributor to disease pathogenesis, among whose mechanisms include alterations in the function of stability and translational elements within both coding and non-coding regions of messenger RNA. A major component in this regulatory paradigm is the binding both to RNA stability and also to translational control elements by microRNAs (miRNAs). miRNAs are non-coding endogenously transcribed RNAs that undergo a well characterized series of processing steps that generate short single stranded (~20–22) RNA fragments that bind to complementary regions within a range of targets and in turn lead to mRNA degradation or attenuated translation as a result of trafficking to processing bodies. This article will highlight selected advances in the role of miRNAs in liver disease including non-alcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma and will briefly discuss the utility of miRNAs as biomarkers of liver injury and neoplasia. PMID:21420035
Arslan, Uğur; Türkoğlu, Sedat; Balcioğlu, Serhat; Tavil, Yusuf; Karakan, Tarkan; Cengel, Atiye
To demonstrate whether there is a relationship between the presence of nonalcoholic fatty liver disease (NAFLD) and the presence and extent of coronary artery disease (CAD). Ninety-two consecutive patients who planned to undergo coronary angiographies (CAG) without known CAD, other than findings of acute coronary syndrome, were enrolled in this study. Abdominal ultrasonography was performed before the CAG to detect NAFLD. CAD was defined as a stenosis of at least 50% in at least one major coronary artery. The extent of CAD was measured according to the number of major coronary artery/arteries affected by CAD. All the risk factors for CAD were included in a binary logistic regression model. Forward, backward, or step-wise selections were not used. P<0.05 was accepted as being significant. Sixty-five of the 92 patients (70.7%) were detected, by abdominal ultrasonography, to have fatty liver and 43 patients out of 92 (46.7%) were detected, by CAG, to have significant CAD. According to the results of logistic regression analysis, the presence of NAFLD independently increased the risk for CAD, as seen in CAG [odds ratio (OR), 95% confidence interval (CI): 6.73 (1.14-39.61); P=0.035]; this was despite factoring in the other risk factors for CAD and the components of metabolic syndrome. NAFLD was more commonly found in patients as the extent of CAD increased (P=0.001). The presence of NAFLD is independently associated with the presence and extent of CAD. Future studies are needed to explain the mechanisms of this relationship.
Clements, Amanda; Greenslade, Lynda
Nurses are seeing more and more patients with liver disease, many of whom are under 65. Most common causes are avoidable and, as liver disease may take up to 30 years to develop, identifying those at risk is key. Patients with liver disease often have a fluctuating course of complications that needs a team approach to care. Improving end-of-life care can also reduce the number of these patients who die in hospital. This article, the first in a two-part series, explores some common complications of liver disease and best practice for nurses treating patients with end-stage liver disease.
The relationship between liver disease and pregnancy is of great clinical impact. Severe liver disease in pregnancy is rare; however, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and represents a severe threat to foetal and maternal survival. A rapid differential diagnosis between liver disease related or unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. This report summarizes the recommendation of an expert panel established by the Italian Association for the Study of the Liver (AISF) on the management of liver disease during pregnancy. The article provides an overview of liver disease occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and an assessment of the available treatment options. The report contains in three sections: (1) specific liver diseases of pregnancy; (2) liver disease occurring during pregnancy; and (3) pregnancy in patients with pre-existing chronic liver disease. Each topic is discussed considering the most relevant data available in literature; the final statements are formulated according to both scientific evidence and clinical expertise of the involved physicians, and the AISF expert panel recommendations are reported.
Rybicka, Malwina; Krysiak, Robert; Okopień, Bogusław
Veno-occlusive disease (VOD) is seen most often in the group of bone marrow transplant recipients. The essence of this disease is the obstruction of the hepatic sinusoidal and centrolobular venous outflow, because of the injury to the endothelium of the liver vessels. It results in congestion of the liver and hepatomegaly. The typical clinical symptoms of VOD are: jaundice, portal hypertension with peripheral oedemas and the weight gain. Depending on the extent of the injury of the hepatic vessels, VOD is divided into three grades: mild, moderate and severe. The clinical markers that inform about the severity of the disease are: the rate of the serum bilirubin growth and the rate of the weight gain growth within the first 2 weeks since the beginning of the disease. Severe VOD is the third of the most often cause of death among people who underwent bone marrow transplantation. The mortality rate is diverse and depends on severity of the disease. The effectiveness of the VOD therapy is limited, so it is worth putting greater pressure on the prophylaxis of VOD or on finding more effective modes of treatment.
Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández-Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan
Disease nonalcoholic fatty liver disease (NAFLD) comprises a series of histologically similar to those induced by alcohol consumption in people with very little or no liver damage same. The importance of NAFLD is its high prevalence in our Western societies, from the point of view liver in its progressive evolution from steatosis to steatohepatitis, cirrhosis and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with accelerated atherosclerosis and cardiovascular events, the leading cause of morbidity and mortality. This updated January 2016 revision consists of two parts. In this second part, the treatment of NAFLD and its influence on cardiovascular disease and drugs used in the control of cardiovascular risk factors showing a beneficial effect on the liver disease will be reviewed. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.
Gao, Bin; Radaeva, Svetlana; Park, Ogyi
Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-γ. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-γ and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed. Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease. PMID:19542050
Kawaguchi, Takumi; Taniguchi, Eitaro; Itou, Minoru; Sakata, Masahiro; Sumie, Shuji; Sata, Michio
Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis. PMID:21731901
Levine, Robert J.; Conn, Harold O.
Plasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis. Tyrosine tolerance tests in patients with cirrhosis were characterized by larger than normal increments in tyrosine levels and by delayed returns toward fasting levels. The results of phenylalanine conversion tests were abnormal in approximately one-half of patients with either hepatitis or biliary obstruction and four-fifths of patients with cirrhosis. Abnormalities were characterized by elevated fasting plasma tyrosine levels, or small and delayed increments in tyrosine levels, or both. Abnormal phenylalanine conversion test results in patients with cirrhosis did not correlate closely with any clinical feature of cirrhosis or with the results of any standard liver function test; there was positive correlation only with abnormal ammonia tolerance, a test of portalsystemic shunting. Tests of tyrosine metabolism do not appear to be useful for routine clinical assessment of liver function. Tyrosine tolerance tests and phenylalanine conversion tests done for purposes of diagnosis of other diseases may yield misleading results in patients with liver disease. PMID:6074004
Jansen, Peter L M; Ghallab, Ahmed; Vartak, Nachiket; Reif, Raymond; Schaap, Frank G; Hampe, Jochen; Hengstler, Jan G
In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and
Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong
Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future.
Mercado, M A; Medina, H; Rossano, A; Acosta, E; Rodríguez, M; Chan, C; Orozco, H
Approximately half of patients with colorectal cancer will develop hepatic metastases and it is estimated that up to 10% of that group will have resectable liver disease. Surgical resection remains the first line treatment option of metastatic liver tumors and has yielded a 20 to 40% five year survival rate. Selection of appropriate patients for resection is critical to a successful outcome. The best results are obtained in patients with isolated metastases. Factors that are associated with a poorer results are the presence of four or more lesions or a surgical margin less than 1 cm. Endocrine metastases can be resected in a palliative fashion but each case has to be individualized. This is also true for non colorectal-nonendocrine metastases. For this tumors the experience is anecdotal and confined to limited reported series. Adjuvant treatment (infusional chemotherapy and chemoembolization) can also have a role in treatment as well as cryotherapy.
Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong
Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425
Levene, Adam P; Goldin, Robert D
Fatty liver disease includes non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), each of which is increasing in prevalence. Each represents a histological spectrum that extends from isolated steatosis to steatohepatitis and cirrhosis. NAFLD is associated with obesity, diabetes, and insulin resistance, and is considered to be the liver manifestation of the metabolic syndrome. The pathogenesis of NAFLD and ALD involves cytokines, adipokines, oxidative stress, and apoptosis. Histopathology is the gold standard for assessing the severity of liver damage in NAFLD and ALD. We have reviewed the literature, and described and compared the epidemiology, natural disease history, pathogenesis and histopathology of NAFLD and ALD. © 2012 Blackwell Publishing Ltd.
Mehta, Aneesh K; Lyon, G Marshall
Patients with chronic liver diseases sustain impairment to immune systems, which worsens over time. These defects in their host defense lead to risks of bacterial infections and increased morbidity. Providers should have heightened surveillance for infectious diseases and suspect one with any acute change in status. Patient history may reveal rare infections and allow initiation of early appropriate therapy. There should be a low threshold for obtaining diagnostic cultures and peritoneal fluid samples and discussing possible causes with an infectious diseases consultant or a microbiology laboratory. These maneuvers will maximize therapy in patients at high risk for death due to infectious disease.
Muratori, Paolo; Fabbri, Angela; Lalanne, Claudine; Lenzi, Marco; Muratori, Luigi
To assess the frequency and clinical impact of associated extrahepatic autoimmune diseases (EAD) on autoimmune liver diseases (ALD). We investigated 608 patients with ALD (327 autoimmune hepatitis - AIH and 281 primary biliary cirrhosis - PBC) for concomitant EAD. In both AIH and PBC, we observed a high prevalence of EAD (29.9 and 42.3%, respectively); both diseases showed a significant association with autoimmune thyroid disease, followed by autoimmune skin disease, celiac disease, and vasculitis in AIH patients and sicca syndrome, CREST syndrome, and celiac disease in PBC patients. At diagnosis, AIH patients with concurrent EAD were more often asymptomatic than patients with isolated AIH (P<0.01). Our study confirms the strict association between ALD and EAD, in particular with autoimmune thyroid disease. In the light of our results, all patients with an EAD should be assessed for the concomitant presence of an asymptomatic ALD.
Pons, Mònica; Simón-Talero, Macarena; Millán, Laura; Ventura-Cots, Meritxell; Santos, Begoña; Augustin, Salvador; Genescà, Joan
Transient elastography has been proposed as a tool to predict the risk of decompensation in patients with chronic liver disease. We aimed to identify risk groups of disease progression, using a combination of baseline liver stiffness measurement (LSM) and its change over time (delta-LSM) in patients with compensated advanced chronic liver disease (cACLD). Ninety-four patients with baseline LSM ≥10kPa, Child-Pugh score 5 and without previous decompensation were included. A second LSM was performed during follow-up and data on liver function and liver-related events were collected. The primary endpoint was a composite that included death, liver decompensation and impairment in at least 1 point in Child-Pugh score. After a median follow-up of 43.6 months, 15% of patients presented the primary endpoint. Multivariate analysis identified baseline LSM (OR 1.12, P=0.002) and delta-LSM (OR 1.02, P=0.048) as independent predictors of the primary endpoint. A high risk group represented by patients with baseline LSM ≥21kPa and delta-LSM ≥10% (risk of progression 47.1%, 95% CI: 23-71%) was identified, while patients with LSM <21kPa and delta-LSM <10% presented zero risk of progression (P=0.03). Simple classification rules using baseline LSM and delta-LSM identify cACLD patients at low or high risk of disease progression. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
The study of the epidemiology of toxic liver injury has been limited in Korea. The number of hospitalizations for toxic liver injury has been estimated to be 2,400 persons per year. About 30~40% of fulminant hepatitis was attributed to toxic hepatitis. The frequent causative agents of toxic hepatitis in Korea are herbal medicines (34-40%), folk remedies (23-34%), and prescribed medicines (24-55%). However, the most common agents causing severe liver injury including fulminant hepatitis are herbal medicine and folk remedies. Antituberculosis drugs and acetaminophen are two common causes of fulminant hepatitis among prescribed drugs. Alcohol is one of the leading causes of chronic liver disease in Korea. No nationwide study on the epidemiology of alcoholic liver disease (ALD) has been carried out, but 7-31% of cirrhosis has been reported to be alcoholic in a few single-center studies. Alcohol could be a risk factor for the development of hepatocellular carcinoma (HCC) in chronic viral hepatitis. Several studies have shown that alcohol increased the risk of HCC in liver cirrhosis with HBsAg or anti-HCV. Furthermore, alcoholic cirrhosis with occult hepatitis B virus infection increased the risk of HCC.
Ahmed, Khulood T; Almashhrawi, Ashraf A; Rahman, Rubayat N; Hammoud, Ghassan M; Ibdah, Jamal A
Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver. Liver disease can cause significant morbidity and mortality in both pregnant women and their infants. This review summarizes liver diseases that are unique to pregnancy. We discuss clinical conditions that are seen only in pregnant women and involve the liver; from Hyperemesis Gravidarum that happens in 1 out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy (0.5%-1.5% prevalence), to the more frequent condition of preeclampsia (10% prevalence) and its severe form; hemolysis, elevated liver enzymes, and a low platelet count syndrome (12% of pregnancies with preeclampsia), to the rare entity of Acute Fatty Liver of Pregnancy (incidence of 1 per 7270 to 13000 deliveries). Although pathogeneses behind the development of these aliments are not fully understood, theories have been proposed. Some propose the special physiological changes that accompany pregnancy as a precipitant. Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions. Reaching a timely and accurate diagnosis of such conditions can be challenging. The timing of the condition in relation toward which trimester it starts at is a key. Accurate diagnosis can be made using specific clinical findings and blood tests. Some entities have well-defined criteria that help not only in making the diagnosis, but also in classifying the disease according to its severity. Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy. In specific conditions, it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes. PMID:24282353
Demirkan, Gokhan; Salomon, Arthur R.; Gruppuso, Philip A.
Summary Regulation of protein function via reversible phosphorylation is an essential component of cell signaling. Our ability to understand complex phosphorylation networks in the physiological context of a whole organism or tissue remains limited. This is largely due to the technical challenge of isolating serine/threonine phosphorylated peptides from a tissue sample. In the present study, we developed a phosphoproteomic strategy to purify and identify phosphopeptides from a tissue sample by employing protein gel filtration, protein SAX (strong anion exchange) and SCX (strong cation exchange) chromatography, peptide SCX chromatography and TiO2 affinity purification. By applying this strategy to the mass spectrometry-based analysis of rat liver homogenates, we were able to identify with high confidence and quantify over four thousand unique phosphopeptides. Finally, the reproducibility of our methodology was demonstrated by its application to analysis of the mammalian Target of Rapamycin (mTOR) signaling pathways in liver samples obtained from rats in which hepatic mTOR was activated by refeeding following a period of fasting. PMID:22903715
Kerr, Thomas A.; Davidson, Nicholas O.
Summary Posttranscriptional regulation of gene expression is increasingly recognized as a model for inherited and acquired disease. Recent work has expanded understanding of the range of mechanisms that regulate several of these distinct steps including mRNA splicing, trafficking, and/or stability. Each of these pathways is implicated in disease pathogenesis and each represent important avenues for therapeutic intervention. This review will summarize important mechanisms controlling mRNA processing and the regulation of mRNA degradation, including the role of miRNAs and RNA binding proteins. These pathways provide important opportunities for therapeutic targeting directed at splicing and degradation in order to attenuate genetic defects in RNA metabolism. We will highlight developments in vector development and validation for therapeutic manipulation of mRNA expression with a focus on potential applications in metabolic and immune-mediated liver disease. PMID:19918970
He, Xi-Xi; Wu, Xiao-Li; Chen, Ren-Pin; Chen, Chao; Liu, Xiao-Gang; Wu, Bin-Jiao; Huang, Zhi-Ming
Background Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome with the main characteristic of diffuse liver cells with fatty changes. The clinical evolution of NAFLD includes simple non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, and even hepatocellular carcinoma. Methods and Findings We conducted this review to identify the effectiveness of omega-3 polyunsaturated fatty acids (ω-3 PUFA) in NAFLD. We searched PubMed, Cochrane Library and Embase. All randomized controlled trials (RCTs) of ω-3 PUFA treatment for NAFLD were considered. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as inverse variance (IV), fixed or random, with 95% confidence intervals (CIs). We included seven RCTs involving 442 patients (227 for the experimental group and 215 for the control group). All the patients were divided into two groups: one treated with ω-3 PUFA and the other was the control group (generally placebo). The demographics of the ω-3 PUFA and control groups were comparable. Beneficial changes in alanine aminotransferase (ALT) (IV 95% CI: −7.61 [−12.83 to −2.39], p = 0.004), total cholesterol (TC) (IV 95% CI: −13.41 [−21.44 to −5.38], p = 0.001), triglyceride (TG) (IV 95% CI: −43.96 [−51.21 to −36.71], p<0.00001) and high-density lipoprotein cholesterol (HDL-C) (IV 95% CI: 6.97 [2.05 to 11.90], p = 0.006) favored ω-3 PUFA treatment. Omega-3 PUFA tended towards a beneficial effect on aspartate aminotransferase (AST) (IV 95% CI: −6.89 [−17.71 to 3.92], p = 0.21), γ-glutamyl transferase (GGT) (IV 95% CI: −8.28 [−18.38 to 1.83], p = 0.11) and low-density lipoprotein cholesterol (LDL-C) (IV 95% CI: −7.13 [−14.26 to 0.0], p = 0.05). Conclusions Supplementation with ω-3 PUFA is a
Zhang, Nan; Lu, Yunxia; Shen, Xinru; Bao, Yingying; Cheng, Jingjing; Chen, Li; Li, Bao; Zhang, Qiu
Fenofibrate is widely used in clinical practice, but its influence on chronic endoplasmic reticulum (ER) stress induced by feeding a high-calorie and high-cholesterol diet (HCD) has still not been studied. We thus investigated its effects on the liver of the nonalcoholic fatty liver disease (NAFLD) mouse model. Male C57BL/6 mice fed an HCD for 3 months were treated with fenofibrate (HCD + FF, 40 mg/kg, once daily) via gavage for 4 weeks. Insulin sensitivity, serum lipid and inflammatory cytokines were measured. Liver tissues were procured for histological examination as well as analysis of hepatic triglyceride levels, distribution of inflammatory cytokines and genes involved in ER stress. Our results showed that chronic feeding of an HCD successfully induced an NAFLD model accompanied by inflammatory activation, apoptosis and severe ER stress in the liver. Fenofibrate administration significantly improved symptoms of NAFLD and decreased apoptosis, expression of inflammatory cytokines and genes involved in ER stress, such as inositol-requiring enzyme 1α (IRE1α), X-box binding protein 1 (XBP1) and JNK phosphorylation. Thus, our study suggests that fenofibrate protected against inflammatory injury and apoptosis, maybe alleviating ER stress through the IRE1α-XBP1-JNK pathway in the liver of NAFLD mice. © 2015 S. Karger AG, Basel
Nassir, Fatiha; Ibdah, Jamal A
Mammalian sirtuins are seven members belonging to the silent information regulator 2 family, a group of Class III histone/protein deacetylases. Sirtuins (SIRT 1-7) have different subcellular localization and function and they regulate cellular protein function through various posttranslational modifications. SIRT1 and 3, the most studied sirtuins, use the product of cellular metabolism nicotinamide adenine dinucleotide as a cofactor to post-translationally deacetylate cellular proteins and consequently link the metabolic status of the cell to protein function. Sirtuins have been shown to play a key role in the development and rescue of various metabolic diseases including non-alcoholic fatty liver disease (NAFLD). NAFLD is currently the most chronic liver disease due mainly to high-calorie consumption and lower physical activity. No pharmacological approach is available to treat NAFLD, the current recommended treatment are lifestyle modification such as weight loss through calorie restriction and exercise. Recent studies have shown downregulation of sirtuins in human as well as animal models of NAFLD indicating an important role of sirtuins in the dynamic pathophysiology of NAFLD. In this review, we highlight the recent knowledge on sirtuins, their role in NAFLD and their unique potential role as novel therapeutic target for NAFLD treatment. PMID:28028356
Zain, Shamsul Mohd; Mohamed, Rosmawati; Cooper, David N.; Razali, Rozaimi; Rampal, Sanjay; Mahadeva, Sanjiv; Chan, Wah-Kheong; Anwar, Arif; Rosli, Nurul Shielawati Mohamed; Mahfudz, Anis Shafina; Cheah, Phaik-Leng; Basu, Roma Choudhury; Mohamed, Zahurin
Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in ‘second hit’ hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH. PMID:24743702
Tziomalos, Konstantinos; Athyros, Vasilios G; Paschos, Paschalis; Karagiannis, Asterios
Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of elevated transaminase levels and affects approximately one third of the general population. Patients with NAFLD are at increased risk for cardiovascular events, which represent the leading cause of death in this population. We discuss the safety and efficacy of statins in this population. We reviewed the most recent literature on the safety of statins in patients with NAFLD and on their effects on liver histology and cardiovascular events. It appears that statins can be safely administered to patients with NAFLD, including those with elevated transaminase levels (<3 times the upper limit of normal). Post-hoc analyses of randomized controlled trials also suggest that statins might reduce cardiovascular morbidity in this population. On the other hand, there are few and controversial data on the effects of statins on liver histology in patients with NAFLD. Statins appear to be safe and might also reduce cardiovascular events in patients with NAFLD. Ongoing and future studies will clarify whether statins might also have a role in the treatment of NAFLD. Copyright © 2015 Elsevier Inc. All rights reserved.
Donaldson, P T
Understanding the genetic basis of "complex disease" has been heralded as one of the major challenges of the post genome era. However what are "complex diseases" and how will understanding the genetics of such diseases advance medical science? There has been a great deal of "hype" about the potential of the human genome mapping project. The three major claims are that this information will: (a) be used in diagnosis; (b) provide useful prognostic indices for disease management (including the development of individualised treatment regimens, based on the findings of both immunogenetic and pharmacogenetic studies); and (c) provide insight into the pathogenesis of these diseases. Of these three objectives the last has the greatest potential and is the least exaggerated claim. In this review I shall highlight major associations, discuss some of the practical issues that arise, and outline how current knowledge of the immunogenetic basis of chronic liver disease is beginning to inform the debate about disease pathogenesis.
Neto, Joao Seda; Carone, Eduardo; Pugliese, Renata P S; Fonseca, Eduardo A; Porta, Gilda; Miura, Irene; Danesi, Vera B; Guimaraes, Teresa C; Godoy, Andre L; Porta, Adriana; Vincenzi, Rodrigo; Carnevale, Francisco; Kondo, Mario; Chapchap, Paulo
The Pediatric End-Stage Liver Disease (PELD) scoring system is a formula developed to provide a continuous numerical assessment of the risk of death in order to allocate livers to children in need of transplantation. The PELD scoring system was introduced in Brazil in July 2006. An important change was made in the system: the final number for listing patients less than 12 years old for transplantation was the calculated PELD score multiplied by 3. The consequences of this allocation policy were analyzed in 2 ways in this research: nationally and in the state of São Paulo (SP State). In the analysis of the national data, a comparison of the pre-PELD era (July 2003 to July 2006) and the post-PELD era (August 2006 to April 2009) showed that the total number of pediatric transplants for children under 12 years of age decreased 7%. Regionally, in SP State, there was a 62% increase in the number of deceased donor liver transplantation procedures for the pediatric population after the introduction of the modified PELD system. There was also a 6.1-fold increase in split liver transplantation as well as a statistically significant decrease in the time on the waiting list (P < 0.001). In conclusion, changing the allocation policy in Brazil in order to benefit pediatric patients on the waiting list had different results according to analyses of national and regional data. A significant increase in deceased donor liver transplantation/split liver transplantation and a shorter time on the waiting list were observed in SP State. The modified PELD scoring system is simple and optimizes the utilization of deceased donor liver grafts in centers performing pediatric transplants. (c) 2010 AASLD
Li, L; Liu, D-W; Yan, H-Y; Wang, Z-Y; Zhao, S-H; Wang, B
The association between obesity and nonalcoholic fatty liver disease (NAFLD) has not been fully quantified, and the magnitude of NAFLD risk associated with obesity is still unclear. A meta-analysis of cohort studies was performed to elucidate the NAFLD risk associated with obesity. Pubmed, Web of Science and Embase were searched for cohort studies assessing NAFLD risk associated with obesity or increased body mass index (BMI). Relative risks (RRs) with 95% confidence intervals (95%CIs) were pooled using random-effects model of meta-analysis. Twenty-one cohort studies including 13 prospective studies and 8 retrospective studies were finally included. There were a total of 381,655 participants in the meta-analysis. Compared with normal weight, obesity independently led to a 3.5-fold increased risk of developing NAFLD (RR = 3.53, 95%CI 2.48 to 5.03, P < 0.001). Meta-analysis also suggested an obvious dose-dependent relationship between BMI and NAFLD risk (per 1-unit increment in BMI: RR = 1.20, 95%CI 1.14 to 1.26, P < 0.001). Subgroup analyses further identified the robustness of the association above. No obvious risk of publication bias was observed. Obese individuals have a 3.5-fold increased risk of developing NAFLD, and there is an obvious dose-dependent relationship between BMI and NAFLD risk. © 2016 World Obesity. © 2016 World Obesity.
Peng, Jennifer L; Patel, Milan Prakash; McGee, Breann; Liang, Tiebing; Chandler, Kristina; Tayarachakul, Sucharat; O'Connor, Sean; Liangpunsakul, Suthat
Excessive alcohol use not only causes alcoholic liver disease (ALD) but also increases the risk of liver-related mortality in patients who already have other chronic liver diseases. Screening for alcohol misuse or alcohol use disorder (AUD) among patients with underlying liver disease is essential. This clinical review covers what is known about ALD, the impact of alcohol in patients with underlying liver diseases, current management of alcohol misuse and AUD, and the management of alcohol misuse and AUD specifically in patients with liver diseases. Several treatment options for alcohol misuse and AUD exist such as psychosocial intervention and behavioral and pharmacological therapies. The strategies used in the treatment of alcohol misuse and AUD are still applicable in those who consume alcohol and have underlying liver disease. However, certain medications still need to be carefully used due to potentially worsening already compromised liver function. Screening of ongoing alcohol use in subjects with liver disease is important, and prompt intervention is needed to prevent the associated morbidity and mortality from the detrimental effects of continued alcohol use on underlying liver disease. Considering alcoholism is a complex disease, probably a multidisciplinary approach combining psychotherapy and comprehensive medical care will be the most effective. Future research could focus on identifying additional treatment options for addressing the psychotherapy component since the self-determination and will to quit drinking alcohol can play such a crucial role in promoting abstinence.
Alt, Yvonne; Grimm, Anna; Schlegel, Liesa; Grambihler, Annette; Kittner, Jens M.; Wiltink, Jörg; Galle, Peter R.; Wörns, Marcus A.; Schattenberg, Jörn M.
Background Patients with chronic liver disease often suffer from unspecific symptoms and report severe impairment in the quality of life. The underlying mechanisms are multifactorial and include disease-specific but also liver related causes. The current analysis evaluated the association of hepatocellular apoptosis in non-viral chronic liver disease and health-related quality of life (HRQL). Furthermore we examined factors, which influence patient's physical and mental well-being. Methods A total of 150 patients with non-infectious chronic liver disease were included between January 2014 and June 2015. The German version of the Chronic Liver Disease Questionnaire (CLDQ-D), a liver disease specific instrument to assess HRQL, was employed. Hepatocellular apoptosis was determined by measuring Cytokeratin 18 (CK18, M30 Apoptosense ELISA). Results Female gender (5.24 vs. 5.54, p = 0.04), diabetes mellitus type II (4.75 vs. 5.46, p<0.001) and daily drug intake (5.24 vs. 6.01, p = 0.003) were associated with a significant impairment in HRQL. HRQL was not significantly different between the examined liver diseases. Levels of CK18 were the highest in patients with NASH compared to all other disease entities (p<0.001). Interestingly, CK18 exhibited significant correlations with obesity (p<0.001) and hyperlipidemia (p<0.001). In patients with cirrhosis levels of CK18 correlated with the MELD score (r = 0.18, p = 0.03) and were significantly higher compared to patients without existing cirrhosis (265.5 U/l vs. 186.9U/l, p = 0.047). Additionally, CK18 showed a significant correlation with the presence and the degree of hepatic fibrosis (p = 0.003) and inflammation (p<0.001) in liver histology. Finally, there was a small negative association between CLDQ and CK18 (r = -0.16, p = 0.048). Conclusion Different parameters are influencing HRQL and CK18 levels in chronic non-viral liver disease and the amount of hepatocellular apoptosis correlates with the impairment in HRQL in
Rajapaksa, Ushani S.; Lawrence, Tessa M.; Peng, Yan-Chun; Liu, Jinghua; Xu, Keyi; Hu, Ke; Qin, Ling; Liu, Ning; Sun, Huanqin; Yan, Hui-Ping; Repapi, Emmanouela; Rowland-Jones, Sarah; Thimme, Robert; McKeating, Jane A.; Dong, Tao
Objective Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) co-infection is recognized as a major cause of morbidity and mortality among HIV-1 infected patients. Our understanding of the impact of HIV infection on HCV specific immune responses and liver disease outcome is limited by the heterogeneous study populations with genetically diverse infecting viruses, varying duration of infection and anti-viral treatment. Methods Viral-specific immune responses in a cohort of 151 HCV mono- and HIV co-infected former plasma donors infected with a narrow source of virus were studied. HCV and HIV specific T cell responses were correlated with clinical data. Results HIV-1 accelerated liver disease progression and decreased HCV specific T cell immunity. The magnitude of HCV specific T cell responses inversely correlated with lower HCV RNA load and reduced liver injury as assessed by non-invasive markers of liver fibrosis. HIV co-infection reduced the frequency of HCV specific CD4+ T cells with no detectable effect on CD8+ T cells or neutralizing antibody levels. Conclusion Our study highlights the impact of HIV co-infection on HCV specific CD4+ T cell responses in a unique cohort of patients for both HCV and HIV and suggests a crucial role for these cells in controlling chronic HCV replication and liver disease progression. PMID:27455208
Lebensztejn, Dariusz M; Wierzbicka, Aldona; Socha, Piotr; Pronicki, Maciej; Skiba, Elżbieta; Werpachowska, Irena; Kaczmarski, Maciej
There is a need to replace liver biopsy with non-invasive markers that predict the degree of liver fibrosis in fatty liver disease related to obesity. Therefore, we studied four potential serum markers of liver fibrosis and compared them with histopathological findings in liver biopsy in children with non-alcoholic fatty liver disease (NAFLD). We determined fasting serum level of hyaluronic acid (HA), laminin, YKL-40 and cytokeratin-18 M30 in 52 children (age range 4-19, mean 12 years, 80 % of them were overweight or obese) with biopsy-verified NAFLD. Viral hepatitis, autoimmune and metabolic liver diseases (Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis) were excluded. Fibrosis stage was assessed in a blinded fashion by one pathologist according to Kleiner. Receiver operating characteristics (ROC) analysis was used to calculate the power of the assays to detect liver fibrosis (AccuROC, Canada). Liver fibrosis was diagnosed in 19 children (37 %). The levels of HA and CK18M30 were significantly higher in children with fibrosis compared to children without fibrosis (p=0.04 and 0.05 respectively). The ability of serum HA (cut-off 19.1 ng/ml, Se=84 %, Sp=55 %, PPV=52 %, NPV=86 %) and CK18M30 (cut-off 210 u/l, Se=79 %, Sp=60 %, PPV=56 %, NPV=82 %) to differentiate children with fibrosis from those without fibrosis was significant (AUC=0.672 and 0.666, respectively). The combination of both markers was superior (AUC=0.73, p=0.002). Laminin and YKL-40 levels did not allow a useful prediction. Cytokeratin-18 and hyaluronic acid are suitable serum markers predicting liver fibrosis in children with NAFLD. Studying these markers may identify patients at risk of disease progression.
Ur Rahman, Zia; Hurairah, Abu
Our objective was to study nonalcoholic fatty liver disease (NAFLD) as a relevant risk factor associated with hepatocellular carcinoma (HCC) in patients with and without cirrhosis. HCC is a common cancer worldwide that predominantly involves patients with hepatic cirrhosis. HCC has recently been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders. This association is alarming due to the high prevalence of NAFLD globally, which may contribute to the rising incidence of HCC. A 31-year-old female with a history of dyslipidemia, hypertension, and diabetes mellitus presented with abdominal pain that persisted for six months. The pain was associated with gastrointestinal symptoms and weight loss. She was drug-free and a nonalcoholic and a nonsmoker. The physical examination was unremarkable. The abdominal exam showed a soft and non-tender abdomen, with no organomegaly or ascites. The laboratory evaluation was unremarkable. The imaging studies showed a hypodense lesion in the right hepatic lobe with strong arterial enhancement. Subsequently, the patient underwent a liver biopsy. The histopathology results were consistent with HCC. The patient underwent an uneventful segment VI liver resection and tumor-free margins were achieved. In our patient, NAFLD was designated as an independent etiology for HCC, without cirrhosis. Our patient recovered well and has been disease free for over a year. HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk of HCC. These results provide new targets for surveillance, prevention, early recognition, and effective treatment of HCC associated with NAFLD. PMID:27733959
Hevia Ojanguren, C; Fanjul Cabeza, B; González Vázquez, M I; Linares Rodríguez, A; Rodrigo Sáez, L
Assessment of immunity was performed in 150 patients with alcoholic liver disease (15 steatosis, 30 hepatitis and 105 cirrhosis: 34 in grade A, 34 in grade B and 37 in grade C, according to Child-Pugh classification). This assessment was based on the total lymphocyte count and a delayed hypersensitivity skin multiple test. Likewise, nutritional status of patients was studied using anthropometric and biochemical parameters (triceps skinfold thickness, arm muscle circumference and serum albumin). The association between alcoholic liver disease, malnutrition and immunity was analyzed. The results show that lymphopenia and disorders in cell-mediate immunity were more common in those patients with cirrhosis, increasing the number of anergic patients while the degree of hepatocellular insufficiency worsens (8.8% in grade A, 11.8% in grade B and 32.4% in grade C). Although there where significantly more alterations of delayed cutaneous hypersensitivity in cirrhotics with malnutrition (hypoergy: 55.2% and anergy: 37.9%) than in those well nourished (hypoergy: 23.7% and anergy: 10.5%, p < 0.01), lymphopenia didn't show differences between these groups. We think that immunity mus'nt be considered a parameter in nutritional assessment.
Lee, Sang Woo; Kim, Sung Hoon; Min, Seon Ok; Kim, Kyung Sik
There are many limitations for conducting liver disease research in human beings due to the high cost and potential ethical issues. For this reason, conducting a study that is difficult to perform in humans using appropriate animal models, can be beneficial in ascertaining the pathological physiology, and in developing new treatment modalities. However, it is difficult to determine the appropriate animal model which is suitable for research purposes, since every patient has different and diverse clinical symptoms, adverse reactions, and complications due to the pathological physiology. Also, it is not easy to reproduce identically various clinical situations in animal models. Recently, the Guide for the Care and Use of Laboratory Animals has tightened up the regulations, and therefore it is advisable to select the appropriate animals and decide upon the appropriate quantities through scientific and systemic considerations before conducting animal testing. Therefore, in this review article the authors examined various white rat animal testing models and determined the appropriate usable rat model, and the pros and cons of its application in liver disease research. The authors believe that this review will be beneficial in selecting proper laboratory animals for research purposes.
Lee, Sang Woo; Kim, Sung Hoon; Min, Seon Ok
There are many limitations for conducting liver disease research in human beings due to the high cost and potential ethical issues. For this reason, conducting a study that is difficult to perform in humans using appropriate animal models, can be beneficial in ascertaining the pathological physiology, and in developing new treatment modalities. However, it is difficult to determine the appropriate animal model which is suitable for research purposes, since every patient has different and diverse clinical symptoms, adverse reactions, and complications due to the pathological physiology. Also, it is not easy to reproduce identically various clinical situations in animal models. Recently, the Guide for the Care and Use of Laboratory Animals has tightened up the regulations, and therefore it is advisable to select the appropriate animals and decide upon the appropriate quantities through scientific and systemic considerations before conducting animal testing. Therefore, in this review article the authors examined various white rat animal testing models and determined the appropriate usable rat model, and the pros and cons of its application in liver disease research. The authors believe that this review will be beneficial in selecting proper laboratory animals for research purposes. PMID:26421020
Efstathiadou, Zoe A; Kita, Marina D; Polyzos, Stergios A
Thyroid hormones are crucial for hepatic lipid and glucose metabolism. Nonalcoholic fatty liver disease (NAFLD), a very common and potentially serious disease of modern society, shares common clinical features with hypothyroidism, such as obesity, insulin resistance and dyslipidemia. Furthermore, in certain studies, increased prevalence of hypothyroidism was observed in patients with NAFLD. However, whether there is a linear relationship between thyroid hormone levels and NAFLD incidence and severity, including values within or in proximity to the reference range remains a contradictory subject in the literature. On the other hand, attempts to treat NAFLD with thyromimetic drugs remain at an early stage. In this review, data derived from observational studies along with evidence on possible treatment with thyroid hormone analogues are presented.
Vere, Cristin Constantin; Streba, Costin Teodor; Streba, Letitia Maria; Ionescu, Alin Gabriel; Sima, Felix
“Psychosocial stress” is an increasingly common concept in the challenging and highly-demanding modern society of today. Organic response to stress implicates two major components of the stress system, namely the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Stress is anamnestically reported by patients during the course of disease, usually accompanied by a decline in their overall health status. As the mechanisms involving glucocorticoids and catecholamines have been deciphered, and their actions on immune cell function deeper understood, it has become clear that stress has an impact on hepatic inflammatory response. An increasing number of articles have approached the link between psychosocial stress and the negative evolution of hepatic diseases. This article reviews a number of studies on both human populations and animal models performed in recent years, all linking stress, mainly of psychosocial nature, and the evolution of three important liver-related pathological entities: viral hepatitis, cirrhosis and hepatocellular carcinoma. PMID:19554650
Wang, Jun; Guo, Xufeng; Wu, Pengbo; Song, Jia; Ye, Chuncui; Yu, Shijie; Zhang, Jixiang; Dong, Weiguo
Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and non-alcoholic fatty liver disease (NAFLD), but the results remain inconsistent. In this study, a meta-analysis was performed to assess the association of PPAR-γ Pro12Ala polymorphism with NAFLD risk. A total of 8 case-control studies, including 1697 cases and 2427 controls, were selected. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the Pro12Ala polymorphism was associated with the susceptibility to NAFLD. Besides, stratified analysis with ethnicity also indicated that no significant association between PPAR-γ Pro12Ala and the risk of NAFLD under all for genetic model in both Asian and Caucasian populations was observed. This meta-analysis indicated that the Pro12Ala polymorphism is not associated with NAFLD risk. Large and well-designed studies are warranted to validate our findings. © 2013.
Prince, M; Hudson, M
Since liver transplantation was first performed in 1968 by Starzl et al, advances in case selection, liver surgery, anaesthetics, and immunotherapy have significantly increased the indications for and success of this operation. Liver transplantation is now a standard therapy for many end stage liver disorders as well as acute liver failure. However, while demand for cadaveric organ grafts has increased, in recent years the supply of organs has fallen. This review addresses current controversies resulting from this mismatch. In particular, methods for increasing graft availability and difficulties arising from transplantation in the context of alcohol related cirrhosis, primary liver tumours, and hepatitis C are reviewed. Together these three indications accounted for 42% of liver transplants performed for chronic liver disease in the UK in 2000. Ethical frameworks for making decisions on patients' suitability for liver transplantation have been developed in both the USA and the UK and these are also reviewed. PMID:11884694
Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.
Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz
We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.
Telles-Correia, Diogo; Barbosa, António; Cortez-Pinto, Helena; Campos, Carlos; Rocha, Nuno B F; Machado, Sérgio
The liver is the organ by which the majority of substances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first-pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity. PMID:28217372
Saithanyamurthi, Hemamala; Faust, Alison Jazwinski
Drug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from mild elevation of liver enzymes on routine blood work to acute liver failure and death. Approximately 10% of all patients with DILI develop acute liver failure resulting in death or liver transplantation. DILI may be prolonged with persistence of elevated liver enzymes for longer than 6 months in approximately 5% to 20% of cases. Cirrhosis and long-term liver-related morbidity and mortality have also been described but are rare, occurring in 1% to 3% of cases.
Chaturvedi, Kanupriya; Vohra, Pankaj
A cross sectional study was conducted in 100 children, aged 5 to 12 years, to find the prevalence of non-alcoholic fatty liver diseases (NAFLD), at New Delhi. Those with fatty liver on ultrasonography with no apparent etiology, were labeled as NAFLD. Three (3%) children had evidence of fatty liver on ultrasonography.
Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco; Miraglia del Giudice, Emanuele; Nobili, Valerio
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD.CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02).Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.
Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis. Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD. CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage. We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02). Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage. PMID:22927922
Limongi, Vivian; Dos Santos, Daniele Costa; de Oliveira da Silva, Aurea Maria; Boin, Ilka de Fátima Santana Ferreira; Stucchi, Raquel Silveira Bello
AIM: To increase inspiratory muscle strength and improve the quality of life of candidates for liver transplantation. METHODS: Twenty-three candidates for liver transplantation participated in the control group and 14 made up the intervention group. The control group consisted of 18 men and 5 women, body mass index (BMI) 27.3 ± 4.5 kg/m2 and Model for End-Stage Liver Disease (MELD) 18.2 ± 6.1. The intervention group consisted of 11 men and 3 women, BMI 28.6 ± 5.4 kg/m2 and MELD 18 ± 4.5. The presence or absence of ascites was identified in the first patient evaluation and after three months. We evaluated maximal inspiratory pressure (MIP) and maximal expiratory pressure, spirometry, root mean square (RMS) of diaphragm and rectus abdominis, and the quality of life. The exercises were performed daily by patients at home for three months and were supervised at distance monthly. The manual consisted of diaphragmatic breathing exercises, diaphragmatic isometric exercise, Threshold IMT®, lifting upper limbs with a bat and strengthening the abdomen. RESULTS: There was significant difference (P = 0.01) between the first (initial) and the third month (final) MIP in the control group and in the intervention group, but there was no difference (P = 0.45) between the groups. The RMS of the diaphragm was lower (P = 0.001) and the functional capacity was higher (P = 0.006) in the intervention group compared to the control. The general health and mental health domains received higher scores after three months in the control group (P = 0.01) and the intervention group (P = 0.004), but there was no significant difference between them. The comparison between the presence of initial ascites with the presence of ascites was performed after three months in the control group (P = 0.083) and intervention group (P = 0.31). There was no significant difference, in relation to the presence of ascites after three months between groups (P = 0.21). In the intervention group, patients with
Limongi, Vivian; Dos Santos, Daniele Costa; de Oliveira da Silva, Aurea Maria; Boin, Ilka de Fátima Santana Ferreira; Stucchi, Raquel Silveira Bello
To increase inspiratory muscle strength and improve the quality of life of candidates for liver transplantation. Twenty-three candidates for liver transplantation participated in the control group and 14 made up the intervention group. The control group consisted of 18 men and 5 women, body mass index (BMI) 27.3 ± 4.5 kg/m(2) and Model for End-Stage Liver Disease (MELD) 18.2 ± 6.1. The intervention group consisted of 11 men and 3 women, BMI 28.6 ± 5.4 kg/m(2) and MELD 18 ± 4.5. The presence or absence of ascites was identified in the first patient evaluation and after three months. We evaluated maximal inspiratory pressure (MIP) and maximal expiratory pressure, spirometry, root mean square (RMS) of diaphragm and rectus abdominis, and the quality of life. The exercises were performed daily by patients at home for three months and were supervised at distance monthly. The manual consisted of diaphragmatic breathing exercises, diaphragmatic isometric exercise, Threshold IMT(®), lifting upper limbs with a bat and strengthening the abdomen. There was significant difference (P = 0.01) between the first (initial) and the third month (final) MIP in the control group and in the intervention group, but there was no difference (P = 0.45) between the groups. The RMS of the diaphragm was lower (P = 0.001) and the functional capacity was higher (P = 0.006) in the intervention group compared to the control. The general health and mental health domains received higher scores after three months in the control group (P = 0.01) and the intervention group (P = 0.004), but there was no significant difference between them. The comparison between the presence of initial ascites with the presence of ascites was performed after three months in the control group (P = 0.083) and intervention group (P = 0.31). There was no significant difference, in relation to the presence of ascites after three months between groups (P = 0.21). In the intervention group, patients with ascites at the end
Li, Sha; Tan, Hor-Yue; Wang, Ning; Zhang, Zhang-Jin; Lao, Lixing; Wong, Chi-Woon; Feng, Yibin
A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.
Zhang, Jiao-Jiao; Meng, Xiao; Li, Ya; Zhou, Yue; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin
Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action. PMID:28333073
Li, Sha; Tan, Hor-Yue; Wang, Ning; Zhang, Zhang-Jin; Lao, Lixing; Wong, Chi-Woon; Feng, Yibin
A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed. PMID:26540040
Kholodenko, Irina V; Yarygin, Konstantin N
The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.
Yarygin, Konstantin N.
The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable. PMID:28210629
In Taiwan, as well as in the other countries around the world, liver disease has reigned over the list of leading causes of mortality, and its resistance to early detection renders the disease even more threatening. It is therefore crucial to develop an auxiliary system for diagnosing liver disease so as to enhance the efficiency of medical diagnosis and to expedite the delivery of proper medical treatment. The study accordingly integrated the case-based reasoning (CBR) model into several common classification methods of data mining techniques, including back-propagation neural network (BPN), classification and regression tree, logistic regression, and discriminatory analysis, in an attempt to develop a more efficient model for early diagnosis of liver disease and to enhance classification accuracy. To minimize possible bias, this study used a ten-fold cross-validation to select a best model for more precise diagnosis results and to reduce problems caused by false diagnosis. Through a comparison of five single models, BPN and CBR emerged to be the top two methods in terms of overall performance. For enhancing diagnosis performance, CBR was integrated with other methods, and the results indicated that the accuracy and sensitivity of each CBR-added hybrid model were higher than those of each single model. Of all the CBR-added hybrid models, the BPN-CBR method took the lead in terms of diagnosis capacity with an accuracy rate of 95%, a sensitivity of 98%, and a specificity of 94%. After comparing the five single and hybrid models, the study found BPN-CBR the best model capable of helping physicians to determine the existence of liver disease, achieve an accurate diagnosis, diminish the possibility of a false diagnosis being given to sick people, and avoid the delay of clinical treatment. Copyright © 2011 Elsevier B.V. All rights reserved.
Bartlett, Jaclyn R.; Friedman, Kenneth J.; Ling, Simon C.; Pace, Rhonda G.; Bell, Scott C.; Bourke, Billy; Castaldo, Giuseppe; Castellani, Carlo; Cipolli, Marco; Colombo, Carla; Colombo, John L.; Debray, Dominique; Fernandez, Adriana; Lacaille, Florence; Macek, Milan; Rowland, Marion; Salvatore, Francesco; Taylor, Christopher J.; Wainwright, Claire; Wilschanski, Michael; Zemková, Dana; Hannah, William B.; Phillips, M. James; Corey, Mary; Zielenski, Julian; Dorfman, Ruslan; Wang, Yunfei; Zou, Fei; Silverman, Lawrence M.; Drumm, Mitchell L.; Wright, Fred A.; Lange, Ethan M.; Durie, Peter R.; Knowles, Michael R.
Context A subset (~3–5%) of patients with cystic fibrosis (CF) develops severe liver disease (CFLD) with portal hypertension. Objective To assess whether any of 9 polymorphisms in 5 candidate genes (SERPINA1, ACE, GSTP1, MBL2, and TGFB1) are associated with severe liver disease in CF patients. Design, Setting, and Participants A 2-stage design was used in this case–control study. CFLD subjects were enrolled from 63 U.S., 32 Canadian, and 18 CF centers outside of North America, with the University of North Carolina at Chapel Hill (UNC) as the coordinating site. In the initial study, we studied 124 CFLD patients (enrolled 1/1999–12/2004) and 843 CF controls (patients without CFLD) by genotyping 9 polymorphisms in 5 genes previously implicated as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 CFLD patients (enrolled 1/2005–2/2007) and 1088 CF controls. Main Outcome Measures We compared differences in distribution of genotypes in CF patients with severe liver disease versus CF patients without CFLD. Results The initial study showed CFLD to be associated with the SERPINA1 (also known as α1-antiprotease and α1-antitrypsin) Z allele (P value=3.3×10−6; odds ratio (OR) 4.72, 95% confidence interval (CI) 2.31–9.61), and with transforming growth factor β-1 (TGFB1) codon 10 CC genotype (P=2.8×10−3; OR 1.53, CI 1.16–2.03). In the replication study, CFLD was associated with the SERPINA1 Z allele (P=1.4×10−3; OR 3.42, CI 1.54–7.59), but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (P=1.5×10−8; OR 5.04, CI 2.88–8.83). Conclusion The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater odds (OR ~5) to develop severe liver disease with portal hypertension. PMID:19738092
Lee, Eaum Seok; Kim, Seok Hyun; Kim, Hyun Jin; Kim, Kyung Hee; Lee, Byung Seok; Ku, Bon Jeong
Background/Aims Growth differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β superfamily. GDF-15 is emerging as a biomarker for several diseases. The aim of this study was to determine the clinical performances of GDF-15 for the prediction of liver fibrosis and severity in chronic liver disease. Methods The serum GDF-15 levels were examined via enzyme immunoassay in 145 patients with chronic liver disease and 101 healthy individuals. The patients with chronic liver disease consisted of 54 patients with chronic hepatitis, 44 patients with compensated liver cirrhosis, and 47 patients with decompensated liver cirrhosis. Results Of the patients with chronic liver diseases, the decompensated liver cirrhosis patients had an increased serum GDF-15 (3,483 ng/L) level compared with the patients with compensated liver cirrhosis (1,861 ng/L) and chronic hepatitis (1,232 ng/L). The overall diagnostic accuracies of GDF-15, as determined by the area under the receiver operating characteristic curves, were as follows: chronic hepatitis=0.656 (>574 ng/L, sensitivity, 53.7%; specificity, 79.2%), compensated liver cirrhosis=0.886 (>760 ng/L, sensitivity, 75.6%; specificity, 92.1%), and decompensated liver cirrhosis=0.984 (>869 ng/L, sensitivity, 97.9%; specificity, 94.1%). Conclusions This investigation represents the first study to demonstrate the availability of GDF-15 in chronic liver disease. GDF-15 comprised a useful biomarker for the prediction of liver fibrosis and severity in chronic liver disease. PMID:27728964
Vidal, F; Perez, J; Morancho, J; Pinto, B; Richart, C
Alcohol dehydrogenase activity was measured in samples of liver tissue from a group of alcoholic and non-alcoholic subjects to determine whether decreased liver alcohol dehydrogenase activity is a consequence of ethanol consumption or liver damage. The alcoholic patients were classified further into the following groups: control subjects with no liver disease (group 1), subjects with non-cirrhotic liver disease (group 2), and subjects with cirrhotic liver disease (group 3). The non-alcoholic subjects were also divided, using the same criteria, into groups 4, 5, and 6, respectively. The analysis of the results showed no significant differences when mean alcohol dehydrogenase activities of alcoholic and non-alcoholic patients with similar degrees of liver pathology were compared (groups 1 v 4, 2 v 5, and 3 v 6. Alcohol dehydrogenase activity was, however, severely reduced in patients with liver disease compared with control subjects. Our findings suggest that alcohol consumption does not modify hepatic alcohol dehydrogenase activity. The reduction in specific alcohol dehydrogenase activity in alcoholic liver disease is a consequence of liver damage. PMID:2379876
Singh, Bhagirath; Qin, Nan; Reid, Gregor
Extensive analysis of the complexity and diversity of microbiota using metagenomics in the gut and other body sites has provided evidence that dysbiosis occurs in many disease states. With the application of next generation sequencing technology this research is starting to uncover the impact of microbiota on metabolic, physiological and immunological pathways and elucidate the cellular and molecular mechanisms involved. To highlight these advances we have focused on autoimmunity and gut and liver related diseases and discuss the opportunities and challenges of translating microbiome research towards its application in humans. Towards this goal we discuss the application of fecal microbiome transplantation (FMT) for the treatment of multiple chronic gut associated inflammatory diseases such as Clostridium difficile infection (CDI) and inflammatory bowel disease (IBD). The potential role of human migration across continents and cultures leading to alteration in their microbiome and its implication in health and disease is also discussed.
Simonelli, Maria Chiara; Giannitelli, Sara Maria; Businaro, Luca; Trombetta, Marcella; Rainer, Alberto
Background and Aim Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to cirrhosis, eventually leading to hepatocellular carcinoma (HCC). HCC ranks as the third highest cause of cancer-related death globally, requiring an early diagnosis of NAFLD as a potential risk factor. However, the molecular mechanisms underlying NAFLD are still under investigation. So far, many in vitro studies on NAFLD have been hampered by the limitations of 2D culture systems, in which cells rapidly lose tissue-specific functions. The present liver-on-a-chip approach aims at filling the gap between conventional in vitro models, often scarcely predictive of in vivo conditions, and animal models, potentially biased by their xenogeneic nature. Methods HepG2 cells were cultured into a microfluidically perfused device under free fatty acid (FFA) supplementation, namely palmitic and oleic acid, for 24h and 48h. The device mimicked the endothelial-parenchymal interface of a liver sinusoid, allowing the diffusion of nutrients and removal of waste products similar to the hepatic microvasculature. Assessment of intracellular lipid accumulation, cell viability/cytotoxicity and oxidative stress due to the FFA overload, was performed by high-content analysis methodologies using fluorescence-based functional probes. Results The chip enables gradual and lower intracellular lipid accumulation, higher hepatic cell viability and minimal oxidative stress in microfluidic dynamic vs. 2D static cultures, thus mimicking the chronic condition of steatosis observed in vivo more closely. Conclusions Overall, the liver-on-a-chip system provides a suitable culture microenvironment, representing a more reliable model compared to 2D cultures for investigating NAFLD pathogenesis. Hence, our system is amongst the first in vitro models of human NAFLD developed within a microfluidic device in a sinusoid
Marqués, E; Jiménez, C; Manrique, A; Vallejo, G H; Clemares, M; Ortega, P; Moreno, E
Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%-15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P = .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 +/- 8.13 years vs 48.8 +/- 13.9; P = .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.
Gustot, Thierry; Fernandez, Javier; Szabo, Gyongyi; Albillos, Agustin; Louvet, Alexandre; Jalan, Rajiv; Moreau, Richard; Moreno, Christophe
Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Zhi-Feng, Wu; Le-Yuan, Zhou; Xiao-Hui, Zhou; Ya-Bo, Gao; Jian-Ying, Zhang; Yong, Hu; Zhao-Chong, Zeng
Liver tissue interstitial fluid (TIF) a special microenvironment around liver cells, which may play a vital role in cell communication during liver injury. Moreover, toll-like receptor 4 (TLR4) is an important trigger of the immune response that may also play a role in liver injuries, including radiation-induced liver disease (RILD). Therefore, the purpose of this study was to identify the roles of the TLR4-dependent immune response and TIFs in RILD after radiation therapy (RT) for liver cancer. This study consisted of two phases, and in the primary phase, the livers of TLR4 mutant (TLR4(-)) and normal (TLR4(+)) mice were irradiated with 30 Gy. TIF was then obtained from mouse livers and assessed by cytokine array analysis 20 days after irradiation, and cytokines in the TIFs, TLR4 and RILD were analyzed. In the second or validation phase, hepatocytes were isolated from TLR4(+) or TLR4(-) mice irradiated with 8 Gy and were co-cultured with TIFs from mouse livers, apoptosis of the hepatocytes was then measured using flow cytometry. We found that severe RILD was accompanied by higher expression of granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor receptor 2(VEGFR-2) in liver TIFs, from in TLR4(+) mice compared with TLR4(-) mice (P < 0.05). In both TLR4(+) and TLR4(-) hepatocytes, apoptosis after irradiaton was increased significantly after co-culture in TIFs from TLR4(+) mice that had their livers irradiated, compared with TIFs from TLR4(-) mice that had their livers irradiated or TIFs from unirradiated mice (P < 0.05). In summary, these findings indicate that the TLR4-dependent immune response may promote RILD by enhancing the expression of GM-CSF, VEGFR-2 and TRAIL in liver TIFs.
Malnutrition is the most frequent and nearly universal consequence in alcoholic liver disease (ALD) that adversely affects clinical outcomes. Sarcopenia or skeletal muscle loss is the major component of malnutrition in liver disease. There are no effective therapies to prevent or reverse sarcopenia in ALD because the mechanisms are not well understood. Consequences of liver disease including hyperammonemia, hormonal perturbations, endotoxemia and cytokine abnormalities as well as the direct effects of alcohol and its metabolites contribute to sarcopenia in ALD. This article focuses on the prevalence, methods to quantify malnutrition, specifically sarcopenia and potential therapies including novel molecular targeted treatments. Copyright © 2016 Elsevier Inc. All rights reserved.
Kim, Hyun-Jin; Lee, Hae-Kag; Cho, Jae-Hwan; Yang, Han-Jun
[Purpose] The purpose of this study was to carry out a comparitive analysis of hepatic fibrosis results of the liver hardness of patients with chronic liver disease as measured by elastography (TE), shear wave elastography (SWE), and liver biopsy. [Subjects and Methods] This study was a retrospective analysis of 304 patients who underwent SWE and TE before and after liver biopsy, taken from among patients who had been checked for liver fibrosis by liver biopsy between August 2013 and August 2014. We used receiver operating characteristic (ROC) curve to prove the diagnostic significance of liver stiffness, and then analyzed the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SWE and TE, as well as the kappa index through cross-analysis of SWE, TE, and liver biopsy. [Results] For liver hardness, the sensitivity of SWE was 84.39%, the specificity of SWE was 97.92%, the accuracy of SWE was 87.33%, the positive predictive value of SWE was 99.32%, and the negative predictive value of SWE was 63.51%. The sensitivity of TE was 94.80%, the specificity of TE was 77.08%, the accuracy of TE was 90.95%, the positive predictive value of TE was 93.97%, and the negative predictive value of TE was 80.43%. [Conclusion] It is our opinion that SWE and TE are non-invasive methods that are more effective than the invasive methods used for diagnosing liver hardness. Invasive methods cover only a section of liver tissue, and are more likely to cause side effects during biopsy.
Costiniuk, Cecilia T.; Brunet, Laurence; Rollet-Kurhajec, Kathleen C.; Cooper, Curtis L.; Walmsley, Sharon L.; Gill, M. John; Martel-Laferriere, Valérie; Klein, Marina B.
Background. Tobacco smoking has been shown to be an independent risk factor for liver fibrosis in hepatitis C virus (HCV) infection in some cross-sectional studies. No longitudinal study has confirmed this relationship, and the effect of tobacco exposure on liver fibrosis in human immunodeficiency virus (HIV)-HCV coinfected individuals is unknown. Methods. The study population consisted of participants from the Canadian Co-infection Cohort study (CTN 222), a multicenter longitudinal study of HIV-HCV coinfected individuals from 2003 to 2014. Data were analyzed for all participants who did not have significant fibrosis or end-stage liver disease (ESLD) at baseline. The association between time-updated tobacco exposure (ever vs nonsmokers and pack-years) and progression to significant liver fibrosis (defined as an aspartate-to-platelet ratio index [APRI] ≥1.5) or ESLD was assessed by pooled logistic regression. Results. Of 1072 participants included in the study, 978 (91%) had ever smoked, 817 (76%) were current smokers, and 161 (15%) were previous smokers. Tobacco exposure was not associated with accelerated progression to significant liver fibrosis nor with ESLD when comparing ever vs never smokers (odds ratio [OR] = 1.06, 95% confidence interval [CI], 0.43–1.69 and OR = 1.20, 95% CI, 0.21–2.18, respectively) or increases in pack-years smoked (OR = 1.05, 95% CI, 0.97–1.14 and OR = 0.94, 95% CI, 0.83–1.05, respectively). Both time-updated alcohol use in the previous 6 months and presence of detectable HCV ribonucleic acid were associated with APRI score ≥1.5. Conclusions. Tobacco exposure does not appear to be associated with accelerated progression of liver disease in this prospective study of HIV-HCV coinfected individuals. PMID:27047987
Krähenbühl, S; Reichen, J
Carnitine metabolism was studied in 79 patients with chronic liver disease, including 22 patients with noncirrhotic liver disease and 57 patients with different types of cirrhosis (22 patients with hepatitis B- or C-associated cirrhosis, 15 patients with alcohol-induced cirrhosis, 15 patients with primary biliary cirrhosis [PBC], and 5 patients with cryptogenic cirrhosis), and compared with 28 control subjects. In comparison with control subjects, patients with noncirrhotic liver disease showed no change in the plasma carnitine pool, whereas patients with cirrhosis had a 29% increase in the long-chain acylcarnitine concentration. Analysis of subgroups of patients with cirrhosis showed that patients with alcohol-induced cirrhosis had an increase in the total plasma carnitine concentration (67.8 +/- 29.5 vs. 55.2 +/- 9.9 micromol/L in control subjects), resulting from increases in both the short-chain and long-chain acylcarnitine concentration. In this group of patients, the acylcarnitine concentrations showed a close correlation with the total carnitine concentration, and the total carnitine concentration with the serum bilirubin concentration. Urinary excretion of carnitine was not different between patients with noncirrhotic or cirrhotic liver disease and control patients. However, patients with PBC showed an increased urinary excretion of total carnitine (52.5 +/- 40.0 vs. 28.0 +/- 16.7 micromol carnitine/mmol creatinine), resulting from an increase in the fractional excretion of both free carnitine and short-chain acylcarnitine. The current studies show that patients with cirrhosis are normally not carnitine deficient. Patients with alcohol-induced cirrhosis have increased plasma carnitine concentrations, which may result from increased carnitine biosynthesis because of increased skeletal muscle protein turnover. The increase in the fractional carnitine excretion in patients with primary biliary cirrhosis may result from competition of bile acids and
Wilkins, Benjamin J.; Pack, Michael
The liver performs a large number of essential synthetic and regulatory functions that are acquired during fetal development and persist throughout life. Their disruption underlies a diverse group of heritable and acquired diseases that affect both pediatric and adult patients. Although experimental analyses used to study liver development and disease are typically performed in cell culture models or rodents, the zebrafish is increasingly used to complement discoveries made in these systems. Forward and reverse genetic analyses over the past two decades have shown that the molecular program for liver development is largely conserved between zebrafish and mammals, and that the zebrafish can be used to model heritable human liver disorders. Recent work has demonstrated that zebrafish can also be used to study the mechanistic basis of acquired liver diseases. Here, we provide a comprehensive summary of how the zebrafish has contributed to our understanding of human liver development and disease. PMID:23897685
Lo, Robert S.; Austin, Andrew S.; Freeman, Jan G.
Intestinal microbiota plays an important role in health and disease. Alteration in its healthy homeostasis may result in the development of numerous liver disorders including complications of liver cirrhosis. On the other hand, restoration and modulation of intestinal flora through the use of probiotics is potentially an emerging therapeutic strategy. There is mounting evidence that probiotics are effective in the treatment of covert and overt hepatic encephalopathy, as well as in the prevention of recurrence of encephalopathy. The beneficial effect of probiotics also extends to liver function in cirrhosis, nonalcoholic fatty liver disease, and alcoholic liver disease. On the other hand, data associating probiotics and portal hypertension is scanty and conflicting. Probiotic therapy has also not been shown to prevent primary or secondary spontaneous bacterial peritonitis. Larger clinical studies are required before probiotics can be recommended as a treatment modality in liver diseases. PMID:25436233
Jarido, Veronica; Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer; Thomson, Joanne; Stephenson, Kristen; Francis, Heather
The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.
Day, Christopher R; Kempson, Stephen A
Betaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs. The remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease. A significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices. The accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease. Copyright © 2016 Elsevier B.V. All rights reserved.
Sebastiani, Giada; Ghali, Peter; Wong, Philip; Klein, Marina B; Deschenes, Marc; Myers, Robert P
OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases. METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey. RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune/cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians’ characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians’ main concerns regarding noninvasive fibrosis assessment methods were access/availability (42.3%), lack of guidelines for clinical use (26.9%) and cost/lack of reimbursement (14.4%). CONCLUSIONS: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better
Li, C J; Nanji, A A; Siakotos, A N; Lin, R C
Liver proteins form adducts with acetaldehyde and are modified by products of lipid peroxidation in alcohol-fed animals. It has been hypothesized that the formation of these modified liver proteins may contribute to liver injury in alcoholic liver disease. The present work was performed to determine the extent of protein modification in rats with experimental alcoholic liver disease. Rats were fed ethanol intragastrically with medium chain triglycerides (MCTs), palm oil, corn oil, or fish oil. The group fed MCTs and ethanol showed no liver injury, rats fed palm oil and ethanol showed only fatty liver, rats fed corn oil and ethanol showed fatty liver with moderate necrosis and inflammation, and rats fed fish oil and ethanol showed fatty liver with severe necrosis and inflammation. Antibodies were raised by using keyhole limpet hemocyanin modified in vitro by 4-hydroxynonenal (4-HNE) or acetaldehyde as immunogens. When liver extracts were examined by Western blot analysis, the intensities of the acetaldehyde-modified protein band (37 kd) in the alcohol-fed animals were significantly different among the ethanol-treated groups and correlated with plasma acetaldehyde concentrations. It was strongest in rats fed fish oil and ethanol, followed by rats fed palm oil and ethanol and rats fed corn oil and ethanol, whereas rats fed MCTs and ethanol showed the weakest intensity. The 37-kd protein-adetaldehyde adduct was located mainly in the pericentral region of the liver. No acetaldehyde adduct was detected in the control rats that were pair-fed with isocaloric amounts of dextrose. Western blot analysis using the anti-4-HNE antibody showed four distinctive bands (48, 45, 40, and 38 kd) in the liver extracts of alcohol-fed rats. Control animals showed only a weak 38-kd band. Although the intensities of the 48-, 40-, and 38-kd bands were similar among the different ethanol-treated groups, the intensity of the 45-kd band decreased from MCTs and ethanol > palm oil and ethanol
Ravindran, J; Jayadev, R; Lachmanan, S R; Merican, I
Liver disease is an important and serious condition in pregnancy. The Confidential Enquiries Into Maternal Deaths in Malaysia showed that there were 23 maternal deaths attributed to liver disease between 1991-1994. Over the same period, there were 1066 reported maternal deaths with 929 of them being due to direct and indirect causes. Thus 2.15% of such deaths were due to liver disease in Malaysia. The three main causes of maternal deaths due to liver disease in pregnancy were hepatitis (6 cases), acute fatty liver in pregnancy (6 cases) and septicaemia (4 cases). Liver disease is common at a mean of thirty weeks of gestation with a preponderance to women of low parity. Only two patients in this series had no antenatal care. The majority of cases (45.8%) presented between 28-37 weeks of gestation. All cases delivered by spontaneous vaginal delivery. Remediable factors that were identified included failure to appreciate the severity of disease. Case summaries of all the cases of maternal deaths due to liver disease are discussed and a guideline to management of liver disease in pregnancy presented.
Fernández-Iglesias, Anabel; Gracia-Sancho, Jordi
Liver microcirculation plays an essential role in the progression and aggravation of chronic liver disease. Hepatic sinusoid environment, mainly composed by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, intimately cooperate to maintain global liver function and specific phenotype of each cell type. However, continuous liver injury significantly deregulates liver cells protective phenotype, leading to parenchymal and non-parenchymal dysfunction. Recent data have enlightened the molecular processes that mediate hepatic microcirculatory injury, and consequently, opened the possibility to develop new therapeutic strategies to ameliorate liver circulation and viability. The present review summarizes the main cellular components of the hepatic sinusoid, to afterward focus on non-parenchymal cells phenotype deregulation due to chronic injury, in the specific clinical context of liver cirrhosis and derived portal hypertension. Finally, we herein detail new therapies developed at the bench-side with high potential to be translated to the bedside. PMID:28239607
Cesaro, Claudia; Tiso, Angelo; Del Prete, Anna; Cariello, Rita; Tuccillo, Concetta; Cotticelli, Gaetano; Del Vecchio Blanco, Camillo; Loguercio, Carmelina
There is a strong relationship between liver and gut: the portal system receives blood from the gut, and intestinal blood content activates liver functions. The liver, in turn, affects intestinal functions through bile secretion into the intestinal lumen. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of complications of liver cirrhosis, such as infections, hepatic encephalopathy, spontaneous bacterial peritonitis, and renal failure. Probiotics have been suggested as a useful integrative treatment of different types of chronic liver damage, for their ability to augment intestinal barrier function and prevent bacterial translocation. This review summarizes the main literature findings about the relationships between gut microbiota and chronic liver disease, both in the pathogenesis and in the treatment by probiotics of the liver damage.
Fagiuoli, Stefano; Daina, Erica; D'Antiga, Lorenzo; Colledan, Michele; Remuzzi, Giuseppe
While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management
Wang, Xing-He; Li, Chun-Yan; Muhammad, Ishfaq; Zhang, Xiu-Ying
In this study, we investigated the correlation between the serum fatty acid composition and hepatic steatosis, inflammation, hepatocellular ballooning scores, and liver fatty acids composition in mice fed a high-fat diet. Livers were collected for non-alcoholic fatty liver disease score analysis. Fatty acid compositions were analysed by gas chromatography. Correlations were determined by Pearson correlation coefficient. Exposed to a high-fat diet, mice developed fatty liver disease with varying severity without fibrosis. The serum fatty acid variation became more severe with prolonged exposure to a high-fat diet. This variation also correlated significantly with the variation in livers, with the types of fatty acids corresponding to liver steatosis, inflammation, and hepatocellular ballooning scores. Results of this study lead to the following hypothesis: the extent of serum fatty acid variation may be a preliminary biomarker of fatty liver disease caused by high-fat intake.
Li, B; Wang, Q X; Ma, X
Autoimmune liver diseases are a group of abnormal autoimmune-mediated inflammatory hepatobiliary injuries, mainly including autoimmune hepatitis(AIH), primary biliary cholangitis(PBC), and primary sclerosing cholangitis (PSC). The diagnosis and treatment of autoimmune liver diseases, an important type of non-viral liver disease, have become a prominent issue in hepatology. In 2016, many new advances have been achieved in the clinical and basic research on autoimmune liver diseases, including the phase 3 clinical trial of obeticholic acid, the proposal of UK-PBC risk score, and the research on gut microbiota associated with PSC. This article reviews the research advances in the diagnosis and treatment of autoimmune liver diseases in 2016.
Price, Jennifer C.; Thio, Chloe L.
Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART-era liver disease is now the most common non-AIDS related cause of death among HIV-infected patients, accounting for 14-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART-era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART-era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases. PMID:20851211
Grønkjær, Lea Ladegaard
Studies suggest that periodontal disease, a source of subclinical and persistent infection, may be associated with various systemic conditions, including liver cirrhosis. The aim of this study was to examine the literature and determine the relationship between periodontal disease and liver cirrhosis and to identify opportunities and directions for future research in this area. A systematic review of English articles in the PubMed, EMBASE, and Scopus databases was conducted using search terms including 'liver cirrhosis', 'end-stage liver disease', 'liver diseases', 'oral health', 'periodontal disease', 'mouth disease', 'gingivitis', and 'periodontitis'. Thirteen studies published between 1981 and 2014 were found to include data on oral health and periodontal disease in cirrhotic patients. Studies indicated an increased incidence of periodontal disease in patients with liver cirrhosis, measured with several different periodontal indices. The reported prevalence of periodontal disease in cirrhosis patients ranged from 25.0% to 68.75% in four studies and apical periodontitis was found in 49%-79% of the patients. One study found that mortality was lower among patients who underwent dental treatment versus non-treated patients. Another study suggested an association between periodontal disease and the progression of liver cirrhosis, but data are sparse and conflicting as to whether periodontal disease is correlated to cirrhosis aetiology and severity. Despite the clinical reality of periodontal disease in liver cirrhosis patients, there are few published studies. Before clinical implications can be addressed, more data on the prevalence of and correlation between periodontal disease and liver cirrhosis aetiology, duration, and progression are needed.
Tokushige, Katsutoshi; Hyogo, Hideyuki; Nakajima, Tomoaki; Ono, Masafumi; Kawaguchi, Takumi; Honda, Koichi; Eguchi, Yuichiro; Nozaki, Yuichi; Kawanaka, Miwa; Tanaka, Saiyu; Imajo, Kento; Sumida, Yoshio; Kamada, Yoshihiro; Fujii, Hideki; Suzuki, Yasuaki; Kogiso, Tomomi; Karino, Yoshiyasu; Munekage, Kensuke; Kuromatsu, Ryoko; Oeda, Satoshi; Yanase, Mikio; Mori, Kohjiro; Ogawa, Yuji; Seko, Yuya; Takehara, Tetsuo; Itoh, Yoshito; Nakajima, Atsushi; Kanemasa, Kazuyuki; Nishino, Ken; Masaki, Naohiko; Takahashi, Hirokazu; Seike, Masataka; Torimura, Takuji; Saibara, Toshiji; Toyota, Joji; Chayama, Kazuaki; Hashimoto, Etsuko
In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.
Lu, Fake; Zheng, Wei; Tai, Dean C. S.; Lin, Jian; Yu, Hanry; Huang, Zhiwei
Liver fibrosis is the excessive accumulation of extracellular matrix proteins such as collagens, which may result in cirrhosis, liver failure, and portal hypertension. In this study, we apply a multimodal nonlinear optical microscopy platform developed to investigate the fibrotic liver diseases in rat models established by performing bile duct ligation (BDL) surgery. The three nonlinear microscopy imaging modalities are implemented on the same sectioned tissues of diseased model sequentially: i.e., second harmonic generation (SHG) imaging quantifies the contents of the collagens, the two-photon excitation fluorescence (TPEF) imaging reveals the morphology of hepatic cells, while coherent anti-Stokes Raman scattering (CARS) imaging maps the distributions of fats or lipids quantitatively across the tissue. Our imaging results show that during the development of liver fibrosis (collagens) in BDL model, fatty liver disease also occurs. The aggregated concentrations of collagen and fat constituents in liver fibrosis model show a certain correlationship between each other.
Lisman, Ton; Bernal, William
Liver diseases may be accompanied by profound changes in the hemostatic system including thrombocytopenia, decreased plasma levels of pro- and anticoagulants, and alterations in plasma levels of fibrinolysis. The net effect of the hemostatic changes in chronic and acute liver diseases is a hemostatic system that is in relative balance due to the simultaneous decline in pro- and antihemostatic drivers. A unique category of liver diseases are those induced by pregnancy. In acute fatty liver of pregnancy, profound hemostatic changes occur, which may be caused by a combination of liver failure and disseminated intravascular coagulation. Hemostatic changes in preeclampsia and HELLP syndrome are dominated by thrombocytopenia, although alterations in plasmatic coagulation may also occur. Post-partum bleeds, bleeding from cesarean section wounds, and hepatobiliary bleeds may occur in both patient groups. Patients with intrahepatic cholestasis of pregnancy do not show clinically relevant hemostatic alterations, despite biochemical evidence of liver injury.
Kim, Jong Won; Park, Surim; Lim, Chae Woong; Lee, Kyuhong; Kim, Bumseok
Recent episodes of severe air pollution in eastern Asia have been reported in the scientific literature and news media. Therefore, there is growing concern about the systemic effects of air pollution on human health. Along with the other well-known harmful effects of air pollution, recently, several animal models have provided strong evidence that air pollutants can induce liver toxicity and act to accelerate liver inflammation and steatosis. This review briefly describes examples where exposure to air pollutants was involved in liver toxicity, focusing on how particulate matter (PM) or carbon black (CB) may be translocated from lung to liver and what liver diseases are closely associated with these air pollutants.
Björklund, Jessica; Laursen, Tea Lund; Kazankov, Konstantin; Thomsen, Karen Louise; Hamilton-Dutoit, Stephen; Stenbøg, Elisabeth; Grønbæk, Henning
Non-alcoholic fatty liver disease (NAFLD) is characterized by liver fat accumulation and non-alcoholic steatohepatitis (NASH) with inflammation and fibrosis, which may lead to cirrhosis also in childhood. NAFLD/NASH in children are related to obesity and the metabolic syndrome, and incidence and prevalence are expected to increase. Children having liver steatosis and elevated liver enzymes are most often asymptomatic, and a liver biopsy is necessary for correct diagnosis and staging. The treatment should focus on lifestyle changes, as pharmacological therapy needs further evaluation.
Mofrad, Farshid Babapour; Zoroofi, Reza Aghaeizadeh; Tehrani-Fard, Ali Abbaspour; Akhlaghpoor, Shahram; Sato, Yoshinobu
Liver-shape analysis and quantification is still an open research subject. Quantitative assessment of the liver is of clinical importance in various procedures such as diagnosis, treatment planning, and monitoring. Liver-shape classification is of clinical importance for corresponding intra-subject and inter-subject studies. In this research, we propose a novel technique for the liver-shape classification based on Spherical Harmonics (SH) coefficients. The proposed liver-shape classification algorithm consists of the following steps: (a) Preprocessing, including mesh generation and simplification, point-set matching, and surface to template alignment; (b) Liver-shape parameterization, including surface normalization, SH expansion followed by parameter space registration; (c) Feature selection and classification, including frequency based feature selection, feature space reduction by Principal Component Analysis (PCA), and classification. The above multi-step approach is novel in the sense that registration and feature selection for liver-shape classification is proposed and implemented and validated for the normal and diseases liver in the SH domain. Various groups of SH features after applying conventional PCA and/or ordered by p-value PCA are employed in two classifiers including Support Vector Machine (SVM) and k-Nearest Neighbor (k-NN) in the presence of 101 liver data sets. Results show that the proposed specific features combined with classifiers outperform existing liver-shape classification techniques that employ liver surface information in the spatial domain. In the available data sets, the proposed method can successful classify normal and diseased livers with a correct classification rate of above 90 %. The performed result in average is higher than conventional liver-shape classification method. Several standard metrics such as Leave-one-out cross-validation and Receiver Operating Characteristic (ROC) analysis are employed in the experiments and
Lonardo, Amedeo; Ballestri, Stefano; Marchesini, Giulio; Angulo, Paul; Loria, Paola
The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome.
Karlsen, Tom H; Lammert, Frank; Thompson, Richard J
Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Ghent, Cameron N.; Bloomer, Joseph R.
Pruritus in hepatobiliary disease is commonly believed to be caused by retention of bile acids with their sequestration in the skin. HOwever, we have recently demonstrated that skin levels of bile acids in patients with cholestasis correlate poorly with pruritus. In this report, we present additional data concerning the relationship of pruritus to bile acid retention: (1) the urinary excretion of sulfated and nonsulfated bile acids was not significantly different in patients with cholestasis who itched compared to those who did not; (2) one patient with itch associated with a liver abscess had normal levels of bile acids in serum, skin, and urine; (3) patients with primary biliary cirrhosis who itched had lower serum bile acid levels than patients with mechanical biliary obstruction who did not itch. These studies support our premise that pruritus in hepatobiliary diseases is not directly related to bile acid retention. They suggest that the type of cholestatic disorder, and not simply the magnitude of the cholestasis, as estimated by the elevation of serum bile acids, is important. We propose that the agent responsible for pruritus is produced in response to cholestasis, possibly through activation of the alternate pathway of bile acid synthesis. Properties of the hypothetical pruritogen are discussed. PMID:452625
Patel, Yuval A.; Berg, Carl L.
Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts. PMID:26815171
Park, Sang Hoon
Recently, obesity (BMI>or=25 kg/m2) and type II diabetes mellitus have reached epidemic proportions in Korea, and rates of nonalcoholic fatty liver disease (NAFLD) are between 10% and 25% of the general population. NAFLD in Korea is as closely associated with several components of metabolic syndrome including, obesity, hypertension, diabetes and dyslipidemia as it is in Western countries. Insulin resistance and hyperinsulinemia may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity. And, obesity induced accumulation of fat in the adipose tissue leads to an imbalance in the regulation of adipokines, such as downregulation of adiponectin and upregulation of retinol-binding protein 4 (RBP4) and ghrelin. High BMI, the AST/ALT ratio, and ALT levels could be used to distinguish NASH from simple steatosis in Korean patients. In large number of NAFLD patients who underwent a voluntary medical checkup, even a small weight reduction was associated with improvements in their hepatic steatosis grade on ultrasonography, serum aminotransferase levels, and related metabolic abnormalities. Subjects with fatty liver disease should be advised to lose weight through lifestyle modifications. Small animal and human studies of treatment with PPAR agonists and betaine have been reported in the Korean literature. It is now acknowledged that NAFLD is the most common liver disease in Korea, largely due to the considerable increase in metabolic abnormalities such as obesity and diabetes. Future studies should continue to focus both on the pathogenesis and the treatment of NAFLD in order to accumulate more of our own data.
Pavlides, Michael; Banerjee, Rajarshi; Sellwood, Joanne; Kelly, Catherine J.; Robson, Matthew D.; Booth, Jonathan C.; Collier, Jane; Neubauer, Stefan; Barnes, Eleanor
Background & Aims Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. Methods Patients with chronic liver disease (n = 112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27 months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1–1.99, 2–2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. Results Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF <2 was 100%. Two patients with LIF 2–2.99 and eight with LIF ⩾3 had a clinical event. Patients with LIF ⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF <1 (p = 0.02) and LIF 1–1.99 (p = 0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. Conclusions Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease. PMID:26471505
Mendoza, Michael; Caltharp, Shelley; Song, Ming; Collin, Lindsay; Konomi, Juna V; McClain, Craig J; Vos, Miriam B
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.
Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal
Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis.
Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal
Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis. PMID:27128907
Janczyk, Wojciech; Socha, Piotr
Non-alcoholic fatty liver disease is increasingly prevalent in children, together with obesity. Transaminases, tests for insulin resistance, ultrasonography and MRI are variably used as surrogates markers of steatosis. Other liver diseases, such as Wilson disease, should be excluded. A liver biopsy is performed in selected cases: young children, familial history of severe disease, inconclusive tests for other pathologies, suspected advanced fibrosis, hypertransaminasemia despite weight loss and in clinical trials. Weight reduction, and changes in lifestyle, are the front-line treatment. Drug therapy is under evaluation. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Kummer, Sebastian; Klee, Dirk; Kircheis, Gerald; Friedt, Michael; Schaper, Joerg; Häussinger, Dieter; Mayatepek, Ertan; Meissner, Thomas
The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication.
Lyberopoulou, Aggeliki; Chachami, Georgia; Gatselis, Nikolaos K; Kyratzopoulou, Eleni; Saitis, Asterios; Gabeta, Stella; Eliades, Petros; Paraskeva, Efrosini; Zachou, Kalliopi; Koukoulis, George K; Mamalaki, Avgi; Dalekos, George N; Simos, George
Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients' sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.
Ahya, Shubhada N; José Soler, Maria; Levitsky, Josh; Batlle, Daniel
Acid-base and potassium disorders occur frequently in the setting of liver disease. As the liver's metabolic function worsens, particularly in the setting of renal dysfunction, hemodynamic compromise, and hepatic encephalopathy, acid-base disorders ensue. The most common acid-base disorder is respiratory alkalosis. Metabolic acidosis alone or in combination with respiratory alkalosis also is common. Acid-base disorders in patients with liver disease are complex. The urine anion gap may help to distinguish between chronic respiratory alkalosis and hyperchloremic metabolic acidosis when a blood gas is not available. A negative urine anion gap helps to rule out chronic respiratory alkalosis. In this disorder a positive urine anion gap is expected owing to suppressed urinary acidification. Distal renal tubular acidosis occurs in autoimmune liver disease such as primary biliary cirrhosis, but often is a functional defect from impaired distal sodium delivery. Potassium disorders are often the result of the therapies used to treat advanced liver disease.
Zhang, Jie; Lu, Fanggen; Ouyang, Chunhui; Cheng, Zongyong; Wang, Xuehong; Liu, Xiaowei
To understand the value of Child-Pugh (CP) classification and model of end-stage liver disease (MELD) score for patients with cirrhosis and their prognosis by retrospectively analyzing the two methods in hemorrhage death and non-hemorrhage death in patients with liver cirrhosis. A total of 72 patients who died of cirrhosis (the death group) were analyzed retrospectively, and the initial data in the hospital before death were collected. The initial information of the control group (88 patients) at the same time was also obtained. The death group was divided into two subgroups: esophagus varicosity burst massive hemorrhage death group and non-hemorrhage death group. MELD score and CP score of the death group (22.230±13.451, 10.264±2.028) were significantly higher than those of the control group (15.370±6.201, 9.318±1.644; P<0.05). The MELD score and CP score for the massive bleeding death group were close to those of the control group. There was significant difference between the non-hemorrhage death group and the control group. The ratio of patients with CP grade A and MELD scores<20 died for massive bleeding in the death group was more than 70%, and that of CP grade C and MELD scores ≥ 30 in the death group was higher. ROC surve analysis found the accuracy of short-term predication of survival by MELD score and CP classification was improved after eliminating the risk factors of hemorrage. MELD and CP play a role in evaluating the state and prognosis of patients with cirrhosis. MELD score and CP classification predict the short-term survival efficiently on the premise of excluding the risk factors of esophagus and/or stomach bottom varicosity burst massive bleeding. CP and MELD scores are deficiencies, especially for low MELD score (<20) and CP level A patients. The prognostic accuracy may be improved when combining esophageal gastric fundal varices.
Choi, Steve S; Diehl, Anna Mae
Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese
Das, Nupur; Paria, Baishakhi; Sarkar, Sujoy
Introduction: Renal dysfunction is common in chronic liver disease. The cause of this renal dysfunction is either multi-organ involvement in acute conditions or secondary to advanced liver disease. Objectives: The study was undertaken to assess the renal function in chronic liver diseases and find out the association of alteration of renal function with gradation of liver disease. (assessed by child-pugh criteria) and to find out the association of alteration of renal function among the cases of chronic liver disease of different aetiology. Materials and Methods: This cross-sectional, observational study was undertaken in Department of General Medicine, Calcutta National Medical College & Hospital, Kolkata during March 2012 to July 2013 with 50 admitted patients of chronic liver disease after considering the exclusion criteria. The patients were interviewed with a pre-designed and pre-tested schedule, examined clinically, followed by some laboratory investigations relevant to diagnose the aetiology of chronic liver disease, and to assess the severity of liver and renal dysfunction. Data was analysed by standard statistical method. Results: Eighty six percent of the patients were male and the mean age of study population was 43.58 y, 68% patients suffered from alcoholic liver disease, followed by 14% patients had chronic Hepatitis-B, 10% patients developed acute kidney injury, 20% had hepato renal syndrome and 14% had IgA deposition. The distribution of serum urea and creatinine across the categories of Child Pugh classification tested by Mann-Whitney test and the distribution was statistically significant. Conclusion: The present study has found significant association between severity of liver dysfunction and certain parameters of renal dysfunction. PMID:25954647
Kaltenborn, Alexander; Salinas, Ricardo; Jäger, Mark D; Lehner, Frank; Sakirow, Larissa; Klempnauer, Jürgen; Schrem, Harald
BACKGROUND The model of end-stage liver disease (MELD) score is currently used for donor liver allocation in many regions. The objective of this retrospective study was to assess the MELD score and its diverse variants as prognostic models for mortality after liver transplantation. MATERIAL AND METHODS An analysis of 454 consecutive adult liver transplants since the introduction of MELD-based donor liver allocation was conducted. Eight different MELD score variants were investigated. Receiver operating characteristic (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model. The Brier score was used for the prediction of model accuracy and calculated as described before. Study endpoints were 90-day mortality and long-term patient mortality. RESULTS A 90-day mortality of 15.4% (n=69) and long-term mortality of 25% (n=112) were observed. All investigated models fail to reach relevant areas under the ROC curve greater than 0.700 for the prediction of mortality after liver transplantation. All calculated Brier scores were greater than 0.25, indicating a significant lack of model discrimination and calibration of the investigated scores. CONCLUSIONS A prognostic model for the prediction of outcome after transplantation still needs to be identified and should allow weighing urgency against utility in liver transplantation.
Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls
Yin, Wei-Li; Wang, Feng-Mei; Han, Tao
Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935
Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.
Schnabl, Bernd; Brenner, David A.
The human intestine harbors a diverse community of microbes that promote metabolism and digestion in their symbiotic relationship with the host. Disturbance of its homeostasis can result in disease. We review factors that disrupt intestinal homeostasis and contribute to non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), alcoholic liver disease, and cirrhosis. Liver disease has long been associated with qualitative and quantitative (overgrowth) dysbiotic changes in the intestinal microbiota. Extrinsic factors, such as the Western diet and alcohol, contribute to these changes. Dysbiosis results in intestinal inflammation, a breakdown of the intestinal barrier, and translocation of microbial products in animal models. However, the contribution of the intestinal microbiome to liver disease goes beyond simple translocation of bacterial products that promote hepatic injury and inflammation. Microbial metabolites produced in a dysbiotic intestinal environment and host factors are equally important in the pathogenesis of liver disease. We review how the combination of liver insult and disruptions in intestinal homeostasis contribute to liver disease. PMID:24440671
Alempijevic, Tamara; Milutinovic, Aleksandra Sokic; Kovacevic, Nada
Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of AAT phenotypes from Hardy-Weinberg equilibrium (chi-square = 34.77, df 11, P = 0.000) in the patient group was caused by a higher than expected frequency of Pi ZZ homozygotes (f = 0.0143 and f = 0.0005, respectively, P = 0.000). In addition, Pi M homozygotes were more frequent in patients than in controls (63% and 46%, respectively, P = 0.025). Our study results show that Pi ZZ homozygosity in adults could be associated with severe liver disease. Presence of Pi M homozygosity could be associated with liver disease via some mechanism different from Z allele-induced liver damage through accumulation of AAT polymers. PMID:19961268
Lai, Yan-Hua; Duan, Wei-Dong; Yu, Qiang; Ye, Sheng; Xiao, Nian-Jun; Zhang, Dong-Xin; Huang, Zhi-Qiang; Yang, Zhan-Yu; Dong, Jia-Hong
AIM: To evaluate the outcomes of patients with end-stage biliary disease (ESBD) who underwent liver transplantation, to define the concept of ESBD, the criteria for patient selection and the optimal operation for decision-making. METHODS: Between June 2002 and June 2014, 43 patients with ESBD from two Chinese organ transplantation centres were evaluated for liver transplantation. The causes of liver disease were primary biliary cirrhosis (n = 8), cholelithiasis (n = 8), congenital biliary atresia (n = 2), graft-related cholangiopathy (n = 18), Caroli’s disease (n = 2), iatrogenic bile duct injury (n = 2), primary sclerosing cholangitis (n = 1), intrahepatic bile duct paucity (n = 1) and Alagille’s syndrome (n = 1). The patients with ESBD were compared with an end-stage liver disease (ESLD) case control group during the same period, and the potential prognostic values of multiple demographic and clinical variables were assessed. The examined variables included recipient age, sex, pre-transplant clinical status, pre-transplant laboratory values, operation condition and postoperative complications, as well as patient and allograft survival rates. Survival analysis was performed using Kaplan-Meier curves, and the rates were compared using log-rank tests. All variables identified by univariate analysis with P values < 0.100 were subjected to multivariate analysis. A Cox proportional hazard regression model was used to determine the effect of the study variables on outcomes in the study group. RESULTS: Patients in the ESBD group had lower model for end-stage liver disease (MELD)/paediatric end-stage liver disease (PELD) scores and a higher frequency of previous abdominal surgery compared to patients in the ESLD group (19.2 ± 6.6 vs 22.0 ± 6.5, P = 0.023 and 1.8 ± 1.3 vs 0.1 ± 0.2, P = 0.000). Moreover, the operation time and the time spent in intensive care were significantly higher in the ESBD group than in the ESLD group (527.4 ± 98.8 vs 443.0 ± 101.0, P = 0
Yang, Benqiang; Zhang, Libo; Chen, Yenwei
A new method is proposed to establish the statistical fractal model for liver diseases classification. Firstly, the fractal theory is used to construct the high-order tensor, and then Generalized N-dimensional Principal Component Analysis (GND-PCA) is used to establish the statistical fractal model and select the feature from the region of liver; at the same time different features have different weights, and finally, Support Vector Machine Optimized Ant Colony (ACO-SVM) algorithm is used to establish the classifier for the recognition of liver disease. In order to verify the effectiveness of the proposed method, PCA eigenface method and normal SVM method are chosen as the contrast methods. The experimental results show that the proposed method can reconstruct liver volume better and improve the classification accuracy of liver diseases. PMID:24224174
Lin, Qi-Chang; Chen, Li-Da; Chen, Gong-Ping; Zhao, Jian-Ming; Chen, Xiao; Huang, Jie-Feng; Wu, Li-Hua
Obstructive sleep apnea (OSA) is suggested as a potential risk factor of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still far from clear. The aim of this observational study was to investigate the influence of OSA-related hypoxia on severity of liver injury in patients with NAFLD. Consecutive patients with ultrasound-diagnosed NAFLD who underwent standard polysomnography were enrolled. Fasting blood samples were obtained from all patients for biological profile measurements, and demographic data were collected. Subjects were divided into control, moderate, and severe groups. A total of 85 subjects with 73 males and 12 females were included (mean age, 44.67 ± 1.28 years; mean body mass index, 27.28 ± 0.33 kg/m(2)). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, gamma glutamyltransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose, and high-sensitivity C-reactive protein significantly increased with the aggravation of OSA. In multivariate analysis, oxygen desaturation index was the major contributing factor for elevated ALT (β = 0.435, p = 0.000), average O2 saturation was the major independent predictor of elevated AST (β = -0.269, p = 0.020). OSA-related hypoxia was independently associated with the biochemical evidence of liver injury in the presence of NAFLD.
Drasdo, Dirk; Hoehme, Stefan; Hengstler, Jan G
From the more than 100 liver diseases described, many of those with high incidence rates manifest themselves by histopathological changes, such as hepatitis, alcoholic liver disease, fatty liver disease, fibrosis, and, in its later stages, cirrhosis, hepatocellular carcinoma, primary biliary cirrhosis and other disorders. Studies of disease pathogeneses are largely based on integrating -omics data pooled from cells at different locations with spatial information from stained liver structures in animal models. Even though this has led to significant insights, the complexity of interactions as well as the involvement of processes at many different time and length scales constrains the possibility to condense disease processes in illustrations, schemes and tables. The combination of modern imaging modalities with image processing and analysis, and mathematical models opens up a promising new approach towards a quantitative understanding of pathologies and of disease processes. This strategy is discussed for two examples, ammonia metabolism after drug-induced acute liver damage, and the recovery of liver mass as well as architecture during the subsequent regeneration process. This interdisciplinary approach permits integration of biological mechanisms and models of processes contributing to disease progression at various scales into mathematical models. These can be used to perform in silico simulations to promote unravelling the relation between architecture and function as below illustrated for liver regeneration, and bridging from the in vitro situation and animal models to humans. In the near future novel mechanisms will usually not be directly elucidated by modelling. However, models will falsify hypotheses and guide towards the most informative experimental design.
Saab, Sammy; Konyn, Peter G.; Viramontes, Matthew R.; Jimenez, Melissa A.; Grotts, Jonathan F.; Hamidzadah, Wally; Dang, Veronica P.; Esmailzadeh, Negin L.; Choi, Gina; Durazo, Francisco A.; El-Kabany, Mohamed M.; Han, Steven-Huy B.; Tong, Myron J.
Abstract Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease. Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record. Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%–86.8%) did not know that Norco® (hydrocone/acetaminophen), Vicodin® (hydrocone/acetaminophen) and Percocet® (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol® #3 contained acetaminophen. Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management. PMID:28097095
Saab, Sammy; Konyn, Peter G; Viramontes, Matthew R; Jimenez, Melissa A; Grotts, Jonathan F; Hamidzadah, Wally; Dang, Veronica P; Esmailzadeh, Negin L; Choi, Gina; Durazo, Francisco A; El-Kabany, Mohamed M; Han, Steven-Huy B; Tong, Myron J
Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease. Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record. Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%-86.8%) did not know that Norco® (hydrocone/acetaminophen), Vicodin® (hydrocone/acetaminophen) and Percocet® (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol® #3 contained acetaminophen. Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management.
Objectives: Studies suggest that periodontal disease, a source of subclinical and persistent infection, may be associated with various systemic conditions, including liver cirrhosis. The aim of this study was to examine the literature and determine the relationship between periodontal disease and liver cirrhosis and to identify opportunities and directions for future research in this area. Methods: A systematic review of English articles in the PubMed, EMBASE, and Scopus databases was conducted using search terms including ‘liver cirrhosis’, ‘end-stage liver disease’, ‘liver diseases’, ‘oral health’, ‘periodontal disease’, ‘mouth disease’, ‘gingivitis’, and ‘periodontitis’. Results: Thirteen studies published between 1981 and 2014 were found to include data on oral health and periodontal disease in cirrhotic patients. Studies indicated an increased incidence of periodontal disease in patients with liver cirrhosis, measured with several different periodontal indices. The reported prevalence of periodontal disease in cirrhosis patients ranged from 25.0% to 68.75% in four studies and apical periodontitis was found in 49%–79% of the patients. One study found that mortality was lower among patients who underwent dental treatment versus non-treated patients. Another study suggested an association between periodontal disease and the progression of liver cirrhosis, but data are sparse and conflicting as to whether periodontal disease is correlated to cirrhosis aetiology and severity. Conclusion: Despite the clinical reality of periodontal disease in liver cirrhosis patients, there are few published studies. Before clinical implications can be addressed, more data on the prevalence of and correlation between periodontal disease and liver cirrhosis aetiology, duration, and progression are needed. PMID:26770799
Parikh, Neal S; Merkler, Alexander E; Schneider, Yecheskel; Navi, Babak B; Kamel, Hooman
Liver disease is associated with both hemorrhagic and thrombotic processes, including an elevated risk of intracranial hemorrhage. We sought to assess the relationship between liver disease and outcomes after stroke, as measured by discharge disposition. Using administrative claims data, we identified a cohort of patients hospitalized with stroke in California, Florida, and New York from 2005 to 2013. The predictor variable was liver disease. All diagnoses were defined using validated diagnosis codes. Ordinal logistic regression was used to analyze the association between liver disease and worsening discharge disposition: home, nursing/rehabilitation facility, or death. Secondarily, multiple logistic regression was used to analyze the association between liver disease and in-hospital mortality. Models were adjusted for demographics, vascular risk factors, and comorbidities. We identified 121 428 patients with intracerebral hemorrhage and 703 918 with ischemic stroke. Liver disease was documented in 13 584 patients (1.7%). Liver disease was associated with worse discharge disposition after both intracerebral hemorrhage (global odds ratio, 1.28; 95% confidence interval, 1.19-1.38) and ischemic stroke (odds ratio, 1.23; 95% confidence interval, 1.17-1.29). Similarly, liver disease was associated with in-hospital death after both intracerebral hemorrhage (odds ratio, 1.33; 95% confidence interval, 1.23-1.44) and ischemic stroke (odds ratio, 1.60; 95% confidence interval, 1.51-1.71). Liver disease was associated with worse hospital discharge disposition and in-hospital mortality after stroke, suggesting worse functional outcomes. © 2016 American Heart Association, Inc.
Goessling, Wolfram; Sadler, Kirsten C.
As the incidence of hepatobiliary diseases increases, we must improve our understanding of the molecular, cellular, and physiological factors that contribute to the pathogenesis of liver disease. Animal models help us identify disease mechanisms that might be targeted therapeutically. Zebrafish (Danio rerio) have traditionally been used to study embryonic development but are also important to the study of liver disease. Zebrafish embryos develop rapidly; all of their digestive organs are mature in larvae by 5 days of age. At this stage, they can develop hepatobiliary diseases caused by developmental defects or toxin- or ethanol-induced injury and manifest premalignant changes within weeks. Zebrafish are similar to humans in hepatic cellular composition, function, signaling, and response to injury as well as the cellular processes that mediate liver diseases. Genes are highly conserved between humans and zebrafish, making them a useful system to study the basic mechanisms of liver disease. We can perform genetic screens to identify novel genes involved in specific disease processes and chemical screens to identify pathways and compounds that act on specific processes. We review how studies of zebrafish have advanced our understanding of inherited and acquired liver diseases as well as liver cancer and regeneration. PMID:26319012
Goessling, Wolfram; Sadler, Kirsten C
As the incidence of hepatobiliary diseases increases, we must improve our understanding of the molecular, cellular, and physiological factors that contribute to the pathogenesis of liver disease. Animal models help us identify disease mechanisms that might be targeted therapeutically. Zebrafish (Danio rerio) have traditionally been used to study embryonic development but are also important to the study of liver disease. Zebrafish embryos develop rapidly; all of their digestive organs are mature in larvae by 5 days of age. At this stage, they can develop hepatobiliary diseases caused by developmental defects or toxin- or ethanol-induced injury and manifest premalignant changes within weeks. Zebrafish are similar to humans in hepatic cellular composition, function, signaling, and response to injury as well as the cellular processes that mediate liver diseases. Genes are highly conserved between humans and zebrafish, making them a useful system to study the basic mechanisms of liver disease. We can perform genetic screens to identify novel genes involved in specific disease processes and chemical screens to identify pathways and compounds that act on specific processes. We review how studies of zebrafish have advanced our understanding of inherited and acquired liver diseases as well as liver cancer and regeneration.
Liu, Haixia; Fu, Jing; Hong, Ruixia; Liu, Li; Li, Fang
Background In order to better monitor non-alcoholic fatty liver disease (NAFLD) patients at higher risk for HCC, there is a need for non-invasive diagnostic approaches to screen for the presence of advanced fibrosis in these patients. The aim of this systematic review and meta-analysis will be to evaluate the diagnostic efficacy of ARFI elastography in detecting hepatic fibrosis in NAFLD patients. Methods Relevant studies were identified from systematic searches of several major electronic databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials). The primary outcomes were the summary sensitivity, summary specificity, the diagnostic odds ratio, and the summary receiver operating characteristic curve (SROC) of ARFI elastography in detecting significant fibrosis (defined as 4>F≥2) in NAFLD patients. Study quality was assessed using the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Review (QUADAS-2). Results The summary sensitivity and specificity of ARFI in detecting significant fibrosis were 80.2% (95% confidence interval (CI): 0.758–0.842; p = 0.0000) and 85.2% (95% CI: 0.808–0.890), p = 0.1617), respectively. The pooled diagnostic odds ratio of ARFI in detecting significant fibrosis was 30.13 (95% CI: 12.08–75; chi-squared = 14.59, p = 0.0237). The area under the SROC curve (AUC) was 0.898 (standard error (SE): 0.031) with a Q* index of 0.830 (SE: 0.033). Conclusions ARFI elastography appears to be modestly accurate in detecting significant fibrosis in NAFLD patients. Future studies in this field should provide head-to-head comparisons of ARFI elastography versus other elastographic imaging modalities in NAFLD patients. PMID:26131717
Chiu, S; Sievenpiper, J L; de Souza, R J; Cozma, A I; Mirrahimi, A; Carleton, A J; Ha, V; Di Buono, M; Jenkins, A L; Leiter, L A; Wolever, T M S; Don-Wauchope, A C; Beyene, J; Kendall, C W C; Jenkins, D J A
Background/Objectives: In the absence of consistent clinical evidence, there are concerns that fructose contributes to non-alcoholic fatty liver disease (NAFLD). To determine the effect of fructose on markers of NAFLD, we conducted a systematic review and meta-analysis of controlled feeding trials. Subjects/Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library (through 3 September 2013). We included relevant trials that involved a follow-up of ⩾7 days. Two reviewers independently extracted relevant data. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean difference (SMD) for intrahepatocellular lipids (IHCL) and mean difference (MD) for alanine aminotransferase (ALT). Inter-study heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Results: Eligibility criteria were met by eight reports containing 13 trials in 260 healthy participants: seven isocaloric trials, in which fructose was exchanged isocalorically for other carbohydrates, and six hypercaloric trials, in which the diet was supplemented with excess energy (+21–35% energy) from high-dose fructose (+104–220 g/day). Although there was no effect of fructose in isocaloric trials, fructose in hypercaloric trials increased both IHCL (SMD=0.45 (95% confidence interval (CI): 0.18, 0.72)) and ALT (MD=4.94 U/l (95% CI: 0.03, 9.85)). Limitations: Few trials were available for inclusion, most of which were small, short (⩽4 weeks), and of poor quality. Conclusions: Isocaloric exchange of fructose for other carbohydrates does not induce NAFLD changes in healthy participants. Fructose providing excess energy at extreme doses, however, does raise IHCL and ALT, an effect that may be more attributable to excess energy than fructose. Larger, longer and higher-quality trials of the effect of fructose on histopathological NAFLD changes are required. PMID:24569542
Sammouda, Mohamed; Sammouda, Rachid; Niki, Noboru; Mukai, Kiyoshi
Liver cancer is one of the leading cancerous diseases that can disappoint a physician before reaching the final diagnosis. Thus far, all cancer diagnoses should and usually do have tissue diagnose. A physician gets a little piece of tissue from the abnormal area and a pathologist determines if it is cancer or not. Therefore, the biopsy is the definitive test for liver cancer. In this paper, we present an unsupervised approach using Hopfield Neural Network (HNN) to segment color images of liver tissues prepared by standard staining method. The segmentation problem is formulated as the minimization of an energy function synonymous to that of HNN for optimization. We modify the HNN to reach a status close to the global minimum in a prespecified time of convergence. Furthermore, the nuclei and their corresponding cytoplasm regions are automatically extracted based on the features of color image histogram. The nuclei and cytoplasm regions are then used to formulate the diagnostic rules. In the analysis, we show a tables of the ratio of (nuclei/cytoplasm) image areas inside different subwindow sizes of the image. Each liver color image is represented in the RGB, HSV and HLS color spaces to investigate the effect of color system choice on the results. The automation of the extraction process in the liver pathological image can be easily implemented in the clinic in order to provide more accurate quantitative information that can help for a better liver cancer diagnosis.
LaRusso, Nicholas F; Tabibian, James H; O'Hara, Steven P
Hepatobiliary health and disease is influenced by multiple factors including genetics, epigenetics, and the environment. Recently, multiple lines of evidence suggest that the microbiome also plays a central role in the initiation and/or progression of several liver diseases. Our current understanding of the dynamic interplay between microbes, microbial products and liver health and pathophysiology is incomplete. However, exciting insights are continually being made that support both a central role of the microbiome and a need for further interrogation of the microbes or microbe-associated molecules involved in the initiation and progression of select liver diseases.
Sherman, Kenneth E.; Thomas, David L.; Chung, Raymond T.
Liver disease continues to represent a critical mediator of morbidity and mortality in those with human immunodeficiency virus (HIV) infection. The frequent presence and overlap of concomitant injurious processes, including hepatitis C virus and hepatitis B virus infections, hepatoxicity associated with antiretroviral therapeutic agents, alcohol, and other toxins, in the setting of immunosuppression lead to rapid fibrotic progression and early development of end-stage liver disease. This conference summary describes the proceedings of a state-of-the-art gathering of international experts designed to highlight the status of current research in epidemiology, natural history, pathogenesis, and treatment of HIV and liver disease. PMID:21898501
Pár, Alajos; Pár, Gabriella
In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease.
Cotrim, Helma P; Parise, Edison R; Figueiredo-Mendes, Cláudio; Galizzi-Filho, João; Porta, Gilda; Oliveira, Claudia P
The prevalence of obesity-related metabolic syndrome has rapidly increased in Brazil, resulting in a high frequency of nonalcoholic fatty liver disease, that didn't receive much attention in the past. However, it has received increased attention since this disease was identified to progress to end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma. Clinical practice guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease have not been established in Brazil. The Brazilian Society of Hepatology held an event with specialists' members from all over Brazil with the purpose of producing guideline for Nonalcoholic Fatty Liver Disease based on a systematic approach that reflects evidence-based medicine and expert opinions. The guideline discussed the following subjects: 1-Concepts and recommendations; 2-Diagnosis; 3-Non-medical treatment; 4-Medical treatment; 5-Pediatrics - Diagnosis; 6-Pediatrics - Non-medical treatment; 7-Pediatrics - Medical tre