Viral eradication reduces both liver stiffness and steatosis in patients with chronic hepatitis C virus infection who received direct-acting anti-viral therapy.

PubMed

Tada, T; Kumada, T; Toyoda, H; Sone, Y; Takeshima, K; Ogawa, S; Goto, T; Wakahata, A; Nakashima, M; Nakamuta, M; Tanaka, J

2018-04-01

Whether direct-acting anti-viral therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection is unclear. To evaluate changes in liver stiffness and steatosis in patients with HCV who received direct-acting anti-viral therapy and achieved sustained virological response (SVR). A total of 198 patients infected with HCV genotype 1 or 2 who achieved SVR after direct-acting anti-viral therapy were analysed. Liver stiffness as evaluated by magnetic resonance elastography, steatosis as evaluated by magnetic resonance imaging-determined proton density fat fraction (PDFF), insulin resistance, and laboratory data were assessed before treatment (baseline) and at 24 weeks after the end of treatment (SVR24). Alanine aminotransferase and homeostatic model assessment-insulin resistance levels decreased significantly from baseline to SVR24. Conversely, platelet count, which is inversely associated with liver fibrosis, increased significantly from baseline to SVR24. In patients with high triglyceride levels (≥150 mg/dL), triglyceride levels significantly decreased from baseline to SVR24 (P = 0.004). The median (interquartile range) liver stiffness values at baseline and SVR24 were 3.10 (2.70-4.18) kPa and 2.80 (2.40-3.77) kPa respectively (P < 0.001). The PDFF values at baseline and SVR 24 were 2.4 (1.7-3.4)% and 1.9 (1.3-2.8)% respectively (P < 0.001). In addition, 68% (19/28) of patients with fatty liver at baseline (PDFF ≥5.2%; n = 28) no longer had fatty liver (PDFF <5.2%) at SVR24. Viral eradication reduces both liver stiffness and steatosis in patients with chronic HCV who received direct-acting anti-viral therapy (UMIN000017020). © 2018 John Wiley & Sons Ltd.

Changes in liver stiffness and steatosis among patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

PubMed

Kobayashi, Natsuko; Iijima, Hiroko; Tada, Toshifumi; Kumada, Takashi; Yoshida, Masahiro; Aoki, Tomoko; Nishimura, Takashi; Nakano, Chikage; Takata, Ryo; Yoh, Kazunori; Ishii, Akio; Takashima, Tomoyuki; Sakai, Yoshiyuki; Aizawa, Nobuhiro; Nishikawa, Hiroki; Ikeda, Naoto; Iwata, Yoshinori; Enomoto, Hirayuki; Hirota, Seiichi; Fujimoto, Jiro; Nishiguchi, Shuhei

2018-05-01

Whether direct-acting antiviral (DAA) therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection remains unclear. We evaluated sequential changes in liver stiffness and steatosis using transient elastography (TE) and the TE-based controlled attenuation parameter (CAP) in patients with HCV who received DAA therapy. A total of 57 patients with HCV who received DAA therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness as evaluated with TE, steatosis as evaluated with CAP, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), 24 weeks after EOT (SVR24), and 48 weeks after EOT (SVR48). Alanine aminotransferase levels, corresponding to the presence of necroinflammatory activity, significantly decreased overall, with significant differences between baseline and EOT, EOT, and SVR24, and baseline and SVR48. However, alanine aminotransferase levels showed no significant changes between SVR24 and SVR48. Median (interquartile range) liver stiffness values at baseline, EOT, SVR24, and SVR48 were 8.3 (5.0-14.8), 7.4 (4.6-14.7), 5.3 (4.1-11.8), and 5.4 (4.0-13.4) kPa, respectively (baseline vs. EOT, P=0.044; EOT vs. SVR24, P=0.011; and SVR24 vs. SVR48, P=0.054). In patients with fatty liver (CAP≥236 dB/m, n=14), CAP values at baseline and SVR48 were 253 (245-278) and 229 (209-249) dB/m, respectively (P=0.020). Liver stiffness at SVR24 might reflect liver fibrosis in the patients who received DAA therapy and achieved SVR. In addition, liver steatosis reduces in the same cohort with fatty liver.

Effect of probiotics and synbiotics consumption on serum concentrations of liver function test enzymes: a systematic review and meta-analysis.

PubMed

Khalesi, Saman; Johnson, David Wayne; Campbell, Katrin; Williams, Susan; Fenning, Andrew; Saluja, Sonia; Irwin, Christopher

2017-11-08

The gut-liver interaction suggests that modification of gut bacterial flora using probiotics and synbiotics may improve liver function. This systematic review and meta-analysis aimed to clarify the effect of probiotics and synbiotics consumption on the serum concentration of liver function enzymes. PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library (Central) were searched from 1980 to August 2017 for studies where adults consumed probiotics and/or synbiotics in controlled trials and changes in liver function enzymes were examined. A total of 17 studies (19 trials) were included in the meta-analysis. Random effects meta-analyses were applied. Probiotics and synbiotics significantly reduced serum alanine aminotransferase [- 8.05 IU/L, 95% confidence interval (CI) - 13.07 to - 3.04; p = 0.002]; aspartate aminotransferase (- 7.79 IU/L, 95% CI: - 13.93 to - 1.65; p = 0.02) and gamma-glutamyl transpeptidase (- 8.40 IU/L, 95% CI - 12.61 to - 4.20; p < 0.001). Changes in the serum concentration of alkaline phosphatase and albumin did not reach a statistically significant level. Changes to bilirubin levels were in favour of the control group (0.95 μmol/L, 95% CI 0.48-1.42; p < 0.001). Subgroup analysis suggested the existence of liver disease at baseline, synbiotics supplementation and duration of supplementation ≥ 8 weeks resulted in more pronounced improvement in liver function enzymes than their counterparts. Probiotics and synbiotics may be suggested as supplements to improve serum concentration of liver enzymes, especially when synbiotics administered for a period ≥ 8 weeks and in individuals with liver disease.

Effect of cod liver oil supplementation on the stearoyl-CoA desaturase index in obese children: a pilot study.

PubMed

Fujita, Yukihiko; Okada, Tomoo; Abe, Yuriko; Kazama, Minako; Saito, Emiko; Kuromori, Yuki; Iwata, Fujihiko; Hara, Mitsuhiko; Ayusawa, Mamoru; Izumi, Hiroyuki; Kitamura, Yohei; Shimizu, Takashi

2015-01-01

To investigate the effects of n-3 polyunsaturated fatty acids on stearoyl-CoA desaturase (SCD) activity, we treated 10 obese children (mean age: 12.9 years) with cod liver oil once daily for 12 weeks. The effects of cod liver oil supplementation on SCD activity, as estimated by the palmitoleate/palmitate ratio, depended on the docosahexaenoic acid (DHA) contents at baseline. Baseline DHA contents were negatively correlated with baseline SCD activity. After the treatment, baseline DHA contents were found to be significantly associated with the reduction of SCD activity. Cod liver oil supplementation may be a complementary treatment for obese children with low baseline contents of DHA. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

PubMed

Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Mizuno, Kazuyuki; Sone, Yasuhiro; Kataoka, Saki; Hashinokuchi, Shinichi

2017-12-01

There is insufficient research on whether direct-acting antiviral (DAA) therapy can improve liver fibrosis in patients with chronic hepatitis C virus (HCV). We evaluated sequential changes in liver stiffness using shear wave elastography in patients with HCV who received DAA therapy. A total of 210 patients with HCV who received daclatasvir and asunaprevir therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness, as evaluated by shear wave elastography, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), and at 24 weeks after EOT (SVR24). Alanine aminotransferase levels (ALT) decreased over time, and there were significant differences between baseline and EOT and between EOT and SVR24. Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to SVR24. The median (interquartile range) liver stiffness values at baseline, EOT, and SVR24 were 10.2 (7.7-14.7), 8.8 (7.1-12.1), and 7.6 (6.3-10.3) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). Additionally, in patients with ALT ≤ 30 (indicating low necroinflammatory activity in the liver) and Fibrosis-4 index > 2.0 (n = 75), the liver stiffness values at baseline, EOT, and SVR24 were 9.6 (7.7-15.2), 9.2 (7.3-12.1), and 7.7 (6.3-10.1) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). These results suggest that early improvement of liver stiffness starts during the administration of DAAs in patients who achieve SVR, and this effect is particularly pronounced in patients with progressive liver fibrosis. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment.

PubMed

Chan, Justin; Gogela, Neliswa; Zheng, Hui; Lammert, Sara; Ajayi, Tokunbo; Fricker, Zachary; Kim, Arthur Y; Robbins, Gregory K; Chung, Raymond T

2018-02-01

Liver fibrosis stage determines risk of morbidity and mortality from chronic hepatitis C virus (HCV) infection. Prior data have shown long-term reversal of liver fibrosis, measured by vibration-controlled transient elastography (VCTE), in patients successfully treated with interferon-based therapies. Our study sought to determine the effect of treatment with modern HCV direct-acting antiviral (DAA) therapy on noninvasive liver fibrosis measurements. A total of 70 patients had VCTE-based liver stiffness measurement (LSM) taken before treatment, directly after treatment completion, and at least 12 months after completion of DAA therapy. Our primary outcome was a >30% improvement in VCTE score at the end of follow-up, relative to baseline. The sustained virologic response rate in our cohort was 95.7%. In our cohort, 34 (48.6%) met the primary outcome. Those who had baseline elevated alanine aminotransferase (OR 3.27; 95% CI 1.13-9.47) and genotype 1 (OR 14.63; 95% CI 1.70-125.83) had higher odds of meeting that outcome, and this remained significant after adjusting for age, baseline body mass index, gender, baseline elevated alkaline phosphatase levels, treatment experience, liver transplant status, smoking, and baseline liver stiffness. Treatment of chronic HCV with modern DAA therapy was associated with a significant improvement in LSM by VCTE measurement, suggesting possible early improvement in liver fibrosis along with resolution of inflammation over the first year after treatment completion.

Impact of Hypocaloric Hyperproteic Diet on Gut Microbiota in Overweight or Obese Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study.

PubMed

Pataky, Zoltan; Genton, Laurence; Spahr, Laurent; Lazarevic, Vladimir; Terraz, Sylvain; Gaïa, Nadia; Rubbia-Brandt, Laura; Golay, Alain; Schrenzel, Jacques; Pichard, Claude

2016-09-01

NAFLD is likely to become the most common cause of chronic liver disease. The first-line treatment includes weight loss. To analyze the impact of a hypocaloric hyperproteic diet (HHD) on gut microbiota in NAFLD patients. Fifteen overweight/obese patients with NAFLD were included. At baseline and after a 3-week HHD (Eurodiets(®), ~1000 kcal/day, ~125 g protein/day), we measured gut microbiota composition and function by shotgun metagenomics; body weight; body composition by bioelectrical impedance analysis; liver and visceral fat by magnetic resonance imaging; plasma C-reactive protein (CRP); and liver tests. Results between both time points, expressed as median (first and third quartile), were compared by Wilcoxon signed-rank tests. At baseline, age was 50 (47-55) years and body mass index 34.6 (32.4, 36.7) kg/m(2). HDD decreased body weight by 3.6 % (p < 0.001), percent liver fat by 65 % (p < 0.001), and CRP by 19 % (p = 0.014). HDD was associated with a decrease in Lachnospira (p = 0.019), an increase in Blautia (p = 0.026), Butyricicoccus (p = 0.024), and changes in several operational taxonomic units (OTUs) of Bacteroidales and Clostridiales. The reduced liver fat was negatively correlated with bacteria belonging to the Firmicutes and Bacteroidetes phyla (a Ruminococcaceae OTU, r = -0.83; Bacteroides, r = -0.73). The associated metabolic changes concerned mostly enzymes involved in amino acid and carbohydrate metabolism. In this pilot study, HHD changes gut microbiota composition and function in overweight/obese NAFLD patients, in parallel with decreased body weight, liver fat, and systemic inflammation. Future studies should aim to confirm these bacterial changes and understand their mode of action. Under clinicaltrials.gov: NCT01477307.

Randomized trial of an uncertainty self-management telephone intervention for patients awaiting liver transplant.

PubMed

Bailey, Donald E; Hendrix, Cristina C; Steinhauser, Karen E; Stechuchak, Karen M; Porter, Laura S; Hudson, Julie; Olsen, Maren K; Muir, Andrew; Lowman, Sarah; DiMartini, Andrea; Salonen, Laurel Williams; Tulsky, James A

2017-03-01

We tested an uncertainty self-management telephone intervention (SMI) with patients awaiting liver transplant and their caregivers. Participants were recruited from four transplant centers and completed questionnaires at baseline, 10, and 12 weeks from baseline (generally two and four weeks after intervention delivery, respectively). Dyads were randomized to either SMI (n=56) or liver disease education (LDE; n=59), both of which involved six weekly telephone sessions. SMI participants were taught coping skills and uncertainty management strategies while LDE participants learned about liver function and how to stay healthy. Outcomes included illness uncertainty, uncertainty management, depression, anxiety, self-efficacy, and quality of life. General linear models were used to test for group differences. No differences were found between the SMI and LDE groups for study outcomes. This trial offers insight regarding design for future interventions that may allow greater flexibility in length of delivery beyond our study's 12-week timeframe. Our study was designed for the time constraints of today's clinical practice setting. This trial is a beginning point to address the unmet needs of these patients and their caregivers as they wait for transplants that could save their lives. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The insulin resistance phenotype (muscle or liver) interacts with the type of diet to determine changes in disposition index after 2 years of intervention: the CORDIOPREV-DIAB randomised clinical trial.

PubMed

Blanco-Rojo, Ruth; Alcala-Diaz, Juan F; Wopereis, Suzan; Perez-Martinez, Pablo; Quintana-Navarro, Gracia M; Marin, Carmen; Ordovas, Jose M; van Ommen, Ben; Perez-Jimenez, Francisco; Delgado-Lista, Javier; Lopez-Miranda, Jose

2015-10-16

The aim of the study was to determine whether basal insulin resistance (IR) phenotype (muscle and/or liver) determines the effect of long-term consumption of a Mediterranean diet or a low-fat diet on tissue-specific IR and beta cell function. The study was performed in 642 patients included in The effect of an olive oil rich Mediterranean diet on type 2 diabetes mellitus risk and incidence study (CORDIOPREV-DIAB). A total of 327 patients were randomised to a Mediterranean diet (35% fat; 22% from monounsaturated fatty acids) and 315 to a low-fat diet (<28% fat). At baseline, the patients were classified into four phenotypes according to the type of IR: (1) no IR; (2) muscle IR; (3) liver IR; (4) muscle + liver IR. The hepatic insulin resistance index (HIRI), muscular insulin sensitivity index (MISI) and disposition index were analysed at baseline and after 2 years of follow-up. At baseline, 322 patients presented no IR, 106 presented muscle IR, 109 presented liver IR, and 105 presented muscle + liver IR. With both dietary interventions, HIRI decreased in all patients (p < 0.001) and MISI increased in muscle IR and muscle + liver IR patients (p < 0.01). Long-term intake of the Mediterranean diet increased the disposition index and insulinogenic index in the muscle IR patients (p = 0.042 and p = 0.044, respectively) and the disposition index in the muscle + liver IR patients (p = 0.048), whereas the low-fat diet increased the disposition index in the liver IR patients (p = 0.017). Although both diets improve insulin sensitivity, there are differences based on basal IR phenotypes. Moreover, according to insulinogenic and disposition index data, a low-fat diet might be more beneficial to patients with liver IR, whereas patients with muscle IR and muscle + liver IR might benefit more from a Mediterranean diet. Trial registration ClinicalTrials.gov NCT00924937 FUNDING: The study was supported by the Ministerio de Economia y Competitividad (AGL2012/39615) and by the Ministerio de Ciencia e Innovacion (PIE14/00005 and PI13/00023).

Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers

PubMed Central

van Rijn, Rianne; van Leeuwen, Otto B.; Matton, Alix P. M.; Burlage, Laura C.; Wiersema‐Buist, Janneke; van den Heuvel, Marius C.; de Kleine, Ruben H. J.; de Boer, Marieke T.; Gouw, Annette S. H.

2018-01-01

Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; http://www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE‐preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655–664 2018 AASLD. PMID:29369470

Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials.

PubMed

Seko, Yuya; Sumida, Yoshio; Sasaki, Kazuyo; Itoh, Yoshito; Iijima, Hiroaki; Hashimoto, Toshio; Ishii, Shinichi; Inagaki, Nobuya

2018-01-01

We aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L). This post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated. The mean ALT change at 12 weeks was -10.3 ± 11.7 and -3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was -16.0 ± 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2). In T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated.

Indocyanine green: A test of hepatic function and a measure of plasma volume in the duck

USGS Publications Warehouse

Patton, J.F.

1978-01-01

1. The exponential removal of ICG from the plasma by the mallard duck liver made possible the measurement of fractional dye clearance (K), plasma volume (PV) and plasma clearance (PC).2. Values obtained for K (14.9%/min), PV (39.2 ml/kg) and PC (5.8 ml/min per kg) agreed with those obtained by other techniques used in a number of species.3. Sex did not affect the removal of ICG by the liver. However, increases in K, PV and PC were noted in hen mallards in laying condition.4. The data should prove useful as baseline values for physiological and pathological studies on the avian liver

Impairment of liver synthetic function and the production of plasma proteins in primary breast cancer patients on doxorubicincyclophosphamide (AC) protocol.

PubMed

Saleem, Zikria; Ahmad, Mobasher; Hashmi, Furqan Khurshid; Saeed, Hamid; Aziz, Muhammad Tahir

2016-09-01

Doxorubicin and Cyclophosphamide (AC protocol) combination is usually considered as a first line therapy in newly diagnosed breast cancer patients. Thus, a retrospective observational study was conducted to monitor the effect of AC protocol on liver synthetic functions and production of plasma proteins in breast cancer patients, reporting to specialized cancer care hospital of Lahore, Pakistan. A total of 75 patients (n=75) on AC protocol with breast cancer were observed in this study. The patient data including age, gender, body surface area, dosage, disease status and laboratory biochemical values were recorded by reviewing historical treatment records. Pre-treatment values were taken as baseline values for albumin, globulin, blood urea nitrogen (BUN), albumin/globulin (A/G) ratio and total proteins. The baseline values were compared after each cycle of by applying ANOVA using statistical tool SPSS® version 21. The plasma levels of blood urea nitrogen (BUN), total protein and globulin dropped significantly (p<0.05) in patients of all age groups. However, the albumin levels were not significantly changed (p>0.05). The A/G ratio level increased (p<0.05) as a result of reduction in globulin levels. Significant changes in plasma protein levels were observed in the elderly patients (50 to 65 years) than patients between 20 to 50 years of age. AC protocol impairs liver synthetic functions as observed by decreased blood urea nitrogen (BUN) and plasma protein levels.

Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France.

PubMed

Young, Jacques; Bertherat, Jérôme; Vantyghem, Marie Christine; Chabre, Olivier; Senoussi, Salima; Chadarevian, Rita; Castinetti, Frédéric

2018-05-01

Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. An observational prospective French cohort study (Compassionate Use Programme (CUP)). Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ. © 2018 European Society of Endocrinology.

Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants.

PubMed

Feng, Sandy; Ekong, Udeme D; Lobritto, Steven J; Demetris, Anthony J; Roberts, John P; Rosenthal, Philip; Alonso, Estella M; Philogene, Mary C; Ikle, David; Poole, Katharine M; Bridges, Nancy D; Turka, Laurence A; Tchao, Nadia K

2012-01-18

Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function.

PubMed

Larson-Meyer, D Enette; Newcomer, Bradley R; Heilbronn, Leonie K; Volaufova, Julia; Smith, Steven R; Alfonso, Anthony J; Lefevre, Michael; Rood, Jennifer C; Williamson, Donald A; Ravussin, Eric

2008-06-01

Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m(2)) were randomized to "control (CO)" = 100% energy requirements; "CR" = 25%; "caloric restriction and increased structured exercise (CR+EX)"= 12.5% CR + 12.5% increase in energy expenditure through exercise; or "low-calorie diet (LCD)" = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

Effect of 6-Month Calorie Restriction and Exercise on Serum and Liver Lipids and Markers of Liver Function

PubMed Central

Larson-Meyer, D. Enette; Newcomer, Bradley R.; Heilbronn, Leonie K.; Volaufova, Julia; Smith, Steven R.; Alfonso, Anthony J.; Lefevre, Michael; Rood, Jennifer C.; Williamson, Donald A.; Ravussin, Eric

2009-01-01

objective Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Methods and Procedures Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m2) were randomized to “control (CO)” = 100% energy requirements; “CR” = 25%; “caloric restriction and increased structured exercise (CR+EX)”= 12.5% CR + 12.5% increase in energy expenditure through exercise; or “low-calorie diet (LCD)” = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. Results At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. Discussion CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD. PMID:18421281

Liver Function Tests Following Irreversible Electroporation of Liver Tumors: Experience in 174 Procedures.

PubMed

Froud, Tatiana; Venkat, Shree R; Barbery, Katuzka J; Gunjan, Arora; Narayanan, Govindarajan

2015-09-01

Irreversible electroporation (IRE) is a relatively new ablation modality that uses electric currents to cause cell death. It is commonly used to treat primary and secondary liver tumors in patients with normal liver function and preexisting cirrhosis. Retrospective analysis of 205 procedures sought to evaluate changes in liver function after IRE. Liver function tests (LFTs) results before and after IRE were evaluated from 174 procedures in 124 patients. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALKP), and total bilirubin levels were analyzed. The study was Health Insurance Portability and Accountability Act compliant and institutional review board approved. Informed consent was waived. Changes in LFT results after IRE were compared with baseline and were followed up over time to see if they resolved. Changes were compared with volume of ablation. The greatest perturbations were in transaminase levels. The levels increased sharply within 24 hours after IRE in 129 (74.1%) procedures to extreme levels (more than 20 times the upper limit of normal in one-third of cases). Resolution occurred in 95% and was demonstrated to have occurred by a mean of approximately 10 weeks, many documented as early as 7 days after procedure. ALKP levels elevated in 10% procedures, was slower to increase, and was less likely to resolve. Total bilirubin level demonstrated 2 different patterns of elevation--early and late--and similar to ALKP, it was more likely to remain elevated. There was no increased risk in patients with cirrhosis or cholangiocarcinoma. There was no correlation of levels with volume of ablation. IRE results in significant abnormalities in LFT results, but in most of the cases, these are self-limiting, do not preclude treatment, and are similar to the changes seen after radiofrequency and cryoablation in the liver. Copyright © 2015. Published by Elsevier Inc.

[Vitamin D deficiency in chronic liver disease, clinical-epidemiological analysis and report after vitamin d supplementation].

PubMed

Fernández Fernández, Nereida; Linares Torres, Pedro; Joáo Matias, Diana; Jorquera Plaza, Francisco; Olcoz Goñi, Jose Luis

2016-05-01

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.

Rifaximin Decreases the Incidence and Severity of Acute Kidney Injury and Hepatorenal Syndrome in Cirrhosis.

PubMed

Dong, Tien; Aronsohn, Andrew; Gautham Reddy, K; Te, Helen S

2016-12-01

While the effects of rifaximin have been shown to be protective against acute kidney injury (AKI) and hepatorenal syndrome (HRS) in alcohol-induced cirrhosis, its long-term effects on the renal function of other cirrhotic patients are unknown. To examine the long-term effects of rifaximin on the renal function of patients with cirrhosis from various etiologies. In a retrospective study, we examined cirrhotic patients at the University of Chicago Liver Clinic from January 1, 2011, to December 31, 2014. The study enrolled patients on rifaximin for ≥90 days, who were then matched by age, gender, and MELD score to a control group. Patients with malignancy and renal replacement therapy (RRT) at baseline were excluded. Data were censored at the last follow-up, termination of rifaximin therapy, initiation of RRT, death, or liver transplant. Eighty-eight rifaximin cases were identified and matched to 88 control cases. Baseline characteristics were similar, with the exceptions of more prevalent long-term midodrine use (≥90 days) (17.0 vs 4.5 %, p = 0.01) and baseline ascites (37.5 vs 23.8 %, p = 0.05) in the rifaximin group. There was no difference in the frequency of infections, deaths, liver transplants, or hospitalizations. After controlling for cofounders, the incidence rate ratio of AKI (IRR 0.71, p = 0.02) and HRS (IRR 0.21, p = 0.02), as well as the risk of requiring RRT (OR 0.23, p = 0.01), was lower in the rifaximin group. Long-term use of rifaximin is associated with a decrease incidence of AKI and HRS and a decrease risk of requiring RRT in a general population of cirrhotic patients.

DPP-4 inhibitors improve liver dysfunction in type 2 diabetes mellitus.

PubMed

Kanazawa, Ippei; Tanaka, Ken-ichiro; Sugimoto, Toshitsugu

2014-09-17

Dipeptidyl peptidase-4 (DPP-4) inhibitors might have pleiotropic effects because receptors for incretin exist in various tissues, including liver. We examined whether DPP-4 inhibitors affect liver function in patients with type 2 diabetes. A retrospective review of 459 patients with type 2 diabetes who were prescribed DPP-4 inhibitors was performed. After exclusion of patients with hepatitis B or C, steroid use, and other diseases that might affect liver function and diabetes status, 224 patients were included in the analysis. Forty-four patients (19.6%) with liver injury defined by aspartate transaminase (AST) or alanine transaminase (ALT) over the normal level of 40 U/L. In the patients with liver injury, AST and ALT were significantly decreased after 6 months from the first date of DPP-4 prescription, with mean changes of -6.2 U/L [95% confidence interval (CI) -10.9 to -1.4, p=0.012] and of -11.9 U/L (95%CI -19.5 to -4.2, p=0.003), respectively. Percent changes in AST were significantly and negatively correlated with baseline AST and ALT (r=-0.27, p<0.001 and r=-0.23, p=0.002, respectively), and percent changes in ALT were also negatively correlated with them (r=-0.23, p=0.001 and r=-0.27, p<0.001, respectively). DPP-4 inhibitors improved liver dysfunction in patients with type 2 diabetes.

Characterization of liver function parameter alterations after transjugular intrahepatic portosystemic shunt creation and association with early mortality.

PubMed

Casadaban, Leigh C; Parvinian, Ahmad; Couture, Patrick M; Minocha, Jeet; Knuttinen, M Grace; Bui, James T; Gaba, Ron C

2014-12-01

The purpose of this article is to characterize the temporal evolution and clinical impact of laboratory liver function parameters after transjugular intrahepatic portosystemic shunt (TIPS) creation. In this single-institution retrospective study, 157 patients (98 men and 59 women; median age, 55 years) underwent TIPS between 2000 and 2012 and had 1-month hepatobiliary laboratory follow-up. Medical record review was used to compare baseline, peak, and low bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and international normalized ratio (INR) levels within 30 days after TIPS in surviving and dying patients to assess laboratory responses to shunt creation. TIPSs were created with a hemodynamic success rate of 98%, with median pressure gradient reduction of 13 mm Hg. Ninety-day mortality was 21%. Hepatobiliary laboratory values showed significant increases in the days after TIPS compared with baseline levels (bilirubin, 1.6 vs 3.5 mg/dL; AST, 49 vs 149 U/L; ALT, 26 vs 90 U/L; alkaline phosphatase, 97 vs 177 U/L; and INR, 1.5 vs 2.0; p<0.05 in all cases). Patients surviving to 90 days experienced statistically significant but transient laboratory value elevations-up to twofold over baseline-within days of TIPS, whereas patients dying within 90 days experienced three-to fourfold increases over a longer period that did not return to baseline. Differences in laboratory evolution were statistically significant in surviving versus dying patients. TIPS results in acute transient elevation of hepatobiliary enzymes, which may be more pronounced in patients with early mortality. An exaggerated laboratory elevation in excess of threefold greater than baseline or a prolonged increase exceeding 1 week may herald poorer clinical outcome.

Prediction of liver disease in patients whose liver function tests have been checked in primary care: model development and validation using population-based observational cohorts.

PubMed

McLernon, David J; Donnan, Peter T; Sullivan, Frank M; Roderick, Paul; Rosenberg, William M; Ryder, Steve D; Dillon, John F

2014-06-02

To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. Primary care, Tayside, Scotland. Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. Diagnosis of a liver condition within 2 years. From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

PubMed

Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

2012-12-01

IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cross-sectional and longitudinal evaluation of liver volume and total liver fat burden in adults with nonalcoholic steatohepatitis

PubMed Central

Tang, An; Chen, Joshua; Le, Thuy-Anh; Changchien, Christopher; Hamilton, Gavin; Middleton, Michael S.; Loomba, Rohit; Sirlin, Claude B.

2014-01-01

Purpose To explore the cross-sectional and longitudinal relationships between fractional liver fat content, liver volume, and total liver fat burden. Methods In 43 adults with non-alcoholic steatohepatitis participating in a clinical trial, liver volume was estimated by segmentation of magnitude-based low-flip-angle multiecho GRE images. The liver mean proton density fat fraction (PDFF) was calculated. The total liver fat index (TLFI) was estimated as the product of liver mean PDFF and liver volume. Linear regression analyses were performed. Results Cross-sectional analyses revealed statistically significant relationships between TLFI and liver mean PDFF (R2 = 0.740 baseline/0.791 follow-up, P < 0.001 baseline/P < 0.001 follow-up), and between TLFI and liver volume (R2 = 0.352/0.452, P < 0.001/< 0.001). Longitudinal analyses revealed statistically significant relationships between liver volume change and liver mean PDFF change (R2 = 0.556, P < 0.001), between TLFI change and liver mean PDFF change (R2 = 0.920, P < 0.001), and between TLFI change and liver volume change (R2 = 0.735, P < 0.001). Conclusion Liver segmentation in combination with MRI-based PDFF estimation may be used to monitor liver volume, liver mean PDFF, and TLFI in a clinical trial. PMID:25015398

Thyroid and hepatic function after high-dose 131 I-metaiodobenzylguanidine (131 I-MIBG) therapy for neuroblastoma.

PubMed

Quach, Alekist; Ji, Lingyun; Mishra, Vikash; Sznewajs, Aimee; Veatch, Janet; Huberty, John; Franc, Benjamin; Sposto, Richard; Groshen, Susan; Wei, Denice; Fitzgerald, Paul; Maris, John M; Yanik, Gregory; Hawkins, Randall A; Villablanca, Judith G; Matthay, Katherine K

2011-02-01

(131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function. Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined. In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12  ±  4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76  ±  4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23  ±  5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies. The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction. Copyright © 2010 Wiley-Liss, Inc.

Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis.

PubMed

Bajaj, Jasmohan S; Fagan, Andrew; Sikaroodi, Masoumeh; White, Melanie B; Sterling, Richard K; Gilles, HoChong; Heuman, Douglas; Stravitz, Richard T; Matherly, Scott C; Siddiqui, Mohammed S; Puri, Puneet; Sanyal, Arun J; Luketic, Velimir; John, Binu; Fuchs, Michael; Ahluwalia, Vishwadeep; Gillevet, Patrick M

2017-07-01

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post-LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health-related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre-/post-LT data were compared with age-matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End-Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre-LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907-914 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

PubMed Central

Movsesyan, Nina; Platt, Frances M.

2017-01-01

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID:29119141

Baseline HBV load increases the risk of anti-tuberculous drug-induced hepatitis flares in patients with tuberculosis.

PubMed

Zhu, Chun-Hui; Zhao, Man-Zhi; Chen, Guang; Qi, Jun-Ying; Song, Jian-Xin; Ning, Qin; Xu, Dong

2017-02-01

Hepatitis associated anti-tuberculous treatment (HATT) has been a main obstacle in managing patients co-infected with Mycobacterium tuberculosis and hepatitis B virus (HBV). Therefore, we evaluated the factors related to the severity of adverse effects during HATT, especially those associated with liver failure. A retrospective study was carried out at Tongji Hospital from 2007 to 2012. Increases in serum transaminase levels of >3, 5, and 10 times the upper limit of normal (ULN) were used to define liver damage as mild, moderate, and severe, respectively. Patients with elevated total bilirubin (TBil) levels that were more than 10 times the ULN (>171 μmol/L) with or without decreased (<40%) prothrombin activity (PTA) were diagnosed with liver failure. A cohort of 87 patients was analyzed. The incidence of liver damage and liver failure was 59.8% (n=52) and 25.3% (n=22), respectively. The following variables were correlated with the severity of hepatotoxicity: albumin (ALB) levels, PTA, platelet counts (PLT), and the use of antiretroviral therapies (P<0.05). Hypo-proteinemia and antiretroviral therapy were significantly associated with liver failure, and high viral loads were a significant risk factor with an odds ratio (OR) of 2.066. Judicious follow-up of clinical conditions, liver function tests, and coagulation function, especially in patients with high HBV loads and hypoalbuminemia is recommended. It may be advisable to reconsider the use of antiviral drugs failure during the course of anti-tuberculous treatment of HBV infection patients to avoid the occurrence of furious liver failure.

Diffusion MRI with Semi-Automated Segmentation Can Serve as a Restricted Predictive Biomarker of the Therapeutic Response of Liver Metastasis

PubMed Central

Stephen, Renu M.; Jha, Abhinav K.; Roe, Denise J.; Trouard, Theodore P.; Galons, Jean-Philippe; Kupinski, Matthew A.; Frey, Georgette; Cui, Haiyan; Squire, Scott; Pagel, Mark D.; Rodriguez, Jeffrey J.; Gillies, Robert J.; Stopeck, Alison T.

2015-01-01

Purpose To assess the value of semi-automated segmentation applied to diffusion MRI for predicting the therapeutic response of liver metastasis. Methods Conventional diffusion weighted magnetic resonance imaging (MRI) was performed using b-values of 0, 150, 300 and 450 s/mm2 at baseline and days 4, 11 and 39 following initiation of a new chemotherapy regimen in a pilot study with 18 women with 37 liver metastases from primary breast cancer. A semi-automated segmentation approach was used to identify liver metastases. Linear regression analysis was used to assess the relationship between baseline values of the apparent diffusion coefficient (ADC) and change in tumor size by day 39. Results A semi-automated segmentation scheme was critical for obtaining the most reliable ADC measurements. A statistically significant relationship between baseline ADC values and change in tumor size at day 39 was observed for minimally treated patients with metastatic liver lesions measuring 2–5 cm in size (p = 0.002), but not for heavily treated patients with the same tumor size range (p = 0.29), or for tumors of smaller or larger sizes. ROC analysis identified a baseline threshold ADC value of 1.33 μm2/ms as 75% sensitive and 83% specific for identifying non-responding metastases in minimally treated patients with 2–5 cm liver lesions. Conclusion Quantitative imaging can substantially benefit from a semi-automated segmentation scheme. Quantitative diffusion MRI results can be predictive of therapeutic outcome in selected patients with liver metastases, but not for all liver metastases, and therefore should be considered to be a restricted biomarker. PMID:26284600

Diffusion MRI with Semi-Automated Segmentation Can Serve as a Restricted Predictive Biomarker of the Therapeutic Response of Liver Metastasis.

PubMed

Stephen, Renu M; Jha, Abhinav K; Roe, Denise J; Trouard, Theodore P; Galons, Jean-Philippe; Kupinski, Matthew A; Frey, Georgette; Cui, Haiyan; Squire, Scott; Pagel, Mark D; Rodriguez, Jeffrey J; Gillies, Robert J; Stopeck, Alison T

2015-12-01

To assess the value of semi-automated segmentation applied to diffusion MRI for predicting the therapeutic response of liver metastasis. Conventional diffusion weighted magnetic resonance imaging (MRI) was performed using b-values of 0, 150, 300 and 450s/mm(2) at baseline and days 4, 11 and 39 following initiation of a new chemotherapy regimen in a pilot study with 18 women with 37 liver metastases from primary breast cancer. A semi-automated segmentation approach was used to identify liver metastases. Linear regression analysis was used to assess the relationship between baseline values of the apparent diffusion coefficient (ADC) and change in tumor size by day 39. A semi-automated segmentation scheme was critical for obtaining the most reliable ADC measurements. A statistically significant relationship between baseline ADC values and change in tumor size at day 39 was observed for minimally treated patients with metastatic liver lesions measuring 2-5cm in size (p=0.002), but not for heavily treated patients with the same tumor size range (p=0.29), or for tumors of smaller or larger sizes. ROC analysis identified a baseline threshold ADC value of 1.33μm(2)/ms as 75% sensitive and 83% specific for identifying non-responding metastases in minimally treated patients with 2-5cm liver lesions. Quantitative imaging can substantially benefit from a semi-automated segmentation scheme. Quantitative diffusion MRI results can be predictive of therapeutic outcome in selected patients with liver metastases, but not for all liver metastases, and therefore should be considered to be a restricted biomarker. Copyright © 2015 Elsevier Inc. All rights reserved.

Supplementation of Eurycoma longifolia Jack Extract for 6 Weeks Does Not Affect Urinary Testosterone: Epitestosterone Ratio, Liver and Renal Functions in Male Recreational Athletes

PubMed Central

Chen, Chee Keong; Mohamad, Wan Mohd Zahiruddin Wan; Ooi, Foong Kiew; Ismail, Shaiful Bahari; Abdullah, Mohamad Rusli; George, Annie

2014-01-01

Background: Eurycoma longifolia Jack (ElJ) has been shown to elevate serum testosterone and increased muscle strength in humans. This study investigated the effects of Physta® a standardized water extract of ElJ (400 mg/day for 6 weeks) on testosterone: epitestosterone (T:E) ratio, liver and renal functions in male recreational athletes. Methods: A total of 13 healthy male recreational athletes were recruited in this double blind, placebo-controlled, cross-over study. The participants were required to consume either 400 mg of ElJ or placebo daily for 6 weeks in the first supplementation regimen. Following a 3 week wash-out period, the participants were requested to consume the other supplement for another 6 weeks. Mid-stream urine samples and blood samples were collected prior to and after 6 weeks of supplementation with either ElJ or placebo. The urine samples were subsequently analyzed for T:E ratio while the blood samples were analyzed for liver and renal functions. Results: T:E ratio was not significantly different following 6 weeks supplementation of either ElJ or placebo compared with their respective baseline values. Similarly, there were no significant changes in both the liver and renal functions tests following the supplementation of ElJ. Conclusions: Supplementation of ElJ i.e. Physta® at a dosage of 400 mg/day for 6 weeks did not affect the urinary T:E ratio and hence will not breach any doping policies of the International Olympic Committee for administration of exogenous testosterone or its precursor. In addition, the supplementation of ElJ at this dosage and duration was safe as it did adversely affect the liver and renal functions. PMID:25013692

Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions.

PubMed

Bae, Sun Hyun; Kim, Mi-Sook; Jang, Won Il; Cho, Chul Koo; Yoo, Hyung Jun; Kim, Kum Bae; Han, Chul Ju; Park, Su Cheol; Lee, Dong Han

2015-08-01

This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity≥grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV5Gy-rV35Gy: normal liver volume receiving

Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia.

PubMed

Cheong, June-Won; Kim, Hyeoung-Joon; Lee, Kyoo-Hyung; Yoon, Sung-Soo; Lee, Jae Hoon; Park, Hee-Sook; Kim, Ho Young; Shim, Hyeok; Seong, Chu-Myung; Kim, Chul Soo; Chung, Jooseop; Hyun, Myung Soo; Jo, Deog-Yeon; Jung, Chul Won; Sohn, Sang Kyun; Yoon, Hwi-Joong; Kim, Byung Soo; Joo, Young-Don; Park, Chi-Young; Min, Yoo Hong

2014-06-01

Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA). This was a prospective, multicenter, open-label study to investigate the efficacy of deferasirox (DFX) by serial measurement of serum ferritin (S-ferritin) level, liver iron concentration (LIC) level using relaxation rates magnetic resonance imaging, and other laboratory variables in patients with MDS or AA. A total of 96 patients showing S-ferritin level of at least 1000 ng/mL received daily DFX for up to 1 year. At the end of the study, S-ferritin level was significantly decreased in MDS (p=0.02366) and AA (p=0.0009). LIC level was also significantly reduced by more than 6.7 mg Fe/g dry weight from baseline. Hemoglobin level and platelet counts were significantly increased from baseline (p=0.002 and p=0.025, respectively) for patients showing significant anemia or thrombocytopenia. Elevated alanine aminotransferase was also significantly decreased from baseline. This study shows that DFX is effective in reducing S-ferritin and LIC level in transfusional iron overload patients with MDS or AA and is well tolerated. In addition, positive effects in hematologic and hepatic function can be expected with DFX. Iron chelation treatment should be considered in transfused patients with MDS and AA when transfusion-related iron overload is documented. © 2013 AABB.

Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study.

PubMed

Hess, Anne Lundby; Carayol, Jérôme; Blædel, Trine; Hager, Jörg; Di Cara, Alessandro; Astrup, Arne; Saris, Wim H M; Larsen, Lesli Hingstrup; Valsesia, Armand

2018-01-01

Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p  = 0.02) and insulin ( p  = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss ( p  = 0.004) and between ANGPTL3 and CK-18 (baseline p  = 1.03 × 10 -7 , during weight loss p  = 1.47 × 10 -13 ). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4 - APOA5-ZNF259 - BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss ( p  = 0.007). We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans -acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes.

Quantifying Health Utilities in Patients Undergoing Stereotactic Body Radiation Treatment for Liver Metastases for Use in Future Economic Evaluations.

PubMed

Warren, B; Munoz-Schuffenegger, P; Chan, K K W; Chu, W; Helou, J; Erler, D; Chung, H

2017-09-01

Stereotactic body radiation therapy (SBRT) is increasingly used as an option for those with liver metastases. In order to facilitate future economic impact of health technologies, health utility scores may be used. The EuroQOL-5D-3L (EQ-5D) preference-based healthy utility instrument was used to evaluate the impact of treatment with SBRT on health utility scores. Between August 2013 and October 2014, 31 patients treated with 3-5 fractions of SBRT for liver metastases were enrolled in this study. The EQ-5D instrument was administered at baseline, during and up to 6 months post-SBRT. Mean EQ-5D score at baseline was 0.857, which remained stable across the entire study time period. Transient increases in difficulties with mobility (9.7% reported at baseline to 16.1% on the last day of treatment) and usual activities (3.2% reported at baseline to 34.5% on day two) were found during the course of treatment; these returned to baseline levels subsequently. The mean visual analogue score at baseline was 65.8 and remained unchanged throughout treatment and follow-up. The stability of health utility scores and problems reported by patients undergoing treatment indicate that SBRT for liver metastases does not impart a significant adverse effect on quality of life. These results may be used for future economic evaluation of SBRT. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Enhancement of Functional Connectivity, Working Memory and Inhibitory Control on Multi-modal Brain MR Imaging with Rifaximin in Cirrhosis: Implications for the Gut-Liver-Brain Axis

PubMed Central

Ahluwalia, Vishwadeep; Wade, James B; Heuman, Douglas M; Hammeke, Thomas A; Sanyal, Arun J; Sterling, Richard K; Stravitz, R. Todd; Luketic, Velimir; Siddiqui, Mohammad S; Puri, Puneet; Fuchs, Michael; Lennon, Micheal J; Kraft, Kenneth A; Gilles, HoChong; White, Melanie B; Noble, Nicole A; Bajaj, Jasmohan S

2014-01-01

Objective Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. Aim To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE. Hypothesis Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks. Methods Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. Results were compared before/after rifaximin. Results 20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p=0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. Conclusion A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE. PMID:24590688

Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis.

PubMed

Ahluwalia, Vishwadeep; Wade, James B; Heuman, Douglas M; Hammeke, Thomas A; Sanyal, Arun J; Sterling, Richard K; Stravitz, R Todd; Luketic, Velimir; Siddiqui, Mohammad S; Puri, Puneet; Fuchs, Michael; Lennon, Micheal J; Kraft, Kenneth A; Gilles, HoChong; White, Melanie B; Noble, Nicole A; Bajaj, Jasmohan S

2014-12-01

Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE. Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks. Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. RESULTS were compared before/after rifaximin. 20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p = 0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE.

Clinical research on liver reserve function by 13C-phenylalanine breath test in aged patients with chronic liver diseases

PubMed Central

2010-01-01

Background The objective of this study was to investigate whether the 13C-phenylalanine breath test could be useful for the evaluation of hepatic function in elderly volunteers and patients with chronic hepatitis B and liver cirrhosis. Methods L-[1-13C] phenylalanine was administered orally at a dose of 100 mg to 55 elderly patients with liver cirrhosis, 30 patients with chronic hepatitis B and 38 elderly healthy subjects. The breath test was performed at 8 different time points (0, 10, 20, 30, 45, 60, 90, 120 min) to obtain the values of Delta over baseline, percentage 13CO2 exhalation rate and cumulative excretion (Cum). The relationships of the cumulative excretion with the 13C-%dose/h and blood biochemical parameters were investigated. Results The 13C-%dose/h at 20 min and 30 min combined with the cumulative excretion at 60 min and 120 min correlated with hepatic function tests, serum albumin, hemoglobin, platelet and Child-Pugh score. Prothrombin time, total and direct bilirubin were significantly increased, while serum albumin, hemoglobin and platelet, the cumulative excretion at 60 min and 120 min values decreased by degrees of intensity of the disease in Child-Pugh A, B, and C patients (P < 0.01). Conclusions The 13C-phenylalanine breath test can be used as a non-invasive assay to evaluate hepatic function in elderly patients with liver cirrhosis. The 13C-%dose/h at 20 min, at 30 min and cumulative excretion at 60 min may be the key value for determination at a single time-point. 13C-phenylalanine breath test is safe and helpful in distinguishing different stages of hepatic dysfunction for elderly cirrhosis patients. PMID:20459849

Effect of compound glycyrrhizin injection on liver function and cellular immunity of children with infectious mononucleosis complicated liver impairment.

PubMed

Cao, Zong-xin; Zhao, Zhong-fang; Zhao, Xiu-fen

2006-12-01

To investigate the effects of Compound Glycyrrhizin Injection (CGI) on liver function and cellular immunity of children with infectious mononucleosis complicated liver impairment (IM-LI) and to explore its clinical therapeutic effect. Forty-two patients with IM-LI were randomly assigned, according to the randomizing number table, to two groups, 20 in the control group and 22 in the treated group. All the patients were treated with conventional treatment, but to those in the treated group, CGI was given additionally once a day, at the dosage of 10 ml for children aged below 2 years, 20 ml for 2-4 years old, 30 ml for 5-7 years old and 40 ml for 8- 12 years old, in 100-200 ml of 5% glucose solution by intravenous dripping. The treatment lasted for 2 weeks. T lymphocyte subsets and serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) were detected before and after treatment. Besides, a normal control group consisting of 20 healthy children was also set up. Baseline of the percentage of CD3 + , CD8 + lymphocyte and serum levels of ALT, AST, TBiL in the children with IM-LI were markedly higher, while the percentage of CD4 + lymphocyte and the CD4 + /CD8 + ratio was markedly lower in IM-LI children as compared with the corresponding indices in the healthy children ( P<0.01). These indices were improved after treatment in both groups of patients, but the improvement in the treated group was better than that in the control group (P<0.01). Cellular immunity dysfunction often occurs in patients with IM-LI, and CGI treatment can not only obviously promote the recovery of liver function, but also regulate the immune function in organism.

Quantitative intrahepatic HBV cccDNA correlates with histological liver inflammation in chronic hepatitis B virus infection.

PubMed

Liang, Ling-Bo; Zhu, Xia; Yan, Li-Bo; Du, Ling-Yao; Liu, Cong; Liao, Juan; Tang, Hong

2016-11-01

The aim of this study was to determine the role of baseline hepatitis B virus (HBV) forming covalently closed circular DNA (HBV cccDNA) in liver inflammation in patients infected with HBV with serum alanine aminotransferase (ALT) levels under two times the upper limit of normal (2×ULN). After liver biopsy and serum virological and biochemical marker screening, patients diagnosed with chronic HBV infection with serum ALT levels under 2×ULN and histological liver inflammation of less than grade G2 were prospectively recruited into this study. Recruitment took place between March 2009 and November 2010 at the Center of Infectious Disease, Sichuan University. Patient virological and biochemical markers, as well as markers of liver inflammation, were monitored. A total of 102 patients were recruited and 68 met the inclusion criteria; the median follow-up was 4.1 years (range 3.9-5.2 years). During follow-up, 41 patients (60.3%) exhibited signs of inflammation. Baseline HBV cccDNA >1 copy/cell (odds ratio 9.43, p=0.049) and liver inflammation grade ≥G1 (odds ratio 5.77, p=0.046) were both independent predictors of liver inflammation. A higher baseline intrahepatic HBV cccDNA level may increase the risk of liver inflammation. Further investigations will be required to validate HBV cccDNA as an intrahepatic virological marker of patients who require extended outpatient management. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Efficacy of a Standardized Extract of Prunus mume in Liver Protection and Redox Homeostasis: A Randomized, Double-Blind, Placebo-Controlled Study.

PubMed

Beretta, Alberto; Accinni, Roberto; Dellanoce, Cinzia; Tonini, Annamaria; Cardot, Jean-Michel; Bussière, Anthony

2016-06-01

The antioxidant, anti-inflammatory and hepatoprotective effects of Prunus mume (PM) have previously been demonstrated. This double-blind, placebo-controlled study was designed to evaluate the influence of two doses of a food supplement, made of 150 mg of a standardized PM extract on liver transaminases, lipid profile, glycemia, neopterin and reduced and oxidized thiols in plasma and erythrocytes, during a 3-month treatment period, in healthy subjects with transaminases levels between 20 and 40 UI/L. Forty-five subjects (56.0 ± 11.6 years) were enrolled. The results showed a beneficial and statistically significant effect versus placebo of PM extract on liver function, with a decrease versus baseline in alanine aminotransferase (47%), aspartate aminotransferase (7%), gamma-glutamyl transpeptidase (15%) and glycemia (11%). The lipid profile modification was also positive with an increase versus baseline in HDL cholesterol (13%), and a decrease in LDL/HDL ratio (12%) and triglycerides (8%). The antioxidant action of PM translated into a decrease in oxidized glutathione, reduced/oxidized cysteine-glycine, oxidized cysteine (intracellular pro-oxidant) and neopterin (inflammation biomarker), was associated with an increase in reduced glutathione. These results are in favor of the use of a standardized extract of P. mume for the support of liver health and prevention of common metabolic and inflammation-based diseases. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Left-liver hypertrophy after therapeutic right-liver radioembolization is substantial but less than after portal vein embolization.

PubMed

Garlipp, Benjamin; de Baere, Thierry; Damm, Robert; Irmscher, Romy; van Buskirk, Mark; Stübs, Patrick; Deschamps, Frederic; Meyer, Frank; Seidensticker, Ricarda; Mohnike, Konrad; Pech, Maciej; Amthauer, Holger; Lippert, Hans; Ricke, Jens; Seidensticker, Max

2014-05-01

In patients with liver malignancies potentially amenable to curative extended right hepatectomy but insufficient size of the future liver remnant (FLR), portal vein embolization (PVE) of the tumor-bearing liver is used to induce contralateral liver hypertrophy but leaves the tumor untreated. Radioembolization (RE) treats the tumor in the embolized lobe along with contralateral hypertrophy induction. We performed a matched-pair analysis to compare the capacity for hypertrophy induction of these two modalities. Patients with right-hepatic secondary liver malignancies with no or negligible left-hepatic tumor involvement who were treated by right-lobar PVE (n = 141) or RE (n = 35) at two centers were matched for criteria known to influence liver regeneration following PVE: 1) baseline FLR/Total liver volume ratio (<25 versus ≥ 25%); 2) prior platinum-containing systemic chemotherapy; 3) embolization of segments 5-8 versus 4-8; and 4) baseline platelet count (<200 versus ≥ 200 Gpt/L).The primary endpoint was relative change in FLR volume from baseline to follow-up. Twenty-six matched pairs were identified. FLR volume increase from baseline to follow-up (median 33 [24-56] days after PVE or 46 [27-79] days after RE) was significant in both groups but PVE produced significantly more FLR hypertrophy than RE (61.5 versus 29%, P < 0.001). Time between treatment and follow-up was not correlated with the degree of contralateral hypertrophy achieved in both groups. Although group differences in patient history and treatment setting were present and some bias cannot be excluded, this was minimized by the matched-pair design, as remaining group differences after matching were found to have no significant influence on contralateral hypertrophy development. PVE induces significantly more contralateral hypertrophy than RE with therapeutic (nonlobectomy) doses. However, contralateral hypertrophy induced by RE is substantial and RE minimizes the risk of tumor progression in the treated lobe, possibly making it a suitable modality for selected patients. © 2014 by the American Association for the Study of Liver Diseases.

Improvement in liver pathology of patients with β-thalassemia treated with deferasirox for at least 3 years.

PubMed

Deugnier, Yves; Turlin, Bruno; Ropert, Martine; Cappellini, M Domenica; Porter, John B; Giannone, Vanessa; Zhang, Yiyun; Griffel, Louis; Brissot, Pierre

2011-10-01

Most data on the effects of iron chelation therapy for patients with liver fibrosis come from small studies. We studied the effects of the oral iron chelator deferasirox on liver fibrosis and necroinflammation in a large population of patients with iron overload β-thalassemia. We studied data from 219 patients with β-thalassemia, collected from histologic analyses of biopsy samples taken at baseline and after at least 3 years of treatment with deferasirox. Treatment response was assessed from liver iron concentrations at baseline and the end of the study. Liver fibrosis, necroinflammation, and markers of iron overload and liver enzymes were recorded. Patients were also assessed, by serologic analysis at baseline, for hepatitis C virus infection. By the end of the study, stability of Ishak fibrosis staging scores (change of -1, 0, or +1) or improvements (change of ≤-2) were observed in 82.6% of patients; Ishak necroinflammatory scores improved by a mean value of -1.3 (P<.001). Improvements in fibrosis stage and necroinflammation were independent of hepatitis C virus exposure or reduction in liver iron concentration defined by the response criteria. Absolute changes in concentrations of liver iron by the end of the study did not correlate with improved Ishak fibrosis or necroinflammatory scores. Deferasirox treatment for 3 or more years reversed or stabilized liver fibrosis in 83% of patients with iron-overloaded β-thalassemia. This therapeutic effect was independent of reduced concentration of liver iron (defined by the response criteria) or previous exposure to hepatitis C virus. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Changes in hepatic perfusion assessed by dynamic contrast enhanced MRI, associated with morphologic evaluation, in patients with liver metastases from colorectal cancer treated with first-line chemotherapy.

PubMed

Tampellini, Marco; Gned, Dario; Baratelli, Chiara; Brizzi, Maria Pia; Ottone, Azzurra; Alabiso, Irene; Bertaggia, Chiara; Di Maio, Massimo; Scagliotti, Giorgio Vittorio; Veltri, Andrea

2016-12-01

Blood perfusion of liver metastases can be non-invasively assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to explore whether the ratio of hepatic arterial to total liver blood flow (Hepatic Perfusion Index-HPI) and the area under the enhancement curve (AUC) of selected liver areas in patients with hepatic metastases from colorectal cancer treated with first-line chemotherapy could predict response and/or be a prognostic variable. Sequential liver DCE-MRI studies with morphological imaging reconstruction were performed in 43 consecutive patients at baseline and every 3 months during oxaliplatin-based first-line chemotherapy. Data about HPI of the whole liver, and AUC of metastatic and healthy areas were calculated at each time-point and compared both at baseline and sequentially during the treatment. Baseline HPI and AUC values did not discriminate patients responsive to chemotherapy, nor those with better survival outcomes. HPI and AUC values at 3 months decreased significantly more in responders than non-responders. AUCs calculated from areas of the liver with or without neoplastic lesions varied consistently, being increased in progressing patients and decreased in responding patients. Our results did not support the hypothesis of a predictive or prognostic role of HPI and AUCs calculated by DCE-MRI in liver metastatic CRC patients, thus the primary endpoint of the study was not reached. However, reduced arterial blood flow in metastatic liver can be obtained by chemotherapy alone, without any anti-angiogenic agent; interestingly, HPI and AUC data suggest a possible relationship between tumor metabolism and entire liver perfusion.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erinjeri, Joseph P., E-mail: erinjerj@mskcc.org; Deodhar, Ajita; Thornton, Raymond H.

Hepatic encephalopathy is considered a contraindication to hepatic artery embolization. We describe a patient with a well-differentiated neuroendocrine tumor metastatic to the liver with refractory hepatic encephalopathy and normal liver function tests. The encephalopathy was refractory to standard medical therapy with lactulose. The patient's mental status returned to baseline after three hepatic artery embolization procedures. Arteriography and ultrasound imaging before and after embolization suggest that the encephalopathy was due to arterioportal shunting causing hepatofugal portal venous flow and portosystemic shunting. In patients with a primary or metastatic well-differentiated neuroendocrine tumor whose refractory hepatic encephalopathy is due to portosystemic shunting (rathermore » than global hepatic dysfunction secondary to tumor burden), hepatic artery embolization can be performed safely and effectively.« less

The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.

PubMed

Carbone, Marco; Sharp, Stephen J; Flack, Steve; Paximadas, Dimitrios; Spiess, Kelly; Adgey, Carolyn; Griffiths, Laura; Lim, Reyna; Trembling, Paul; Williamson, Kate; Wareham, Nick J; Aldersley, Mark; Bathgate, Andrew; Burroughs, Andrew K; Heneghan, Michael A; Neuberger, James M; Thorburn, Douglas; Hirschfield, Gideon M; Cordell, Heather J; Alexander, Graeme J; Jones, David E J; Sandford, Richard N; Mells, George F

2016-03-01

The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care. © 2015 by the American Association for the Study of Liver Diseases.

Evaluation of the 13C-octanoate breath test as a surrogate marker of liver damage in animal models.

PubMed

Shalev, Tamar; Aeed, Hussein; Sorin, Vladimir; Shahmurov, Mark; Didkovsky, Elena; Ilan, Yaron; Avni, Yona; Shirin, Haim

2010-06-01

Octanoate (also known as sodium octanoate), a medium-chain fatty acid metabolized in the liver, is a potential substrate for non-invasive breath testing of hepatic mitochondrial beta-oxidation. We evaluated the 13C-octanoate breath test (OBT) for assessing injury in acute hepatitis and two rat models of liver cirrhosis, first testing octanoate absorption (per os or intraperitoneally (i.p.)) in normal rats. We then induced acute hepatitis with thioacetamide (300 mg/kg/i.p., 24-h intervals). Liver injury end points were serum aminotransferase levels and 13C-OBT (24 and 48 h following initial injection). Thioacetamide (200 mg/kg/i.p., twice per week, 12 weeks) was used to induce liver cirrhosis. OBT and liver histological assessment were performed every 4 weeks. Bile duct ligation (BDL) was used to induce cholestatic liver injury. We completed breath tests with 13C-OBT and 13C-methacetin (MBID), liver biochemistry, and liver histology in BDL and sham-operated rats (baseline, 6, 14, 20 days post-BDL). Octanoate absorbs well by either route. Peak amplitudes and cumulative percentage dose recovered at 30 and 60 min (CPDR30/60), but not peak time, correlated with acute hepatitis. Fibrosis stage 3 at week 8 significantly correlated with each OBT parameter. Cholestatic liver injury (serum bilirubin, ALP, gamma-GT, liver histology) was associated with significant suppression of the maximal peak values and CPDR30/60, respectively (P<0.05),using MBID but not 13C-octanoate. OBT is sensitive for potentially evaluating liver function in rat models of acute hepatitis and thioacetamide-induced liver cirrhosis but not in cholestatic liver injury. The MBID test may be better for evaluation of cholestatic liver disease in this model.

Liver Function in Patients With Nonalcoholic Fatty Liver Disease Randomized to Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy: A Secondary Analysis of a Randomized Clinical Trial.

PubMed

Kalinowski, Piotr; Paluszkiewicz, Rafał; Ziarkiewicz-Wróblewska, Bogna; Wróblewski, Tadeusz; Remiszewski, Piotr; Grodzicki, Mariusz; Krawczyk, Marek

2017-11-01

The aim of the study was to compare the influence of sleeve gastrectomy (SG) versus Roux-en-Y gastric bypass (RYGB) on liver function in bariatric patients with non-alcoholic fatty liver disease (NAFLD) in a randomized clinical trial (NCT01806506). Rapid weight loss and malabsorption after bariatric surgery in patients with NAFLD or steatohepatitis (NASH) may impair liver function. Sixty-six morbidly obese patients randomized to SG or RYGB were included in a secondary outcome analysis. Intraoperative liver biopsies were categorized with NAFLD Activity Score (NAS) and liver function tests were done before surgery and after 1, 6 and 12 months. NASH was present in 54.5% RYGB and 51.5% SG patients (P > 0.05). At 12 months excess weight loss was 68.7 ± 19.7% after SG and 62.8 ± 18.5% after RYGB (P > 0.05). At 1 month international normalized ratio (INR) increased after RYGB (0.98 ± 0.05 vs 1.14 ± 0.11; P < 0.05) and SG (0.99 ± 0.06 vs 1.04 ± 0.06; P < 0.05), RYGB induced significantly greater increase in INR in the whole group and NASH patients than SG. After RYGB albumin decreased at 1 month (41.2 ± 2.7 vs 39.0 ± 3.2 g/L; P < 0.05). At 12 months, INR and albumin returned to baseline. At 12 months in NASH group, SG induced significant improvement in aspartate aminotransferase (32.4 ± 17.4 vs 21.5 ± 6.9U/L), alanine aminotransferase (39.9 ± 28.6U/L vs 23.8 ± 14.1U/L), gamma-glutamyl transpeptidase (34.3 ± 16.6 vs 24.5 ± 16.8U/L), and lactate dehydrogenase (510.8 ± 33 vs 292.4 ± 29). Variables predictive of INR change after 1 month included operation type, NAS ≥ 5, bilirubin, body mass index, hemoglobin A1C, and dyslipidemia. Patients with NASH undergoing RYGB are more susceptible to early transient deterioration of liver function than after SG.

Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial.

PubMed

Rogers, Zora R; Wang, Winfred C; Luo, Zhaoyu; Iyer, Rathi V; Shalaby-Rana, Eglal; Dertinger, Stephen D; Shulkin, Barry L; Miller, John H; Files, Bea; Lane, Peter A; Thompson, Bruce W; Miller, Scott T; Ware, Russell E

2011-03-03

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by (99m)Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of ≤1.2% or HJB ≤55/10(6) red blood cells and absent function by PIT ≥4.5% or HJB ≥665/10(6). HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400. © 2011 by The American Society of Hematology

Improved clinicopathologic assessments of acute liver damage due to trauma in Indian ring-necked parakeets (Psittacula krameri manillensis).

PubMed

Williams, Susan M; Holthaus, Lisa; Barron, Heather Wilson; Divers, Stephen J; McBride, Michael; Almy, Frederic; Bush, Sharon; Latimer, Kenneth S

2012-06-01

Increased activities of certain biochemical enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], alkaline phosphatase [ALP]) have been associated with blunt liver injury in many species. To evaluate changes in plasma hepatic biochemical parameters in acute avian liver disease caused by trauma and to compare biochemical changes with histologic lesions in hepatic parenchyma, 30 healthy fasted Indian ring-necked parakeets (Psittacula krameri manillensis) were divided into 2 groups, and traumatic liver injury was caused by endoscopic liver biopsy (group 1) or by liver biopsy and crushing injury to the hepatic parenchyma with endoscopic forceps (group 2) in anesthetized birds. Blood samples were collected at baseline and at 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours in alternate groups to compare analyte values after injury with those at baseline. Results showed consistently decreased plasma ALP activity (excluding 1 time point) throughout the study, which was thought to be associated with isoflurane administration. Plasma glutamate dehydrogenase activity initially increased but rapidly declined thereafter and was attributed to acute focal hepatocellular injury. In both groups, increases in plasma AST, ALT, and LDH activities was most likely caused by muscle injury because creatine kinase activity was concurrently increased. Compared with baseline values, bile acid concentration and y-glutamyl transferase activity were not affected by liver biopsy or crush injury. Plasma sorbitol dehydrogenase activity was the most specific indicator of liver injury in both groups. Histologic changes correlated poorly with biochemical results, possibly because the small area of hepatic parenchyma that was damaged did not affect enzyme values substantially.

Quantitative evaluation of liver cirrhosis using T1 relaxation time with 3 tesla MRI before and after oxygen inhalation.

PubMed

Kim, Kyung Ah; Park, Mi-Suk; Kim, In-Seong; Kiefer, Berthold; Chung, Woo-Suk; Kim, Myeong-Jin; Kim, Ki Whang

2012-08-01

To quantify liver T1 relaxation times before and after oxygen inhalation in patients with and without liver cirrhosis using a 3 Tesla (T) MRI. Institutional Review Board approval and written informed consent were obtained. Ninety-two noncirrhotic patients and 87 patients with hepatitis B viral liver cirrhosis (72 Child-Pugh class A and 15 Child-Pugh class B or C) underwent MRI with a 3.0T system before and after the supply of 100% oxygen at a rate of 15 L/min by means of a nonrebreather ventilation mask for 3 min. T1 maps were acquired using three-dimensional spoiled gradient echo sequences with two different flip angles (2° and 14°) and a fixed TR/TE (2.54 ms/0.95 ms). Liver T1 values were obtained using a T1 processing tool (MapIT software). The mean baseline T1 values of three groups (control, Child-Pugh class A, and Child-Pugh class B/C) were compared using an analysis of variance test. Liver T1 value before and after oxygenation was compared using a paired t-test for each group. The baseline liver T1 value was significantly higher in the control group (941 ± 136 ms) than in Child-Pugh A (858 ± 143 ms) and Child-Pugh B/C (783 ± 164 ms) group (P < 0.001 and P < 0.0001). The reduction in the liver T1 value after oxygen inhalation was significant in the control group (P = 0.012) but not significant in Child-Pugh class A (P = 0.079) and Child-Pugh class B/C (P = 0.752). The baseline liver T1 relaxation time was significantly different between the patients with and without liver cirrhosis. The shortening effect of oxygen on the liver T1 value was significant in the control group but not in the cirrhotic patients. Copyright © 2012 Wiley Periodicals, Inc.

Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients.

PubMed

Debette-Gratien, Marilyne; Woillard, Jean-Baptiste; Picard, Nicolas; Sebagh, Mylène; Loustaud-Ratti, Véronique; Sautereau, Denis; Samuel, Didier; Marquet, Pierre

2016-10-01

This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac). Allelic discrimination assays were used for genotyping. Multivariate time-dependent Cox proportional hazard models, multiple linear regression using the generalized estimating equation and linear mixed-effect models were used for statistical analysis. Expression of CYP3A5 by either or both the donor and the recipient was significantly associated with lower Tac, but not CsA, dose-normalized trough levels. In the whole population, graft loss was only significantly associated with longer exposure to high calcineurin inhibitor (CNI) concentrations (hazard ratio, 6.93; 95% confidence interval, 2.13-22.55), P = 0.00129), whereas in the Tac subgroup, the risk of graft loss was significantly higher in recipient CYP3A5*1 expressers (hazard ratio, 3.39; 95% confidence interval, 1.52-7.58; P = 0.0028). Renal function was significantly associated with: (1) baseline modification of diet in renal disease (β = 0.51 ± 0.05; P < 0.0001); (2) duration of patient follow-up (per visit, β = -0.98 ± 0.22; P < 0.0001); and (3) CNI exposure (per quantile increase, β = -2.42 ± 0.59; P < 0.0001). No genetic factor was associated with patient survival, acute rejection, liver function test results, recurrence of viral or other initial liver disease, or renal function. This study confirms the effect of CYP3A5*3 on tacrolimus dose requirement in liver transplantation and shows unexpected associations between the type of, and exposure to, CNI and either chronic rejection or graft loss. None of the genetic polymorphisms studied had a noticeable impact on renal function degradation at 10 years.

Circulating tumor cell levels are elevated in colorectal cancer patients with high tumor burden in the liver.

PubMed

Kaifi, Jussuf T; Kunkel, Miriam; Dicker, David T; Joude, Jamal; Allen, Joshua E; Das, Avisnata; Zhu, Junjia; Yang, Zhaohai; Sarwani, Nabeel E; Li, Guangfu; Staveley-O'Carroll, Kevin F; El-Deiry, Wafik S

2015-01-01

Metastatic spread is the most common cause of cancer-related death in colorectal cancer (CRC) patients, with the liver being the mostly affected organ. Circulating tumor cells (CTCs) are a prognostic marker in stage IV CRC. We hypothesized that tumor burden in the liver correlates with CTC quantity. Blood (7.5 ml) was prospectively collected from 24 patients with novel stage IV CRC diagnosis. Baseline EpCAM+ CTCs were analyzed with the FDA-approved CellSearch® system. Clinicopathological data were collected, and hepatic tumor burden was determined by radiographic liver volumetry with contrast-enhanced CT scans. CRC primary tumors were immunohistochemically stained for EpCAM expression with BerEP4 monoclonal antibody. Statistical analyses were performed using 2-sample T-test, non-parametric Wilcoxon Rank-Sum test, and Fisher's exact test. CTCs were detected n 17 (71%) of 24 patients. The overall mean CTC number as determined by EpCAM-based CellSearch® detection was 6.3 (SEM 2.9). High baseline CTC numbers (≥3) correlated significantly with a high tumor/liver ratio (≥30%), and with high serum CEA levels, as determined by two-sample T-test on log-transformed data and by Fisher's Exact test on categorical data analysis (P < 0.05). The CRC primary tumors were consistently expressing EpCAM by immunostaining. High tumor burden in the liver and high baseline serum CEA levels are associated with high number of baseline CTCs in stage IV CRC patients. Future studies should further investigate the biological role and expression patterns of single CTCs in cancer patients to further improve personalized treatment strategies.

Changes in Liver Volume in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

PubMed Central

Fitzpatrick, Julie A.; Kim, Jin Un; Cobbold, Jeremy F.L.; McPhail, Mark J.W.; Crossey, Mary M.E.; Bak-Bol, Aluel A.; Zaky, Ashraf; Taylor-Robinson, Simon D.

2016-01-01

Aim Liver volumetric analysis has not been used to detect hepatic remodelling during antiviral therapy before. We measured liver volume (LV) changes on volumetric magnetic resonance imaging during hepatitis C antiviral therapy. Methods 22 biopsy-staged patients (median [range] age 4519–65 years; 9F, 13M) with chronic hepatitis C virus infection were studied. LV was measured at the beginning, end of treatment and 6 months post-treatment using 3D T1-weighted acquisition, normalised to patient weight. Liver outlines were drawn manually on 4 mm thick image slices and LV calculated. Inter-observer agreement was analysed. Patients were also assessed longitudinally using biochemical parameters and liver stiffness using Fibroscan™. Results Sustained viral response (SVR) was achieved in 13 patients with a mean baseline LV/kg of 0.022 (SD 0.004) L/kg. At the end of treatment, the mean LV/kg was 0.025 (SD 0.004, P = 0.024 cf baseline LV/kg) and 0.026 (SD 0.004, P = 0.008 cf baseline LV/kg) 6 months post-treatment (P = 0.030 cf baseline, P = 0.004). Body weight-corrected end of treatment LV change was significantly higher in patients with SVR compared to patients not attaining SVR (P = 0.050). End of treatment LV change was correlated to initial ALT (R2 = 0.479, P = 0.037), but not APRI, AST, viral load or liver stiffness measurements. There was a correlation of 0.89 between observers for measured slice thickness. Conclusions LV increased during anti-viral treatment, while the body weight-corrected LV increase persisted post-antiviral therapy and was larger in patients with SVR. PMID:27194891

Changes in Liver Volume in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy.

PubMed

Fitzpatrick, Julie A; Kim, Jin Un; Cobbold, Jeremy F L; McPhail, Mark J W; Crossey, Mary M E; Bak-Bol, Aluel A; Zaky, Ashraf; Taylor-Robinson, Simon D

2016-03-01

Liver volumetric analysis has not been used to detect hepatic remodelling during antiviral therapy before. We measured liver volume (LV) changes on volumetric magnetic resonance imaging during hepatitis C antiviral therapy. 22 biopsy-staged patients (median [range] age 45(19-65) years; 9F, 13M) with chronic hepatitis C virus infection were studied. LV was measured at the beginning, end of treatment and 6 months post-treatment using 3D T1-weighted acquisition, normalised to patient weight. Liver outlines were drawn manually on 4 mm thick image slices and LV calculated. Inter-observer agreement was analysed. Patients were also assessed longitudinally using biochemical parameters and liver stiffness using Fibroscan™. Sustained viral response (SVR) was achieved in 13 patients with a mean baseline LV/kg of 0.022 (SD 0.004) L/kg. At the end of treatment, the mean LV/kg was 0.025 (SD 0.004, P = 0.024 cf baseline LV/kg) and 0.026 (SD 0.004, P = 0.008 cf baseline LV/kg) 6 months post-treatment (P = 0.030 cf baseline, P = 0.004). Body weight-corrected end of treatment LV change was significantly higher in patients with SVR compared to patients not attaining SVR (P = 0.050). End of treatment LV change was correlated to initial ALT (R (2) = 0.479, P = 0.037), but not APRI, AST, viral load or liver stiffness measurements. There was a correlation of 0.89 between observers for measured slice thickness. LV increased during anti-viral treatment, while the body weight-corrected LV increase persisted post-antiviral therapy and was larger in patients with SVR.

The utility of liver function tests for mortality prediction within one year in primary care using the algorithm for liver function investigations (ALFI).

PubMed

McLernon, David J; Dillon, John F; Sullivan, Frank M; Roderick, Paul; Rosenberg, William M; Ryder, Stephen D; Donnan, Peter T

2012-01-01

Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease. In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices. From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80-0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79-0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%. The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.

Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients.

PubMed

Calmus, Yvon; Kamar, Nassim; Gugenheim, Jean; Duvoux, Christophe; Ducerf, Christian; Wolf, Philippe; Samuel, Didier; Vanlemmens, Claire; Neau-Cransac, Martine; Salamé, Ephrem; Chazouillères, Olivier; Declerck, Nicole; Pageaux, Georges-Philippe; Dubel, Laurence; Rostaing, Lionel

2010-06-27

Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection. This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months. The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time. Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt

PubMed Central

Abdel-Moneim, Adel; Morsy, Basant M.; Mahmoud, Ayman M.; Abo-Seif, Mohamed A.; Zanaty, Mohamed I.

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture. PMID:27298610

Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt.

PubMed

Abdel-Moneim, Adel; Morsy, Basant M; Mahmoud, Ayman M; Abo-Seif, Mohamed A; Zanaty, Mohamed I

2013-01-01

Hepatitis C is a major global health burden and Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. The current study was designed to evaluate the beneficial therapeutic effects of ethanolic extracts of Nigella sativa, Zingiber officinale and their mixture in Egyptian HCV patients. Sixty volunteer patients with proven HCV and fifteen age matched healthy subjects were included in this study. Exclusion criteria included patients on interferon alpha (IFN-α) therapy, infection with hepatitis B virus, drug-induced liver diseases, advanced cirrhosis, hepatocellular carcinoma (HCC) or other malignancies, blood picture abnormalities and major severe illness. Liver function enzymes, albumin, total bilirubin, prothrombin time and concentration, international normalized ratio, alpha fetoprotein and viral load were all assessed at baseline and at the end of the study. Ethanolic extracts of Nigella sativa and Zingiber officinale were prepared and formulated into gelatinous capsules, each containing 500 mg of Nigella sativa and/or Zingiber officinale. Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. Both extracts as well as their mixture significantly ameliorated the altered viral load, alpha fetoprotein, liver function parameters; with more potent effect for the combined therapy. In conclusion, administration of Nigella sativa and/or Zingiber officinale ethanolic extracts to HCV patients exhibited potential therapeutic benefits via decreasing viral load and alleviating the altered liver function, with more potent effect offered by the mixture.

Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial.

PubMed

Nogueira, Monize Aydar; Oliveira, Claudia Pinto; Ferreira Alves, Venâncio Avancini; Stefano, José Tadeu; Rodrigues, Lívia Samara Dos Reis; Torrinhas, Raquel Susana; Cogliati, Bruno; Barbeiro, Hermes; Carrilho, Flair José; Waitzberg, Dan Linetzky

2016-06-01

& aims: Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH. Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic [ALA], 16% eicosapentaenoic [EPA], and 21% docosahexaenoic [DHA] acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment. At baseline, NAS was comparable between the groups (p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased (p ≤ 0.05). However in the placebo group, we also observed increased EPA and DHA (p ≤ 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group (p = 0.02) and with increased EPA (p = 0.04) and DHA (p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline (p = 0.01). In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809). Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

The efficacy of the Peginterferon treatment in chronic hepatitis HDV and compensate liver cirrhosis.

PubMed

Tugui, Letitia; Dumitru, M; Iacob, Speranta; Gheorghe, Liana; Preda, Carmen; Dinu, Ioana; Becheanu, G; Dumbrava, Mona; Nicolae, Ioana; Andrei, Adriana; Lupu, A; Diculescu, M

2014-01-01

To evaluate the efficiency of the treatment with Peginterferon alfa 2a 180 mcg/week, 48 weeks in patients with chronic hepatitis or compensated liver cirrhosis HDV and predictive factors of response to treatment. Prospective study that enrolled 50 patients with chronic hepatitis or compensated cirrhosis HDV between the 1st of January 2011 - 3st of December 2011. The diagnosis of chronic HDV infection was made based on the presence of detectable anti HDV IgG antibodies and HDV-RNA. Patients were evaluated at baseline by CBC, liver function tests, HBV profile, HDV RNA, and by liver biopsy/Fibrotest for evaluating fibrosis and necroinflammatory activity. At 24 weeks CBC (count blood cells), liver function tests, quantitative HBsAg and at 48 and 72 weeks biochemical tests, HDV RNA, HBV DNA, quantitative HBsAg, were performed. Adverse reactions to the treatment were recorded. SVR (sustained virologic response) was recorded in 12 patients (24%) and biochemical response in 28 patients (56%). SVR was correlated with low-grade fibrosis, age, the aminotransferase value and the value of HBsAg at the beginning of the treatment. In week 48 HDV RNA was undetectable in 20 patients (40%). The therapy was well tolerated, except two patients for whom the discontinuation of the treatment was decided for severe exacerbation of cytolysis, respectively hepatic decompensation. In a representative group of patients, the treatment with Peginterferon once again proves its efficacy in treating chronic HDV.

Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

PubMed

Markwardt, Daniel; Holdt, Lesca; Steib, Christian; Benesic, Andreas; Bendtsen, Flemming; Bernardi, Mauro; Moreau, Richard; Teupser, Daniel; Wendon, Julia; Nevens, Frederik; Trebicka, Jonel; Garcia, Elisabet; Pavesi, Marco; Arroyo, Vicente; Gerbes, Alexander L

2017-10-01

The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241). © 2017 by the American Association for the Study of Liver Diseases.

Adding Agnus Castus and Magnolia to Soy Isoflavones Relieves Sleep Disturbances Besides Postmenopausal Vasomotor Symptoms-Long Term Safety and Effectiveness

PubMed Central

De Franciscis, Pasquale; Grauso, Flavio; Luisi, Anna; Schettino, Maria Teresa; Torella, Marco; Colacurci, Nicola

2017-01-01

The effectiveness for vasomotor symptoms and sleep disorders plus the long-term safety of a nutraceutical combination of agnus-castus and magnolia extracts combined with soy isoflavones (SI) and lactobacilli were assessed in postmenopausal women. A controlled study was carried out in menopausal women comparing this nutraceutical combination (ESP group) with a formulation containing isoflavones alone (C group) at the dosage recommended. The Kuppermann index, The Pittsburgh Sleep Quality Index (PSQI), and Short Form 36 (SF-36) were determined at baseline, three, six and 12 months. Endometrial thickness, mammary density and liver function were evaluated at baseline and after 12 months. One hundred and eighty women were enrolled in the study (100 in the ESP group and 80 in the C group). At the end of the treatment, mammary density, endometrial thickness, and hepatic function did not show substantial differences between groups. The Kuppermann index and particularly the tendency for hot flashes progressively and significantly decreased in frequency and severity during ESP versus C treatment. At the same time, a significant increase in sleep quality and psychophysical wellness parameters was observed in the ESP versus C groups. No adverse events were observed. Agnus-castus and magnolia, combined with SI + lactobacilli, can effectively and safely be used in symptomatic postmenopausal women, mainly when quality of sleep is the most disturbing complaint. The endometrium, mammary glands and liver function were unaffected after 12 months of treatment. PMID:28208808

Adding Agnus Castus and Magnolia to Soy Isoflavones Relieves Sleep Disturbances Besides Postmenopausal Vasomotor Symptoms-Long Term Safety and Effectiveness.

PubMed

De Franciscis, Pasquale; Grauso, Flavio; Luisi, Anna; Schettino, Maria Teresa; Torella, Marco; Colacurci, Nicola

2017-02-13

The effectiveness for vasomotor symptoms and sleep disorders plus the long-term safety of a nutraceutical combination of agnus-castus and magnolia extracts combined with soy isoflavones (SI) and lactobacilli were assessed in postmenopausal women. A controlled study was carried out in menopausal women comparing this nutraceutical combination (ESP group) with a formulation containing isoflavones alone (C group) at the dosage recommended. The Kuppermann index, The Pittsburgh Sleep Quality Index (PSQI), and Short Form 36 (SF-36) were determined at baseline, three, six and 12 months. Endometrial thickness, mammary density and liver function were evaluated at baseline and after 12 months. One hundred and eighty women were enrolled in the study (100 in the ESP group and 80 in the C group). At the end of the treatment, mammary density, endometrial thickness, and hepatic function did not show substantial differences between groups. The Kuppermann index and particularly the tendency for hot flashes progressively and significantly decreased in frequency and severity during ESP versus C treatment. At the same time, a significant increase in sleep quality and psychophysical wellness parameters was observed in the ESP versus C groups. No adverse events were observed. Agnus-castus and magnolia, combined with SI + lactobacilli, can effectively and safely be used in symptomatic postmenopausal women, mainly when quality of sleep is the most disturbing complaint. The endometrium, mammary glands and liver function were unaffected after 12 months of treatment.

Low Platelet to White Blood Cell Ratio Indicates Poor Prognosis for Acute-On-Chronic Liver Failure.

PubMed

Jie, Yusheng; Gong, Jiao; Xiao, Cuicui; Zhu, Shuguang; Zhou, Wenying; Luo, Juan; Chong, Yutian; Hu, Bo

2018-01-01

Background. Platelet to white blood cell ratio (PWR) was an independent prognostic predictor for outcomes in some diseases. However, the prognostic role of PWR is still unclear in patients with hepatitis B related acute-on-chronic liver failure (ACLF). In this study, we evaluated the clinical performances of PWR in predicting prognosis in HBV-related ACLF. Methods. A total of 530 subjects were recruited, including 97 healthy controls and 433 with HBV-related ACLF. Liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement, and routine hematological testing were performed at admission. Results . At baseline, PWR in patients with HBV-related ACLF (14.03 ± 7.17) was significantly decreased compared to those in healthy controls (39.16 ± 9.80). Reduced PWR values were clinically associated with the severity of liver disease and the increased mortality rate. Furthermore, PWR may be an inexpensive, easily accessible, and significant independent prognostic index for mortality on multivariate analysis (HR = 0.660, 95% CI: 0.438-0.996, p = 0.048) as well as model for end-stage liver disease (MELD) score. Conclusions . The PWR values were markedly decreased in ACLF patients compared with healthy controls and associated with severe liver disease. Moreover, PWR was an independent prognostic indicator for the mortality rate in patients with ACLF. This investigation highlights that PWR comprised a useful biomarker for prediction of liver severity.

Thermodiffusion for continuous quantification of hepatic microcirculation--validation and potential in liver transplantation.

PubMed

Klar, E; Kraus, T; Bleyl, J; Newman, W H; Bowman, H F; Hofmann, W J; Kummer, R; Bredt, M; Herfarth, C

1999-09-01

Hepatic microcirculation is a main determinant of reperfusion injury and graft quality in liver transplantation. Methods available for the quantification of hepatic microcirculation are indirect, are invasive, or preclude postoperative application. The aim of this study was the validation of thermodiffusion in a new modification allowing long-term use in the clinical setting. In six pigs Doppler flowmeters were positioned around the hepatic artery and portal vein for the measurement of total liver blood flow. Liver perfusion was quantified by thermodiffusion and compared to H(2) clearance as an established technique under baseline conditions, during different degrees of portal venous obstruction and during occlusion of the hepatic artery. Thermodiffusion measurements were recorded for five days postoperatively followed by histological evaluation of the hepatic puncture site. Perfusion data obtained by thermodiffusion were significantly correlated to H(2) clearance (r = 0.94, P < 0. 001) and to liver blood flow (r = 0.9, P < 0.05). The agreement between thermodiffusion and H(2) clearance was excellent (mean difference -2.1 ml/100 g/min; limits of agreement -12.5 and 8.3 ml/100 g/min). Occlusion of the portal vein or hepatic artery was immediately detected by thermodiffusion, indicating a decrease of perfusion by 64 +/- 7% or 27 +/- 5% of baseline, respectively. Perfusion values at baseline and during vascular occlusion were reproducible during the entire observation period. Histological changes of the liver tissue adjacent to the thermodiffusion probes were minute and did not influence long-term measurements. In vivo validation proved that enhanced thermodiffusion is a minimally invasive technique for the continuous, real-time quantification of hepatic microcirculation. Changes in liver perfusion can be safely detected over several days postoperatively. The implication for liver transplantation has led to the clinical application of thermodiffusion. Copyright 1999 Academic Press.

Predisposing Factors of Liver Necrosis after Transcatheter Arterial Chemoembolization in Liver Metastases from Neuroendocrine Tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joskin, Julien, E-mail: j.joskin@gmail.com; Baere, Thierry de, E-mail: Thierry.DEBAERE@igr.fr; Auperin, Anne, E-mail: Anne.AUPERIN@igr.fr

PurposeTo investigate predictive factors for liver necrosis after transcatheter arterial chemoembolization (TACE) of neuroendocrine liver metastases.MethodsA total of 164 patients receiving 374 TACE were reviewed retrospectively to analyze predictive factors of liver necrosis. We analyzed patient age and sex; metastasis number and location; percentage of liver involvement; baseline liver function test; and pretreatment imaging abnormalities such as bile duct dilatation (BDD), portal vein narrowing (PVN), and portal vein thrombosis (PVT). We analyzed TACE technique such as Lipiodol or drug-eluting beads (DEB) as the drug’s vector; dose of chemotherapy; diameter of DEB; and number, frequency, and selectivity of TACE.ResultsLiver necrosis developedmore » after 23 (6.1 %) of 374 TACE. In multivariate analysis, DEB > 300 μm in size induced more liver necrosis compared to Lipiodol (odds ratio [OR] 35.20; p < 0.0001) or with DEB < 300 μm in size (OR 19.95; p < 0.010). Pretreatment BDD (OR 119.64; p < 0.0001) and PVT (OR 9.83; p = 0.030) were predictive of liver necrosis. BDD or PVT responsible for liver necrosis were present before TACE in 59 % (13 of 22) and were induced by a previous TACE in 41 % (9 of 22) of cases.ConclusionDEB > 300 μm in size, BDD, and PVT are responsible for increased rate of liver necrosis after TACE. Careful analysis of BDD or PVT on pretreatment images as well as images taken between two courses can help avoid TACE complications.« less

Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome.

PubMed

Ibrahim, El-Sayed; Alsebaey, Ayman; Zaghla, Hassan; Moawad Abdelmageed, Sabry; Gameel, Khalid; Abdelsameea, Eman

2017-11-01

Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis, with poor survival. Rifaximin is a gut-selective broad-spectrum antibiotic. The aim of this study was to evaluate the role of rifaximin as a primary prevention of HRS. Eighty patients with liver cirrhosis and ascites were enrolled. They were randomized into two groups: control (n=40) and rifaximin group (n=40). Baseline liver function tests, renal function tests, complete blood count, international normalized ratio, urine analysis, and abdominal ultrasonography were carried out. Rifaximin 550 mg was administered twice daily for 12 weeks. Renal functions were measured every 4 weeks with monitoring of HRS occurrence and possible precipitating factor. Both groups were matched for age, sex, virology, serum bilirubin, serum albumin, aspartate aminotransferase, alanine aminotransferase, hemoglobin, white blood cells, platelets, international normalized ratio, potassium, and Child-Pugh score. In contrast to the rifaximin group, the control group showed statistically significant serial blood urea nitrogen (18.84±7.17, 19.85±6.10, 21.54±4.79, and 22.96±5.82 mg/dl; P=0.001) and serum creatinine (0.94±0.25, 1.02±0.24, 1.12±0.16, and 1.21±0.17 mg/dl; P=0.001) levels. The overall blood urea nitrogen and serum creatinine change was statistically higher in the control group than the rifaximin group (20.8 vs. 18.24 mg/dl and 1.07 vs. 0.99 mg/dl, respectively). HRS developed more in the control group than the rifaximin group [9 (22.5%) vs. 2 (5%); P=0.048]. In both groups, HRS was precipitated by spontaneous bacterial peritonitis mainly and large volume paracentesis. The Child-Pugh score, control group, baseline serum sodium, and creatinine were predictors of HRS. Rifaximin may be useful as a primary prevention of HRS.

3-Dimensional liver volume assessment in patients with hepatitis B virus-related liver cirrhosis during long-term oral nucleos(t)ide analogues therapy.

PubMed

Lee, Chang Hun; Kim, In Hee; Moon, Jin Chang; Seo, Seung Young; Kim, Seong Hun; Kim, Sang Wook; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae Ghon; Yang, Jae Do; Yu, Hee Chul

2017-01-14

To assess the effect of long-term oral nucleos(t)ide analogues (NUCs) therapy on liver volume change in patients with suppress hepatitis B virus (HBV)-related liver cirrhosis. We reviewed the data of naïve patients with HBV-related liver cirrhosis, who had taken oral NUCs therapy, between 2003 and 2007 at Chonbuk University Hospital. We analyzed two consecutive sets of abdominal computerized tomography scans-one at the time of treatment initiation and another at the second-year follow-up. Liver volume was calculated by 3-dimensional liver extraction volumetry program. A total of 55 patients (34 males) were included. There was 114.3 mL ± 167.8 mL (12.9% ± 17.9%) of increase in liver volume during the two years of NUCs therapy (993.8 mL ± 242.8 mL at baseline vs 1108.1 mL ± 263.3 mL at two-year follow-up, P < 0.001). The ratio of the measured baseline liver volume to the estimated standard liver volume was improved from 70.8% to 78.0%. An increase in liver volume was shown not only in patients with compensated cirrhosis ( P = 0.046) but also in those with decompensated cirrhosis ( P < 0.001). Significant factors for volume increases were Child-Turcotte-Pugh grade and model for end-stage liver disease score improvement without virological breakthrough. In multiple linear regression analysis, delta albumin and delta alanine aminotransferase levels showed a significant association with the increase in liver volume ( P = 0.002 and 0.005, respectively). Long-term oral NUCs therapy in patients with HBV-related liver cirrhosis lead to significant increase in liver volume assessed with 3-dimensional liver extraction volumetry program.

Liver enzyme monitoring in patients treated with troglitazone.

PubMed

Graham, D J; Drinkard, C R; Shatin, D; Tsong, Y; Burgess, M J

2001-08-15

Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

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

PubMed

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

2012-05-01

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

Fistuloclysis Improves Liver Function and Nutritional Status in Patients with High-Output Upper Enteric Fistula

PubMed Central

Wu, Yin; Ren, Jianan; Wang, Gefei; Zhou, Bo; Ding, Chao; Gu, Guosheng; Chen, Jun; Liu, Song; Li, Jieshou

2014-01-01

Background. We aimed to determine the efficacy of fistuloclysis in patients with high-output upper enteric fistula (EF). Methods. Patients were assigned into the fistuloclysis group (n = 35, receiving fistuloclysis plus total enteral nutrition (TEN)) and the control group (n = 60, receiving TEN). Laboratory variables were measured during the four-week treatment. Results. At baseline, variables were similar between the two groups. Delta value was defined as the changes from baseline to day 28. Compared with the control group, the fistuloclysis group showed greater improvements in liver function (Delta total bilirubin (TB): 20.3 ± 9.7 in the fistuloclysis group versus 15.6 ± 6.3 in the control group, P = 0.040; Delta direct bilirubin (DB): 12.5 ± 3.4 versus 10.0 ± 3.6, P = 0.011; Delta alkaline phosphatase (ALP): 98.4 ± 33.5 versus 57.6 ± 20.9, P < 0.001); nutritional status (Delta total protein: 21.8 ± 8.7 versus 10.7 ± 2.1, P < 0.001; Delta albumin: 11.3 ± 2.5 versus 4.2 ± 1.3, P < 0.001). In the fistuloclysis subgroups, biliary fistula patients had the maximum number of variables with the greatest improvements. Conclusions. Fistuloclysis improved hepatic and nutritional parameters in patients with high-output upper EF, particularly in biliary fistula patients. PMID:24719613

Fistuloclysis improves liver function and nutritional status in patients with high-output upper enteric fistula.

PubMed

Wu, Yin; Ren, Jianan; Wang, Gefei; Zhou, Bo; Ding, Chao; Gu, Guosheng; Chen, Jun; Liu, Song; Li, Jieshou

2014-01-01

Background. We aimed to determine the efficacy of fistuloclysis in patients with high-output upper enteric fistula (EF). Methods. Patients were assigned into the fistuloclysis group (n = 35, receiving fistuloclysis plus total enteral nutrition (TEN)) and the control group (n = 60, receiving TEN). Laboratory variables were measured during the four-week treatment. Results. At baseline, variables were similar between the two groups. Delta value was defined as the changes from baseline to day 28. Compared with the control group, the fistuloclysis group showed greater improvements in liver function (Delta total bilirubin (TB): 20.3 ± 9.7 in the fistuloclysis group versus 15.6 ± 6.3 in the control group, P = 0.040; Delta direct bilirubin (DB): 12.5 ± 3.4 versus 10.0 ± 3.6, P = 0.011; Delta alkaline phosphatase (ALP): 98.4 ± 33.5 versus 57.6 ± 20.9, P < 0.001); nutritional status (Delta total protein: 21.8 ± 8.7 versus 10.7 ± 2.1, P < 0.001; Delta albumin: 11.3 ± 2.5 versus 4.2 ± 1.3, P < 0.001). In the fistuloclysis subgroups, biliary fistula patients had the maximum number of variables with the greatest improvements. Conclusions. Fistuloclysis improved hepatic and nutritional parameters in patients with high-output upper EF, particularly in biliary fistula patients.

Long-term maintenance of weight loss after lifestyle intervention in frail, obese older adults.

PubMed

Waters, D L; Vawter, R; Qualls, C; Chode, S; Armamento-Villareal, R; Villareal, D T

2013-01-01

To determine if long-term weight loss with associated improvement in physical and metabolic health can be maintained after lifestyle intervention in frail, obese older adults. Thirty-month follow-up pilot study of a 1-year lifestyle intervention trial. Community. Sixteen frail, obese (body mass index=36±2 kg/m2) older (71±1 yr.) adults. Body weight and composition, physical function, markers of the metabolic syndrome, glucose and insulin response to an oral glucose tolerance test, bone mineral density (BMD), liver and renal function tests, and food diaries. At 30-month follow-up, weight (101.5±3.8 vs. 94.5±3.9 kg) and BMI (36.0 ±1.7 vs. 33.5±1.7 kg/m2) remained significantly below baseline (all p<0.05). No significant change in fat-free mass (56.7±2.1 vs. 56.9±2.2 kg) or appendicular lean mass (24.1±1.0 vs. 24.1±1.1kg, all p>0.05) occurred between 12 months (end of trial) and 30 months. Improvements in the physical performance test (PPT 27±0.7 vs. 30.2±0.6), insulin sensitivity (4.1±0.8 vs. 3.0±0.6), and insulin area under the curve (12484±2042 vs. 9270±1139 min.mg/dl) remained at 30 months compared to baseline (all p<0.05). Waist circumference (116±3 vs. 109±3 cm) and systolic blood pressure (134±6 vs. 123±5 mm HG) remained decreased at 30 months compared to baseline (all p<0.05). Whole body and lumbar spine BMD did not change; however, total hip BMD progressively decreased at 30 months compared to baseline (0.985±.026 vs. 0.941±.024 g/cm2; p<0.05). There were no adverse effects on liver or renal function. Food frequency questionnaire data showed lower overall caloric intake (-619±157 kcal/day) at 30 months compared to baseline (p<0.05). These findings suggest that long-term maintenance of clinically important weight loss is possible in frail, obese older adults. Weight maintenance appears to be achieved through continued caloric restriction. Larger, long-term studies are needed to follow up on these findings and investigate mechanisms and behaviors underlying maintenance of weight loss and physical function.

Hepatitis B virus sequencing and liver fibrosis evaluation in HIV/HBV co-infected Nigerians.

PubMed

Grant, Jennifer; Agbaji, Oche; Kramvis, Anna; Yousif, Mukhlid; Auwal, Mu'azu; Penugonda, Sudhir; Ugoagwu, Placid; Murphy, Robert; Hawkins, Claudia

2017-06-01

Molecular characteristics of hepatitis B virus (HBV), such as genotype and genomic mutations, may contribute to liver-related morbidity and mortality. The association of these characteristics with liver fibrosis severity in sub-Saharan Africa is uncertain. We aimed to characterise molecular HBV features in human immunodeficiency virus (HIV)/HBV co-infected Nigerians and evaluate associations between these characteristics and liver fibrosis severity before and after antiretroviral therapy (ART) initiation. HIV/HBV co-infected Nigerians underwent liver fibrosis estimation by transient elastography (TE) prior to and 36 months after ART initiation. Basal core promoter/precore (BCP/PC) and preS1/preS2/S regions of HBV were sequenced from baseline plasma samples. We evaluated associations between HBV mutations and liver fibrosis severity by univariate and multivariable regression. At baseline, 94 patients underwent TE with median liver stiffness of 6.4 (IQR 4.7-8.7) kPa. Patients were predominantly infected with HBV genotype E (45/46) and HBe-antigen negative (75/94, 79.8%). We identified BCP A1762T/G1764A in 15/35 (43%), PC G1896A in 20/35 (57%), 'a' determinant mutations in 12/45 (26.7%) and preS2 deletions in 6/16 (37.5%). PreS2 mutations were associated with advanced fibrosis in multivariable analysis. At follow-up, median liver stiffness was 5.2 (IQR 4.1-6.6) kPa. No HBV molecular characteristics were associated with lack of fibrosis regression, although HIV virologic control, body mass index (BMI) and baseline CD4+ T-cell count were associated with a decline in fibrosis stage. Frequent BCP/PC and preS1/preS2/S mutations were found in ART-naïve HIV/HBV co-infected Nigerians. Median liver stiffness declined after initiation of ART, regardless of pre-ART HBV mutational pattern or virologic characteristics. © 2017 John Wiley & Sons Ltd.

Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis.

PubMed

Forsyth, Christopher B; Farhadi, Ashkan; Jakate, Shriram M; Tang, Yueming; Shaikh, Maliha; Keshavarzian, Ali

2009-03-01

Because only 30% of alcoholics develop alcoholic liver disease (ALD), a factor other than heavy alcohol consumption must be involved in the development of alcohol-induced liver injury. Animal and human studies suggest that bacterial products, such as endotoxins, are the second key co-factors, and oxidant-mediated gut leakiness is one of the sources of endotoxemia. Probiotics have been used to prevent and treat diseases associated with gut-derived bacterial products and disorders associated with gut leakiness. Indeed, "probiotic"Lactobacillus rhamnosus has been successfully used to treat alcohol-induced liver injury in rats. However, the mechanism of action involved in the potential beneficial effects of L. rhamnosus in alcohol liver injury is not known. We hypothesized that probiotics could preserve normal barrier function in an animal model of ALD by preventing alcohol-induced oxidative stress and thus prevent the development of hyperpermeability and subsequent alcoholic steatohepatitis (ASH). Male Sprague-Dawley rats were gavaged with alcohol twice daily (8 gm/kg) for 10 weeks. In addition, alcoholic rats were also treated with once daily gavage of either 2.5 x 10(7) live L. rhamnosus Gorbach-Goldin (LGG) or vehicle (V). Intestinal permeability (baseline and at 10 weeks) was determined using a sugar bolus and GC analysis of urinary sugars. Intestinal and liver tissues were analyzed for markers of oxidative stress and inflammation. In addition, livers were assessed histologically for severity of ASH and total fat (steatosis). Alcohol+LGG (ALC+LGG)-fed rats had significantly (P< or =.05) less severe ASH than ALC+V-fed rats. L. rhamnosus Gorbach-Goldin also reduced alcohol-induced gut leakiness and significantly blunted alcohol-induced oxidative stress and inflammation in both intestine and the liver. L. rhamnosus Gorbach-Goldin probiotic gavage significantly ameliorated ASH in rats. This improvement was associated with reduced markers of intestinal and liver oxidative stress and inflammation and preserved gut barrier function. Our study provides a scientific rationale to test probiotics for treatment and/or prevention of alcoholic liver disease in man.

Transient hyperglycemia during liver transplantation does not affect the early graft function.

PubMed

Blasi, Annabel; Beltran, Joan; Martin, Nuria; Martinez-Pallí, Graciela; Lozano, Juan J; Balust, Jaume; Torrents, Abigail; Taura, Pilar

2015-01-01

Background and rationale for the study. Hyperglycemia after graft reperfusion is a consistent finding in liver transplantation (LT) that remains poorly studied. We aim to describe its appearance in LT recipients of different types of grafts and its relation to the graft function. 436 LT recipients of donors after brain death (DBD), donors after cardiac death (DCD), and familial amyloidotic polyneuropathy (FAP) donors were reviewed. Serum glucose was measured at baseline, during the anhepatic phase, after graft reperfusion, and at the end of surgery. Early graft dysfunction (EAD) was assessed by Olthoff criteria. Caspase-3, IFN-γ, IL1β, and IL6 gene expression were measured in liver biopsy. The highest increase in glucose levels after reperfusion was observed in FAP LT recipients and the lowest in DCD LT recipients. Glucose level during the anhepatic phase was the only modifiable predictive variable of hyperglycemia after reperfusion. No relation was found between hyperglycemia after reperfusion and EAD. However, recipients with the highest glucose levels after reperfusion tended to achieve the best glucose control at the end of surgery and those who were unable to control the glucose value after reperfusion showed EAD more frequently. The highest levels of caspase-3 were found in recipients with the lowest glucose values after reperfusion. In conclusion, glucose levels increased after graft reperfusion to a different extent according to the donor type. Contrary to general belief, transient hyperglycemia after reperfusion does not appear to impact negatively on the liver graft function and could even be suggested as a marker of graft quality.

Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy.

PubMed

Sandoval-Sus, Jose D; Mogollon-Duffo, Francis; Patel, Ankita; Visweshwar, Nathan; Laber, Damian A; Kim, Richard; Jagal, Michael V

2017-01-01

We report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control. In December 2015, at the time of the patient's progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient's wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response. We report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell.

Automatic detection of new tumors and tumor burden evaluation in longitudinal liver CT scan studies.

PubMed

Vivanti, R; Szeskin, A; Lev-Cohain, N; Sosna, J; Joskowicz, L

2017-11-01

Radiological longitudinal follow-up of liver tumors in CT scans is the standard of care for disease progression assessment and for liver tumor therapy. Finding new tumors in the follow-up scan is essential to determine malignancy, to evaluate the total tumor burden, and to determine treatment efficacy. Since new tumors are typically small, they may be missed by examining radiologists. We describe a new method for the automatic detection and segmentation of new tumors in longitudinal liver CT studies and for liver tumors burden quantification. Its inputs are the baseline and follow-up CT scans, the baseline tumors delineation, and a tumor appearance prior model. Its outputs are the new tumors segmentations in the follow-up scan, the tumor burden quantification in both scans, and the tumor burden change. Our method is the first comprehensive method that is explicitly designed to find new liver tumors. It integrates information from the scans, the baseline known tumors delineations, and a tumor appearance prior model in the form of a global convolutional neural network classifier. Unlike other deep learning-based methods, it does not require large tagged training sets. Our experimental results on 246 tumors, of which 97 were new tumors, from 37 longitudinal liver CT studies with radiologist approved ground-truth segmentations, yields a true positive new tumors detection rate of 86 versus 72% with stand-alone detection, and a tumor burden volume overlap error of 16%. New tumors detection and tumor burden volumetry are important for diagnosis and treatment. Our new method enables a simplified radiologist-friendly workflow that is potentially more accurate and reliable than the existing one by automatically and accurately following known tumors and detecting new tumors in the follow-up scan.

Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.

PubMed

Philips, Cyriac Abby; Phadke, Nikhil; Ganesan, Karthik; Ranade, Shatakshi; Augustine, Philip

2018-06-21

Alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease. We present the first study to compare outcomes in patients of severe alcoholic hepatitis (SAH) on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor fecal transplantation (FMT) and discuss distinct microbial community and microbiome metabolic functional changes after FMT. Out of 1271 liver disease patients, 809 (63.7%) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT) were included. Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3 months were analyzed between groups. Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT. All the patients were male. The proportions of patients surviving at the end of 1 and 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 63%, 47%, 40% and 75% [p = 0.179] and 38%, 29%, 30%, and 75% [p = 0.036], respectively. When compared with FMT, relative risk and hazard ratios for death were higher in all the other groups. Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes. Healthy donor FMT for SAH improves survival beyond what is offered by current therapies and can function as a cost-effective bridge to liver transplant (LT) or for improving transplant-free survival. Larger studies and randomized trials are unmet needs.

Kinetic analysis of contralateral liver hypertrophy after radioembolization of primary and metastatic liver tumors.

PubMed

Orcutt, Sonia T; Abuodeh, Yazan; Naghavi, Arash; Frakes, Jessica; Hoffe, Sarah; Kis, Bela; Anaya, Daniel A

2018-05-01

Radioembolization induces liver hypertrophy, although the extent and rate of hypertrophy are unknown. Our goal was to examine the kinetics of contralateral liver hypertrophy after transarterial radioembolization. A retrospective study (2010-2014) of treatment-naïve patients with primary/secondary liver malignancies undergoing right lobe radioembolization was performed. Computed tomography volumetry was performed before and 1, 3, and 6 months after radioembolization. Outcomes of interest were left lobe (standardized future liver remnant) degree of hypertrophy, kinetic growth rate, and ability to reach goal standardized future liver remnant ≥40%. Medians were compared with the Kruskall-Wallis test. Time to event analysis was used to estimate time to reach goal standardized future liver remnant. In the study, 25 patients were included. At 1, 3, and 6 months, median degree of hypertrophy was 4%, 8%, and 12% (P < .001), degree of hypertrophy relative to baseline future liver remnants was 11%, 17%, and 31% (P = .015), and kinetic growth rate was 0.8%, 0.5%, and 0.4%/week (P = .002). In patients with baseline standardized future liver remnant <40% (N= 16), median time to reach standardized future liver remnant ≥40% was 7.3 months, with 75% accomplishing standardized future liver remnant ≥40% at 8.2 months. Radioembolization induces hypertrophy of the contralateral lobe to a similar extent as existing methods, although at a lower rate. The role of radioembolization as a dual therapy (neoadjuvant and hypetrophy-inducing) for selected patients needs to be studied. (Surgery 2017;160:XXX-XXX.). Copyright © 2017 Elsevier Inc. All rights reserved.

Randomized clinical trial: benefits of aerobic physical activity for 24 weeks in postmenopausal women with nonalcoholic fatty liver disease.

PubMed

Rezende, Rosamar E F; Duarte, Sebastião M B; Stefano, Jose T; Roschel, Hamilton; Gualano, Bruno; de Sá Pinto, Ana L; Vezozzo, Denise C P; Carrilho, Flair J; Oliveira, Claudia P

2016-08-01

The aim of the study was to evaluate the effectiveness of aerobic physical activity in reducing the frequency of hepatic steatosis and metabolic and cardiovascular risk in postmenopausal women with nonalcoholic fatty liver disease (NAFLD). Forty sedentary postmenopausal women (mean age 55.3 ± 8.0 y) with biopsy-proven NAFLD were randomly divided into two groups: an exercising group (19 participants) and a control group (nonexercising, 21 participants). The exercise group underwent a supervised aerobic physical activity program of 120 min/wk for 24 weeks. The anthropometric parameters; body composition; hepatic, lipid, and glycemic profiles; homeostasis model assessment of insulin resistance index; cytokines; transient elastography (FibroScan; liver stiffness/controlled attenuation parameter); and cardiopulmonary exercise test were evaluated at baseline and after 24 weeks of protocol. At baseline there were no significant differences in anthropometric, metabolic, and inflammatory parameters-stiffness and liver fat content by FibroScan between the groups. After 24 weeks, we observed a decrease of waist circumference, an increase of high-density lipoprotein cholesterol levels (P < 0.05), and improved cardiopulmonary functional capacity in the exercise group. In addition, the controlled attenuation parameter analysis showed no significant decrease of hepatic steatosis in the exercise group. With regard to the systemic inflammation, there were, however, no significant differences in the cytokines between the groups. An aerobic physical activity program of 24 weeks in NAFLD postmenopausal women showed improvement in some variables such as waist circumference, high-density lipoprotein cholesterol, and cardiopulmonary performance that may be beneficial in improving cardiovascular risk factors in this population.

Longitudinal monitoring of liver stiffness by acoustic radiation force impulse imaging in patients with chronic hepatitis B receiving entecavir.

PubMed

Wu, Sheng-Di; Ding, Hong; Liu, Li-Li; Zhuang, Yuan; Liu, Yun; Cheng, Li-Sha; Wang, Si-Qi; Tseng, Yu-Jen; Wang, Ji-Yao; Jiang, Wei

2018-06-01

Acoustic radiation force impulse (ARFI) imaging measures liver stiffness (LS), which significantly correlates with the stage of liver fibrosis in treatment-naive patients with chronic hepatitis B (CHB). We aimed to prospectively assess the clinical usefulness of ARFI during long-term antiviral therapy in CHB. Seventy-one CHB patients were consecutively recruited and paired liver biopsies were performed in 27 patients. LS was assessed by ARFI semiannually during entecavir therapy. LS gradually decreased with treatment and continued to decrease after normalization of alanine aminotransaminase. Overall, 97.2% patients achieved improvement of LS, whereas 19.7% patients had more than 30% reduction in LS values between baseline and week 104. Multivariate linear regression analysis showed that the degree of LS reduction significantly correlated with the baseline levels of LS value, platelet and cholinesterase. In the 27 patients who underwent paired liver biopsies, LS significantly correlated with stage of fibrosis and inflammatory grade at baseline. LS values decreased more significantly in patients with fibrosis regression than those with static histological fibrosis. In CHB patients, LS assessed by ARFI was gradually reduced during antiviral therapy. Longitudinal monitoring of LS may be a promising noninvasive assessment of fibrosis regression during long-term antiviral therapy in CHB. Further large sample studies are needed. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evolution of noninvasive tests of liver fibrosis is associated with prognosis in patients with chronic hepatitis C.

PubMed

Vergniol, Julien; Boursier, Jérôme; Coutzac, Clélia; Bertrais, Sandrine; Foucher, Juliette; Angel, Camille; Chermak, Faiza; Hubert, Isabelle Fouchard; Merrouche, Wassil; Oberti, Frédéric; de Lédinghen, Victor; Calès, Paul

2014-07-01

No data are available about the prediction of long-term survival using repeated noninvasive tests of liver fibrosis in chronic hepatitis C (CHC). We aimed to assess the prognostic value of 3-year liver stiffness measurement (LSM), aspartate aminotransferase to platelet ratio index (APRI), and fibrosis 4 (FIB-4) evolution in CHC. CHC patients with two LSM (1,000-1,500 days interval) were prospectively included. Blood fibrosis tests APRI and FIB-4 were calculated the day of baseline (bLSM) and follow-up (fLSM) LSM. Evolution of fibrosis tests was expressed as delta: (follow-up-baseline results)/duration. Date and cause of death were recorded during follow-up that started the day of fLSM. In all, 1,025 patients were included. Median follow-up after fLSM was 38.0 months (interquartile range [IQR]: 27.7-46.1) during which 35 patients died (14 liver-related death) and seven had liver transplantation. Prognostic accuracy (Harrell C-index) of multivariate models including baseline and delta results was not significantly different between LSM and FIB-4 (P ≥ 0.24), whereas FIB-4 provided more accurate prognostic models than APRI (P = 0.03). By multivariate analysis including LSM variables, overall survival was independently predicted by bLSM, delta (dLSM), and sustained virological response (SVR). Prognosis was excellent in patients having bLSM <7 kPa, SVR, or no increase (<1 kPa/year) in 7-14 kPa bLSM. Prognosis was significantly impaired in patients with an increase (≥ 1 kPa/year) in 7-14 kPa bLSM, or decrease (≤ 0 kPa/year) in ≥ 14 kPa bLSM (P = 0.949 between these two groups). Patients with an increase (>0 kPa/year) in ≥ 14 kPa bLSM had the worst prognosis. Baseline and delta FIB-4 also identified patient subgroups with significantly different prognosis. Three-year evolution of noninvasive tests of liver fibrosis has a strong prognostic value in CHC patients. These tests should be repeated to monitor patients and predict their outcome. © 2014 by the American Association for the Study of Liver Diseases.

HBsAg plasma level kinetics: a new role for an old marker as a therapy response predictor in vertically infected children on combination therapy.

PubMed

Carey, I; Bruce, M; Horner, M; Zen, Y; D'Antiga, L; Bansal, S; Vergani, D; Mieli-Vergani, G

2015-04-01

We aimed to investigate the ability of HBsAg plasma level kinetics to predict therapy response by studying 23 children with infancy-acquired chronic hepatitis B (CHB) during combination sequential therapy with lead-in lamivudine (LAM) and add-on interferon-α (IFN-α) [5 responders (R = anti-HBs seroconversion) and 18 nonresponders (NR)] and to assess their relationship with pretreatment intrahepatic HBV-DNA and cccDNA and HBsAg and HBcAg liver expression. Plasma HBsAg levels were measured in samples before (treatment week 0 = TW0), during (TW9, TW28, TW52) and after (follow-up week = FUW24) therapy by Abbott ARCHITECT(®) assay [log10 IU/mL]. Baseline liver HBV-DNA and cccDNA were quantified by real-time TaqMan PCR [log10 copies/ng genomic DNA]. HBsAg and HBcAg liver expression was evaluated by immunostaining of formalin-fixed, paraffin-embedded specimens [number of positive cells/1000 hepatocytes]. All results are presented as medians. Plasma: at baseline, on-treatment and during follow-up, HBsAg levels were lower in R than NR (TW0: 4.36 vs 4.75;TW28: 2.44 vs 4.35;TW52: 0 vs 4.08 and FUW24: 0.17 vs 4.35, all P < 0.05). Liver: baseline HBV-DNA (3.82 vs 4.71, P = 0.16) and cccDNA (1.98 vs 2.26, P = 0.18) tended to be lower in R than NR, HBsAg expression was lower in R than NR (0.5 vs 4.7, P = 0.03), and HBcAg expression was similar between R and NR. There were positive correlations between plasma HBsAg levels and liver HBV-DNA (r = 0.44, P = 0.04), cccDNA (r = 0.41, P = 0.04) and HBsAg liver expression (r = 0.38, P = 0.05). Lower baseline HBsAg plasma levels, lower HBsAg expression in liver and on-treatment decline of plasma HBsAg levels heralds HBsAg clearance and response to treatment in tolerant children with CHB. © 2014 John Wiley & Sons Ltd.

IDENTIFICATION OF BIOLOGICALLY RELEVANT GENES USING A DATABASE OF RAT LIVER AND KIDNEY BASELINE GENE EXPRESSION

EPA Science Inventory

Microarray data from independent labs and studies can be compared to potentially identify toxicologically and biologically relevant genes. The Baseline Animal Database working group of HESI was formed to assess baseline gene expression from microarray data derived from control or...

Physiological and biochemical basis of clinical liver function tests: a review.

PubMed

Hoekstra, Lisette T; de Graaf, Wilmar; Nibourg, Geert A A; Heger, Michal; Bennink, Roelof J; Stieger, Bruno; van Gulik, Thomas M

2013-01-01

To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. A MEDLINE search was performed using the key words "liver function tests," "functional studies in the liver," "compromised liver," "physiological basis," and "mechanistic background," with and without Boolean operators. Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques ((99m)Tc-galactosyl serum albumin scintigraphy and (99m)Tc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, (99m)Tc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

Liver and Skin Histopathology in Adults with Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B)

PubMed Central

Thurberg, Beth L.; Wasserstein, Melissa P.; Schiano, Thomas; O’Brien, Fanny; Richards, Susan; Cox, Gerald F.; McGovern, Margaret M.

2012-01-01

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin in multiple cells types, and occurs most prominently within the liver, spleen and lungs, leading to significant clinical disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a Phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick disease type B. Eleven of the 17 were enrolled in the trial and each received a single dose of rhASM and underwent a repeat liver biopsy on Day 14. Biopsies were evaluated for fibrosis, sphingomyelin accumulation and macrophage infiltration by light and electron microscopy. When present, fibrosis was periportal and pericellular, predominantly surrounding affected Kupffer cells. Two baseline biopsies exhibited frank cirrhosis. Sphingomyelin was localized to isolated Kupffer cells in mildly affected biopsies and was present in both Kupffer cells and hepatocytes in more severely affected cases. Morphometric quantification of sphingomyelin storage in liver biopsies ranged from 4–44% of the microscopic field. Skin biopsies were also performed at baseline and Day 14 in order to compare the sphingomyelin distribution in a peripheral tissue to that of liver. Sphingomyelin storage was present at lower levels in multiple cell types of the skin, including dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells and Schwann cells. This Phase 1 trial of rhASM in adults with ASMD provided a unique opportunity for a prospective assessment of hepatic and skin pathology in this rare disease and their potential usage as pharmacodynamic biomarkers. PMID:22613999

Monitoring of Total and Regional Liver Function after SIRT.

PubMed

Bennink, Roelof J; Cieslak, Kasia P; van Delden, Otto M; van Lienden, Krijn P; Klümpen, Heinz-Josef; Jansen, Peter L; van Gulik, Thomas M

2014-01-01

Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepatocellular carcinoma or metastatic liver cancer. SIRT is usually well tolerated. However, in most patients, SIRT will result in a (temporary) decreased liver function. Occasionally patients develop radioembolization-induced liver disease (REILD). In case of a high tumor burden of the liver, it could be beneficial to perform SIRT in two sessions enabling the primary untreated liver segments to guarantee liver function until function in the treated segments has recovered or functional hypertrophy has occurred. Clinically used liver function tests provide evidence of only one of the many liver functions, though all of them lack the possibility of assessment of segmental (regional) liver function. Hepatobiliary scintigraphy (HBS) has been validated as a tool to assess total and regional liver function in liver surgery. It is also used to assess segmental liver function before and after portal vein embolization. HBS is considered as a valuable quantitative liver function test enabling assessment of segmental liver function recovery after regional intervention and determination of future remnant liver function. We present two cases in which HBS was used to monitor total and regional liver function in a patient after repeated whole liver SIRT complicated with REILD and a patient treated unilaterally without complications.

Long-Term Telbivudine Treatment Results in Resolution of Liver Inflammation and Fibrosis in Patients with Chronic Hepatitis B.

PubMed

Hou, Jin-Lin; Xu, Daozheng; Shi, Guangfeng; Wan, Mobin; Goodman, Zachary; Tan, Deming; Xie, Qing; Chen, Chengwei; Wei, Lai; Niu, Junqi; Wang, Qinhuan; Ren, Hong; Wang, Yuming; Jia, Jidong; Bao, Weibin; Dong, Yuhong; Trylesinski, Aldo; Naoumov, Nikolai V

2015-08-01

The long-term goal of chronic hepatitis B (CHB) treatment is improvement of liver disease and prevention of cirrhosis. The aim of this study was to assess whether prolonged telbivudine treatment improves liver inflammation and fibrosis. The primary objective was to evaluate the proportion of patients with absence/minimal inflammation (Knodell necroinflammatory score ≤3) on liver biopsy at Year 5. Fifty-seven patients aged 16-70 years with a clinical history of CHB and active viral replication (38 hepatitis B e antigen [HBeAg] positive and 19 HBeAg negative) were followed for 6 years: 33 received telbivudine 600 mg/day continuously for 5 years; 24 received lamivudine 100 mg/day for 2 years and then telbivudine for 3 years. Liver biopsies were taken pre-treatment and after 5 years of treatment. At baseline, mean (standard deviation) serum hepatitis B virus (HBV) DNA load was 8.5 (1.7) log10 copies/mL, Knodell necroinflammatory score was 7.6 (2.9), and Ishak fibrosis score was 2.2 (1.1). After antiviral treatment (median duration: 261 weeks), liver histology improved with increased proportions of patients with absence/minimal liver inflammation (Knodell necroinflammatory score ≤3), from 16% (9/57) at baseline to 98% (56/57), and absence/minimal fibrosis (Ishak score ≤1), from 25% (14/57) at baseline to 84% (48/57). At Year 5, HBV DNA load was <300 copies/mL for all patients; cumulative HBeAg loss and seroconversion rates were 88% and 77%, respectively. At Year 6, 95% of patients with abnormal baseline glomerular filtration rate (60-90 mL/min/1.73 m(2)) improved to normal GFR (>90 mL/min/1.73 m(2)). Long-term telbivudine treatment with profound and durable viral suppression significantly improved liver histology, thus achieving the long-term goals of CHB treatment. FibroScan(®) results after 5 and 6 years of treatment (in almost 20% of patients) were consistent with this information. Novartis and National Science and Technology Major Project (2012ZX10002003). ClinicalTrials.gov # NCT00877149.

Immunological monitoring after organ transplantation: potential role of soluble CD30 blood level measurement.

PubMed

Truong, Dinh Quang; Darwish, Ahmed A; Gras, Jérémie; Wieërs, Grégoire; Cornet, Anne; Robert, Annie; Mourad, Michel; Malaise, Jacques; de Ville de Goyet, Jean; Reding, Raymond; Latinne, Dominique

2007-06-01

Analysing the relevance of soluble CD30 (sCD30) in the bloodstream before and after transplantation may be important for the monitoring of transplant recipients. In this study, 27 patients (15 pediatric liver and 12 adult kidney graft recipients) were investigated. In the liver graft group, the patients who developed acute rejection during the first month (n=9) had a slightly higher sCD30 value on pre-transplantation baseline (day 0) and post-transplantation day 7, when compared to patients with normal graft function (n=6) (day 0: 102(1.6) U/ml versus 118(1.5) U/ml, p=0.52) and (day 7: 69(1.5) U/ml versus 83(1.6) U/ml, p=0.47). Increased serum sCD30 was shown to correlate with increased interleukin-10 circulating levels between day 0 and day 7 (r=0.53; p=0.04), whereas, no correlation could be evidenced between interferon-gamma (IFN-gamma) and sCD30 (r=0.02; p=0.47). Similarly, in the kidney transplantation group, no significant difference was found in sCD30 levels at day 0 in both groups with graft rejection or normal graft function (n=6) (85(1.3) U/ml versus 77(1.6) U/ml, p=0.66), but sCD30 decreased significantly at day 7 post-transplantation from baseline value in the rejection group (n=6) (77(1.6) versus 35(1.4); p=0.02). We conclude that increased serum sCD30 was correlated with increased IL-10 (interleukin-10) circulating levels, but not with IFN-gamma levels in the post-transplantation period. Neither pre-transplantation sCD30 nor sCD30 at day 7 post-transplantation could be correlated with acute rejection in liver graft recipient. The monitoring of sCD30 might constitute a tool to assess the risk of acute rejection in renal transplant but did not appear as a valuable mean for early immunological monitoring in the small group of liver allograft recipients patients analysed in this study.

Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice

PubMed Central

Hasegawa, Tadashi; Ito, Yoshiya; Wijeweera, Jayanthika; Liu, Jie; Malle, Ernst; Farhood, Anwar; McCuskey, Robert S.; Jaeschke, Hartmut

2016-01-01

Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57Bl/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100-fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress (immunostaining for hypochlorous acid-modified epitopes) started at 6 h of reperfusion and peaked at 12–24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury (alanine transaminase activity: 18,000 ± 2,100 U/l; 65% necrosis) compared with lean littermates (alanine transaminase activity: 4,900 ± 720 U/l; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ob mice during reperfusion. In contrast, sham-operated ob/ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil-induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers. PMID:17307725

Energy deficit does not affect immune responses of experimentally infected pacu (Piaractus mesopotamicus).

PubMed

Gimbo, Rodrigo Y; Fávero, Gisele C; Franco Montoya, Luz N; Urbinati, Elisabeth C

2015-04-01

We investigated if the energy deficit following a 30-day starvation period could affect the ability of fish to mount immune responses after experimental exposure to Aeromonas hydrophila. Fish were submitted to two feeding strategies during 30 days: starvation and continuously feeding. Fish were then sampled to allow for the assessment of baseline metabolic and immune system indicators, were next intraperitonially inoculated with A. hydrophila, and finally were sampled at 3 and 24 h after the challenge. The respiratory activity of leukocytes was lower in starved fish at baseline, increasing after bacterial inoculation to levels similar to those seen among fed fish. Levels of serum lysozyme were higher in starved fish at baseline. The same response profile was observed 3 h after inoculation, but among fed fish, these levels increased to values similar to those of starved fish 24 h after infection. Among starved fish, lysozyme concentration did not change over the course of the experiment. The serum ACH activity was lower in starved fish at baseline and increased after bacterial inoculation in both fish groups. Baseline levels of blood glucose of starved fish were lower than those of fed fish and increased 3 h after bacterial inoculation in both fish groups, decreasing in both groups at 24 h after inoculation. Baseline liver glycogen levels were similar in both fish groups and higher than at 3 and 24 h after inoculation. Three hours after bacterial inoculation, liver glycogen was less reduced in fed fish. Baseline levels of blood triglycerides were lower in starved fish and the profile remained unchanged 3 h after inoculation. There was a gradual decrease in fed fish, and the levels of starved fish remained unchanged throughout the observation period. Blood glycerol levels at baseline were higher in starved fish than in fed fish and remained unaltered at 3 h after inoculation. However those levels increased at 24 h. In fed fish there was a gradual increase of glycerol levels up to 24 h after bacterial inoculation. Baseline liver lipid levels of starved fish were lower and this difference in the response profile remained unchanged 3 and 24 h after inoculation. The liver lipid levels of starved fish decreased after inoculation, and remained unchanged in fed fish. As observed in liver lipid, muscle lipid levels of starved fish were lower than in fed fish, throughout the experiment. Starved fish levels remained unchanged; however fed fish levels decreased 24 h after bacterial inoculation. Levels of cortisol were higher in starved fish at baseline and increased in both fish groups 3 h after bacterial inoculation, reaching intermediary levels 24 h after inoculation. Our results show that in pacu, although mounting an immune response triggered after bacterial exposure is an energy-expensive process, fish under energetic deficit status were able to display protection against infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Patient-specific and global convolutional neural networks for robust automatic liver tumor delineation in follow-up CT studies.

PubMed

Vivanti, Refael; Joskowicz, Leo; Lev-Cohain, Naama; Ephrat, Ariel; Sosna, Jacob

2018-03-10

Radiological longitudinal follow-up of tumors in CT scans is essential for disease assessment and liver tumor therapy. Currently, most tumor size measurements follow the RECIST guidelines, which can be off by as much as 50%. True volumetric measurements are more accurate but require manual delineation, which is time-consuming and user-dependent. We present a convolutional neural networks (CNN) based method for robust automatic liver tumor delineation in longitudinal CT studies that uses both global and patient specific CNNs trained on a small database of delineated images. The inputs are the baseline scan and the tumor delineation, a follow-up scan, and a liver tumor global CNN voxel classifier built from radiologist-validated liver tumor delineations. The outputs are the tumor delineations in the follow-up CT scan. The baseline scan tumor delineation serves as a high-quality prior for the tumor characterization in the follow-up scans. It is used to evaluate the global CNN performance on the new case and to reliably predict failures of the global CNN on the follow-up scan. High-scoring cases are segmented with a global CNN; low-scoring cases, which are predicted to be failures of the global CNN, are segmented with a patient-specific CNN built from the baseline scan. Our experimental results on 222 tumors from 31 patients yield an average overlap error of 17% (std = 11.2) and surface distance of 2.1 mm (std = 1.8), far better than stand-alone segmentation. Importantly, the robustness of our method improved from 67% for stand-alone global CNN segmentation to 100%. Unlike other medical imaging deep learning approaches, which require large annotated training datasets, our method exploits the follow-up framework to yield accurate tumor tracking and failure detection and correction with a small training dataset. Graphical abstract Flow diagram of the proposed method. In the offline mode (orange), a global CNN is trained as a voxel classifier to segment liver tumor as in [31]. The online mode (blue) is used for each new case. The input is baseline scan with delineation and the follow-up CT scan to be segmented. The main novelty is the ability to predict failures by trying the system on the baseline scan and the ability to correct them using the patient-specific CNN.

A phase II, randomized, controlled trial of S-adenosylmethionine in reducing serum alpha-fetoprotein (AFP) in patients with hepatitis C cirrhosis and elevated AFP

PubMed Central

Morgan, Timothy R.; Osann, Kathryn; Bottiglieri, Teodoro; Pimstone, Neville; Hoefs, John C.; Hu, Ke-Qin; Hassanein, Tarek; Boyer, Thomas D.; Kong, Lorene; Chen, Wen-Pin; Richmond, Ellen; Gonzalez, Rachel; Rodriguez, Luz M.; Meyskens, Frank L.

2015-01-01

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC while administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum AFP level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 grams/day, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. 110 subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury, or markers of oxidative stress or antioxidant potential. PMID:26130251

Cardiac iron load and function in transfused patients treated with deferasirox (the MILE study).

PubMed

Ho, P Joy; Tay, Lay; Teo, Juliana; Marlton, Paula; Grigg, Andrew; St Pierre, Tim; Brown, Greg; Badcock, Caro-Anne; Traficante, Robert; Gervasio, Othon L; Bowden, Donald K

2017-02-01

To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608). © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea.

PubMed

Nottage, Kerri A; Ware, Russell E; Winter, Bryan; Smeltzer, Matthew; Wang, Winfred C; Hankins, Jane S; Dertinger, Stephen D; Shulkin, Barry; Aygun, Banu

2014-11-01

More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc(99) m liver-spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake, <10% uptake, decreased but ≥10% uptake, and normal. Mean age (N = 40) was 9.1 yrs, range 2.3-17.0. After 3 yrs of treatment, 13 (33%) had uptake on LS scan. These 13 children were younger (median age 6.0 vs. 10.6 yrs, P = 0.008), had a higher HbF at baseline (mean 10.2% vs. 5.8%, P = 0.004) and after 3 yrs (22.9% vs. 13.9%, P < 0.001), achieved MTD more rapidly (median 288 vs. 358 d, P = 0.021), and were more likely to have baseline splenic uptake (P < 0.001). Hydroxyurea at MTD is associated with preserved or improved splenic filtrative function, with 33% demonstrating LS scan uptake after 3 yrs. Younger age, higher %HbF, and baseline splenic function are associated with a favorable outcome. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Gender-Specific Differences in Baseline, Peak, and Delta Serum Creatinine: The NACSELD Experience.

PubMed

O'Leary, Jacqueline G; Wong, Florence; Reddy, K Rajender; Garcia-Tsao, Guadalupe; Kamath, Patrick S; Biggins, Scott W; Fallon, Michael B; Subramanian, Ram M; Maliakkal, B; Thacker, Leroy; Bajaj, Jasmohan S

2017-03-01

Women have lower serum creatinine values than men for similar renal function. We aimed to determine the differential effect of baseline, peak, and delta creatinine between genders on outcomes in infected hospitalized cirrhotic patients. North American Consortium for the Study of End-Stage Liver Disease is a 15-center consortium of tertiary care hepatology centers prospectively enrolling infected cirrhotic inpatients. Baseline, peak, and delta creatinine during hospitalization were compared between genders, and their impact on overall survival, transplant-free survival, probability of transplantation, and need for renal replacement therapy (RRT) was analyzed. In total, 532 patients with cirrhosis (males = 59% median admission MELD = 20) had significantly lower median baseline (1.07 vs. 1.30 mg/dL, p < 0.0001) and peak creatinine (1.47 vs. 1.59 mg/dL, p = 0.024) in women than men during hospitalization for an infection, but both genders had similar delta creatinine levels (0.30 vs. 0.30 mg/dL, p = 0.957). Thirty-day mortality was similar between genders. RRT was not used more often in women (19 vs. 12%, p = 0.050), and women were 1.8 times more likely than men to receive RRT at the same creatinine (p = 0.028). Both peak and delta creatinine significantly predicted 6-month overall and transplant-free survival (p < 0.0001), but the probability of liver transplantation was affected by the interaction between gender and both peak and delta creatinine. Infected hospitalized cirrhotic women are significantly more likely than men to receive RRT at similar creatinine levels. Gender-specific differences in baseline, peak, and delta creatinine need further investigation to determine whether women need acute kidney injury treatment at lower creatinine thresholds than men.

Hepatic sarcoidosis in patients presenting with liver dysfunction: imaging appearance, pathological correlation and disease evolution.

PubMed

Fetzer, David T; Rees, Mitchell A; Dasyam, Anil K; Tublin, Mitchell E

2016-09-01

We hypothesize that hepatic sarcoidosis is a dynamic process that can lead to cirrhosis and portal hypertension, independent of the course of thoracic disease. Therefore, we assess the imaging appearance and progression of hepatic sarcoidosis in subjects presenting with hepatic dysfunction. An IRB-approved, HIPAA-compliant, single-institution retrospective review identified 39 subjects with sarcoidosis-related liver dysfunction. Clinical information was collected. Two abdominal radiologists analyzed baseline and follow-up imaging studies, scoring features of cirrhosis. Chest CT was also analyzed. At presentation, 23 subjects (59.0 %) exhibited >3 cirrhotic features and 15 (38.5 %) >2 findings of portal hypertension. Of subjects with available follow-up, 57.9 % (19 subjects; mean interval 4.7 years) showed worsening of >3 cirrhotic features (Pearson rho = 0.58; p = 0.009). Parenchymal nodules were uncommon (25.6 %), and most regressed. Although 87.2 % of subjects were diagnosed with thoracic sarcoidosis, there was poor correlation between severity of hepatic and chest disease (Pearson rho = 0.30; p = 0.119). A mean of 7.2 years elapsed between diagnosis of pulmonary and liver involvement. Sarcoidosis may present as liver dysfunction, cirrhosis or portal hypertension. Sarcoid-related liver disease may progress and can manifest without, alongside or significantly after a diagnosis of pulmonary disease. • Patients often present with elevated liver function tests indicating cholestasis. • Patients may present with portal hypertension, and some progress to cirrhosis. • Though biopsy can be considered for focal liver lesions, most will regress. • Extent of intra-abdominal involvement may not correlate with severity of thoracic disease. • Liver disease may manifest alongside, prior to or significantly after initial diagnosis.

Green tea polyphenols supplementation and Tai Chi exercise for postmenopausal osteopenic women: safety and quality of life report

PubMed Central

2010-01-01

Background Evidence suggests that both green tea polyphenols (GTP) and Tai Chi (TC) exercise may benefit bone health in osteopenic women. However, their safety in this population has never been systematically investigated. In particular, there have been hepatotoxicity concerns related to green tea extract. This study was to evaluate the safety of 24 weeks of GTP supplementation combined with TC exercise in postmenopausal osteopenic women, along with effects on quality of life in this population. Methods 171 postmenopausal women with osteopenia were randomly assigned to 4 treatment arms for 24 weeks: (1) Placebo (500 mg starch/day), (2) GTP (500 mg GTP/day), (3) Placebo + TC (placebo plus TC training at 60 min/session, 3 sessions/week), and (4) GTP + TC (GTP plus TC training). Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, and total bilirubin at baseline and every 4 weeks. Kidney function (urea nitrogen and creatinine), calcium, and inorganic phosphorus were also assessed at the same times. Qualify of life using SF-36 questionnaire was evaluated at baseline, 12, and 24 weeks. A mixed model of repeated measures ANOVA was applied for analysis. Results 150 subjects completed the study (12% attrition rate). The compliance rates for study agents and TC exercise were 89% and 83%, respectively. Neither GTP supplementation nor TC exercise affected liver or kidney function parameters throughout the study. No adverse event due to study treatment was reported by the participants. TC exercise significantly improved the scores for role-emotional and mental health of subjects, while no effect on quality of life was observed due to GTP supplementation. Conclusions GTP at a dose of 500 mg/day and/or TC exercise at 3 hr/week for 24 weeks appear to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. TC exercise for 24 weeks (3 hr/wk) significantly improved quality of life in terms of role-emotional and mental health in these subjects. ClinicalTrials.gov identifier: NCT00625391. PMID:21143878

Sources of Variance in Baseline Gene Expression in the Rodent Liver

PubMed Central

Corton, J. Christopher; Bushel, Pierre R.; Fostel, Jennifer; O'Lone, Raegan B.

2012-01-01

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. PMID:22230429

Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

PubMed

Donnan, P T; McLernon, D; Dillon, J F; Ryder, S; Roderick, P; Sullivan, F; Rosenberg, W

2009-04-01

To determine the natural history of abnormalities in liver function tests (LFTs), derive predictive algorithms for liver disease and identify the most cost-effective strategies for further investigation. MEDLINE database from 1966 to September 2006, EMBASE, CINAHL and the Cochrane Library. Population-based retrospective cohort study set in primary care in Tayside, Scotland, between 1989 and 2003. Participants were patients with no obvious signs of liver disease and registered with a general practitioner (GP). The study followed up those with an incident batch of LFTs in primary care to subsequent liver disease or mortality over a maximum of 15 years. The health technologies being assessed were primary care LFTs, viral and autoantibody tests, ultrasound and liver biopsy. Measures used were the epidemiology of liver disease in Tayside (ELDIT) database, time-to-event modelling, predictive algorithms derived using the Weibull survival model, decision analyses from an NHS perspective, cost-utility analyses, and one-way and two-way sensitivity analyses. A total of 95,977 patients had 364,194 initial LFTs, with a median follow-up of 3.7 years. Of these, 21.7% had at least one abnormal liver function test (ALFT) and 1090 (1.14%) developed liver disease. Elevated transaminases were strongly associated with diagnosed liver disease, with hazard ratios (HRs) of 4.23 [95% CI (confidence interval) 3.55-5.04] for mild levels and 12.67 (95% CI 9.74-16.47) for severe levels versus normal. For gamma-glutamyltransferase (GGT), these HRs were 2.54 (95% CI 2.17-2.96) and 13.44 (10.71-16.87) respectively. Low albumin was strongly associated with all cause mortality, with ratios of 2.65 (95% CI 2.47-2.85) for mild levels and 4.99 (95% CI 4.26-5.84) for severe levels. Sensitivity for predicting events over 5 years was low and specificity was high. Follow-up time was split into baseline to 3 months, 3 months to 1 year and over 1 year. All LFTs were predictive of liver disease, and high probability of liver disease was associated with being female, methadone use, alcohol dependency and deprivation. The shorter-term models had overall c-statistics of 0.85 and 0.72 for outcome of liver disease at 3 months and 1 year respectively, and 0.88 and 0.82 for all cause mortality at 3 months and 1 year respectively. Calibration was good for models predicting liver disease. Discrimination was low for models predicting events at over 1 year. In cost-utility analyses, retesting dominated referral as an option. However, using the predictive algorithms to identify the top percentile at high risk of liver disease, retesting had an incremental cost-utility ratio of 7588 pounds relative to referral. GGT should be included in the batch of LFTs in primary care. If the patient in primary care has no obvious liver disease and a low or moderate risk of liver disease, retesting in primary care is the most cost-effective option. If the patient with ALFTs in primary care has a high risk of liver disease, retesting depends on the willingness to pay of the NHS. Cut-offs are arbitrary and in developing decision aids it is important to treat the LFT results as continuous variables.

Persistent rotating shift work exposure is a tough second hit contributing to abnormal liver function among on-site workers having sonographic fatty liver.

PubMed

Lin, Yu-Cheng; Chen, Pau-Chung

2015-03-01

To investigate the relationship between elevated serum alanine-transaminase (e-ALT) and persistent rotating shift work (p-RSW) among employees with sonographic fatty liver (SFL), the authors performed a retrospective analysis on a cohort of electronics manufacturing workers. The records of 758 workers (507 men, 251 women) with initially normal ALT and a mean age of 32.9 years were analyzed. A total of 109 workers (14.4%) developed e-ALT after 5 years. Compared with those having neither initial SFL nor p-RSW exposure, multivariate analysis indicated that employees who had initial SFL but without p-RSW finally had a higher risk (odds ratio = 2.9; 95% confidence interval [CI] = 1.7-5.1) for developing e-ALT; workers with baseline SFL plus p-RSW had a 3.7-fold increased risk (95% CI = 1.8-7.5). SFL poses a conspicuous risk for the development of e-ALT, and persistent p-RSW exposure significantly aggravates the development of e-ALT among on-site workers with preexisting SFL. © 2012 APJPH.

Liver enzyme abnormalities in taking traditional herbal medicine in Korea: A retrospective large sample cohort study of musculoskeletal disorder patients.

PubMed

Lee, Jinho; Shin, Joon-Shik; Kim, Me-Riong; Byun, Jang-Hoon; Lee, Seung-Yeol; Shin, Ye-Sle; Kim, Hyejin; Byung Park, Ki; Shin, Byung-Cheul; Lee, Myeong Soo; Ha, In-Hyuk

2015-07-01

The objective of this study is to report the incidence of liver injury from herbal medicine in musculoskeletal disease patients as large-scale studies are scarce. Considering that herbal medicine is frequently used in patients irrespective of liver function in Korea, we investigated the prevalence of liver injury by liver function test results in musculoskeletal disease patients. Of 32675 inpatients taking herbal medicine at 7 locations of a Korean medicine hospital between 2005 and 2013, we screened for liver injury in 6894 patients with liver function tests (LFTs) at admission and discharge. LFTs included t-bilirubin, AST, ALT, and ALP. Liver injury at discharge was assessed by LFT result classifications at admission (liver injury, liver function abnormality, and normal liver function). In analyses for risk factors of liver injury at discharge, we adjusted for age, sex, length of stay, conventional medicine intake, HBs antigen/antibody, and liver function at admission. A total 354 patients (prevalence 5.1%) had liver injury at admission, and 217 (3.1%) at discharge. Of the 354 patients with liver injury at admission, only 9 showed a clinically significant increase after herbal medicine intake, and 225 returned to within normal range or showed significant liver function recovery. Out of 4769 patients with normal liver function at admission, 27 (0.6%) had liver injury at discharge. In multivariate analyses for risk factors, younger age, liver function abnormality at admission, and HBs antigen positive were associated with injury at discharge. The prevalence of liver injury in patients with normal liver function taking herbal medicine for musculoskeletal disease was low, and herbal medicine did not exacerbate liver injury in most patients with injury prior to intake. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Diabetes, plasma glucose and incidence of fatty liver, cirrhosis and liver cancer: A prospective study of 0.5 million people.

PubMed

Pang, Yuanjie; Kartsonaki, Christiana; Turnbull, Iain; Guo, Yu; Clarke, Robert; Chen, Yiping; Bragg, Fiona; Yang, Ling; Bian, Zheng; Millwood, Iona Y; Hao, Juanzhi; Han, Xianyong; Zang, Yajing; Chen, Junshi; Li, Liming; Holmes, Michael V; Chen, Zhengming

2018-05-07

The prevalence of diabetes is increasing rapidly in China. However, evidence is limited about its effects on chronic liver diseases and liver cancer. We aimed to examine the associations of diabetes with chronic liver diseases and liver cancer and of random plasma glucose (RPG) with these liver diseases among participants without diabetes in Chinese adults, and to assess the possible interaction by hepatitis B virus (HBV) infection. The prospective China Kadoorie Biobank recruited 512,891 adults. During 10 years of follow-up, 2,568 liver cancer, 2,082 cirrhosis, 1,298 hospitalised non-alcoholic fatty liver disease (NAFLD), and 244 hospitalised alcoholic liver disease (ALD) were recorded among 503,993 participants without prior history of cancer or chronic liver diseases at baseline. Cox regression was used to estimate hazard ratios (HRs) for each disease by diabetes status (previously diagnosed or screen-detected) and, among those without previously diagnosed diabetes, by levels of RPG. Overall 5.8% of participants had diabetes at baseline. Compared with those without diabetes, individuals with diabetes had adjusted HRs of 1.49 (95% CI 1.30-1.70) for liver cancer, 1.81 (1.57-2.09) for cirrhosis, 1.76 (1.47-2.16) for NAFLD, and 2.24 (1.42-3.54) for ALD. The excess risks decreased but remained elevated in those with longer duration. Among those without previously diagnosed diabetes, RPG was positively associated with liver diseases, with adjusted HRs per 1 mmol/L higher RPG of 1.04 (1.03-1.06) for liver cancer, 1.07 (1.05-1.09) for cirrhosis, 1.07 (1.05-1.10) for NAFLD, and 1.10 (1.05-1.15) for ALD. These associations did not differ by HBV infection. In Chinese adults, diabetes and higher blood glucose levels among those without known diabetes are associated with increased risks of liver cancer and major chronic liver diseases. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Amprenavir and ritonavir plasma concentrations in HIV-infected patients treated with fosamprenavir/ritonavir with various degrees of liver impairment.

PubMed

Seminari, Elena; De Bona, Anna; Gentilini, Gianluca; Galli, Laura; Schira, Giulia; Gianotti, Nicola; Uberti-Foppa, Caterina; Soldarini, Armando; Dorigatti, Fernanda; Lazzarin, Adriano; Castagna, Antonella

2007-10-01

The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment. HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC. Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003). On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Inferior long-term outcomes of liver-kidney transplantation using donation after cardiac death donors: single-center and organ procurement and transplantation network analyses.

PubMed

Wadei, Hani M; Bulatao, Ilynn G; Gonwa, Thomas A; Mai, Martin L; Prendergast, Mary; Keaveny, Andrew P; Rosser, Barry G; Taner, C Burcin

2014-06-01

Limited data are available for outcomes of simultaneous liver-kidney (SLK) transplantation using donation after cardiac death (DCD) donors. The outcomes of 12 DCD-SLK transplants and 54 SLK transplants using donation after brain death (DBD) donors were retrospectively compared. The baseline demographics were similar for the DCD-SLK and DBD-SLK groups except for the higher liver donor risk index for the DCD-SLK group (1.8 ± 0.4 versus 1.3 ± 0.4, P = 0.001). The rates of surgical complications and graft rejections within 1 year were comparable for the DCD-SLK and DBD-SLK groups. Delayed renal graft function was twice as common in the DCD-SLK group. At 1 year, the serum creatinine levels and the iothalamate glomerular filtration rates were similar for the groups. The patient, liver graft, and kidney graft survival rates at 1 year were comparable for the groups (83.3%, 75.0%, and 82.5% for the DCD-SLK group and 92.4%, 92.4%, and 92.6% for the DBD-SLK group, P = 0.3 for all). The DCD-SLK group had worse patient, liver graft, and kidney graft survival at 3 years (62.5%, 62.5%, and 58.9% versus 90.5%, 90.5%, and 90.6%, P = 0.03 for all) and at 5 years (62.5%, 62.5%, and 58.9% versus 87.4%, 87.4%, and 87.7%, P < 0.05 for all). An analysis of the Organ Procurement and Transplantation Network database showed inferior 1- and 5-year patient and graft survival rates for DCD-SLK patients versus DBD-SLK patients. In conclusion, despite comparable rates of surgical and medical complications and comparable kidney function at 1 year, DCD-SLK transplantation was associated with inferior long-term survival in comparison with DBD-SLK transplantation. © 2014 American Association for the Study of Liver Diseases.

The HALT Polycystic Kidney Disease Trials – Analysis of baseline parameters

PubMed Central

Torres, Vicente E.; Chapman, Arlene B.; Perrone, Ronald D.; Bae, K. Ty; Abebe, Kaleab Z.; Bost, James E.; Miskulin, Dana C.; Steinman, Theodore I.; Braun, William; Winklhofer, Franz T.; Hogan, Marie C.; Oskoui, Frederic Rahbari; Kelleher, Cass; Masoumi, Amirali; Glockner, James; Halin, Neil J; Martin, Diego; Remer, Erick; Patel, Nayana.; Pedrosa, Ivan; Wetzel, Louis H.; Thompson, Paul A.; Miller, J. Philip; Meyers, Catherine M.; Schrier, Robert W.

2013-01-01

HALT-PKD consists of two randomized trials comparing treatment with an angiotensin converting inhibitor (ACEI)-angiotensin receptor blocker (ARB) combination vs ACEI alone and standard vs low blood pressure target in Study A (eGFR >60 ml/min/1.73 m2) and ACEI-ARB vs ACEI alone in Study B (eGFR 25-60 ml/min/1.73 m2). It includes the largest cohort of systematically studied ADPKD patients (558 A and 486 B) to date. We used correlation and multiple regression cross-sectional analyses to ascertain associations of baseline parameters with total kidney (TKV) and liver (TLV) or liver cyst (LCV) volumes measured by MRI in Study A and with eGFR in both studies. Lower eGFR and higher natural log transformed urine albumin excretion are independently associated with larger natural log transformed TKV adjusted for height (HtTKV). Higher BSA is independently associated with higher ln(HtTKV) and lower eGFR. Men have larger HtTKV and smaller LCV than women. A weak correlation was found between ln(HtTKV) and ln(HtTLV) or ln(LCV) in women only. Women have higher urine aldosterone excretions and lower plasma potassium levels. In summary, this analysis 1) confirms a strong association between renal volume and functional parameters, 2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and 3) suggests an association between anthropomorphic measures reflecting preand/or post-natal growth and the severity of the disease. PMID:22205355

Computer-aided diagnosis of focal liver lesions by use of physicians' subjective classification of echogenic patterns in baseline and contrast-enhanced ultrasonography.

PubMed

Sugimoto, Katsutoshi; Shiraishi, Junji; Moriyasu, Fuminori; Doi, Kunio

2009-04-01

To develop a computer-aided diagnostic (CAD) scheme for classifying focal liver lesions (FLLs) by use of physicians' subjective classification of echogenic patterns of FLLs on baseline and contrast-enhanced ultrasonography (US). A total of 137 hepatic lesions in 137 patients were evaluated with B-mode and NC100100 (Sonazoid)-enhanced pulse-inversion US; lesions included 74 hepatocellular carcinomas (HCCs) (23: well-differentiated, 36: moderately differentiated, 15: poorly differentiated HCCs), 33 liver metastases, and 30 liver hemangiomas. Three physicians evaluated single images at B-mode and arterial phases with a cine mode. Physicians were asked to classify each lesion into one of eight B-mode and one of eight enhancement patterns, but did not make a diagnosis. To classify five types of FLLs, we employed a decision tree model with four decision nodes and four artificial neural networks (ANNs). The results of the physicians' pattern classifications were used successively for four different ANNs in making decisions at each of the decision nodes in the decision tree model. The classification accuracies for the 137 FLLs were 84.8% for metastasis, 93.3% for hemangioma, and 98.6% for all HCCs. In addition, the classification accuracies for histological differentiation types of HCCs were 65.2% for well-differentiated HCC, 41.7% for moderately differentiated HCC, and 80.0% for poorly differentiated HCC. This CAD scheme has the potential to improve the diagnostic accuracy of liver lesions. However, the accuracy in the histologic differential diagnosis of HCC based on baseline and contrast-enhanced US is still limited.

Hepatic (Liver) Function Panel

MedlinePlus

... Educators Search English Español Blood Test: Hepatic (Liver) Function Panel KidsHealth / For Parents / Blood Test: Hepatic (Liver) ... kidneys ) is working. What Is a Hepatic (Liver) Function Panel? A liver function panel is a blood ...

Quality process measures for rheumatoid arthritis: performance from members enrolled in a national health plan.

PubMed

Tkacz, Joseph; Ellis, Lorie A; Meyer, Roxanne; Bolge, Susan C; Brady, Brenna L; Ruetsch, Charles

2015-02-01

Health care quality problems are reflected in the underuse, overuse, and misuse of health care services. There is evidence suggesting that the quality of rheumatoid arthritis (RA) patient care is suboptimal, which has spurred the development of a number of systematic quality improvement metrics. To investigate a quality process measurement set in a sample of commercially insured RA patients. Medical, pharmacy, and laboratory claims for members with an RA diagnosis (ICD-9-CM 714.x) during calendar years 2008 through 2012 were extracted from the Optum Clinformatics Data Mart database. Eight process quality measures focused on RA patient response and tolerance to therapy were examined in the claims database. Measures were calculated for individual calendar years from 2009 to 2012, inclusive. The majority of adult RA patients received at least 1 prescription for a disease-modifying antirheumatic drug (DMARD) across the 4 measurement years: range = 78.5%-81.6%. Erythrocyte sedimentation rate and C-reactive protein testing were also evident in the majority of the sample, with 67.1%-72.2% of newly diagnosed RA patients receiving baseline testing, and 56.0%-58.7% of existing RA patients receiving annual testing. Among methotrexate users, liver function tests were performed in 74.5%-75.7% of treated patients, serum creatinine tests in 70.1%-72.6% of patients, and complete blood count tests in 74.5%-76.0% of patients. Additionally, most patients initiating a new DMARD had a claim for a baseline serum creatinine test (68.0%-70.3%) and baseline liver function test (69.3%-71.0%). Findings suggest that a majority of RA patients are attaining patient quality process measures, although a considerable proportion of patients (approximately 25%) may be receiving suboptimal care. Further studies are warranted to understand whether attainment of these measures translates into better outcomes.

Day-On, Day-Off emtricitabine, tenofovir disoproxil fumarate and efavirenz single tablet regimen (DODO) as maintenance therapy in HIV-infected patients.

PubMed

Costantini, Andrea; Tontini, Chiara; Rocchi, Monia; Martini, Matteo; Butini, Luca

2018-06-01

Reduced dose schedules may be feasible options to simplify antiretroviral therapy (ART) in selected HIV-1-infected individuals. Efficacy and safety of a Day-on, Day-off (DODO) schedule of tenofovir disoproxil fumarate, emtricitabine and efavirenz (FTC/TDF/EFV) single tablet regimen (STR) was assessed. Twenty-seven patients were prescribed the DODO schedule and were monitored for 48 weeks. Switching criteria were: no previous ART failure, no AIDS-defining illnesses, T CD4 cell nadir >200/mmc, and HIV-RNA below detection limit (40 copies/mL) for at least six months. Clinical and laboratory data, including plasma HIV-RNA levels, T CD4 and CD8 counts, liver and kidney function, lipid levels and ultrasensitive C-reactive protein (us-CRP) were assessed at baseline, week 4, 12, 24, and 48. Statistical analysis was performed by paired Student's T-test for comparison between baseline and each time point and Chi square test for CD4/CD8 ratio comparison. In all, 26 out of 27 patients maintained plasma HIV-RNA levels below the detection limit through the entire follow-up. One patient experienced low level plasma HIV-RNA rebound at week 36 (47 copies/ml) and immediately reverted to the conventional dose schedule of FTC/TDF/EFV; plasma HIV-RNA was undetectable after four weeks. No major changes on liver and kidney function tests, lipid levels and us-CRP were observed. Although no profound modifications of T CD4 count were observed during follow-up, the CD4/CD8 ratio increased significantly at week 48 compared to the baseline (p<0.05). In conclusion, 48-week DODO administration of the fixed dose FTC/TDF/EFV STR combination was safe and effective in maintaining HIV viral replication below the detection limit in a selected group of HIV-1-infected individuals.

Baseline Characteristics of the Autosomal Dominant Polycystic Kidney Disease Subcohort of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).

PubMed

Kim, Hyunsuk; Koh, Junga; Park, Sue K; Oh, Kook Hwan; Kim, Yeong Hoon; Kim, Yaeni; Ahn, Curie; Oh, Yun Kyu

2018-05-24

The aim of this study was to describe the baseline characteristics of autosomal dominant polycystic kidney disease (ADPKD) in a cohort of Korean patients with chronic kidney disease (CKD). From April 2011 to February 2016, patients with CKD stage 1 to 5 (pre-dialysis) were enrolled as an ADPKD subcohort of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease. Baseline characteristics, the correlation of kidney and liver volume and kidney function, and the factors associated with kidney function were analyzed. A total of 364 ADPKD patients with a mean estimated glomerular filtration rate (eGFR) of 68.1 ± 33.3 mL/min/1.73 m 2 (50.5% male with a mean age of 47.0 ± 10.6 years) were enrolled from nine hospitals in Korea. Initially, 55.8% of the patients were asymptomatic, and pain was the most common symptom (12.9%); 87.6% and 77.5% of the patients had hypertension and hepatic cysts, respectively. The height-adjusted total kidney volumes (htTKV) were higher in male patients than in female patients. In contrast, the height-adjusted total liver volumes were higher in female patients than in male patients. The decrease rate of eGFR depending on Log(htTKV) was larger in the group aged between 41 and 50 than the other age groups. Older age, a higher 24-hour urine protein excretion, larger htTKV, and hyperuricemia were independently associated with lower eGFR, whereas using febuxostat was independently associated with higher eGFR. This subcohort will provide clinical characteristics and outcomes of Korean ADPKD patients and can compare with those of other previous cohorts. We have identified factors associated with advanced-stage CKD in Korean patients with ADPKD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Comparison of iron chelation effects of deferoxamine, deferasirox, and combination of deferoxamine and deferiprone on liver and cardiac T2* MRI in thalassemia maior.

PubMed

Ansari, Shahla; Azarkeivan, Azita; Miri-Aliabad, Ghasem; Yousefian, Saeed; Rostami, Tahereh

2017-01-01

Cardiac complications due to iron overload are the most common cause of death in patients with thalassemia major. The aim of this study was to compare iron chelation effects of deferoxamine, deferasirox, and combination of deferoxamine and deferiprone on cardiac and liver iron load measured by T2* MRI. In this study, 108 patients with thalassemia major aged over 10 years who had iron overload in cardiac T2* MRI were studied in terms of iron chelators efficacy on the reduction of myocardial siderosis. The first group received deferoxamine, the second group only deferasirox, and the third group, a combination of deferoxamine and deferiprone. Myocardial iron was measured at baseline and 12 months later through T2* MRI technique. The three groups were similar in terms of age, gender, ferritin level, and mean myocardial T2* at baseline. In the deferoxamine group, myocardial T2* was increased from 12.0±4.1 ms at baseline to 13.5±8.4 ms at 12 months (p=0.10). Significant improvement was observed in myocardial T2* of the deferasirox group (p<0.001). In the combined treatment group, myocardial T2* was significantly increased (p<0.001). These differences among the three groups were not significant at the 12 months. A significant improvement was observed in liver T2* at 12 months compared to baseline in the deferasirox and the combination group. In comparison to deferoxamine monotherapy, combination therapy and deferasirox monotherapy have a significant impact on reducing iron overload and improvement of myocardial and liver T2* MRI.

Acute Kidney Injury after Liver Transplantation.

PubMed

Durand, François; Francoz, Claire; Asrani, Sumeet K; Khemichian, Saro; Pham, Thomas A; Sung, Randall S; Genyk, Yuri S; Nadim, Mitra K

2018-05-29

Since the implementation of the MELD score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of post liver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post LT AKI which then predisposes to posttransplant chronic kidney disease (CKD). Prevention of posttransplant AKI is essential in the improvement of long term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate (GFR). New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post LT in patients with early posttransplant AKI may improve GFR in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late CKD.

Mathematical modeling of serum 13C-retinol in captive rhesus monkeys provides new insights on hypervitaminosis A.

PubMed

Escaron, Anne L; Green, Michael H; Howe, Julie A; Tanumihardjo, Sherry A

2009-10-01

Hypervitaminosis A is increasingly a public health concern, and thus noninvasive quantitative methods merit exploration. In this study, we applied the (13)C-retinol isotope dilution test to a nonhuman primate model with excessive liver stores. After baseline serum chemistries, rhesus macaques (Macaca mulatta; n = 16) were administered 3.5 mumol (13)C(2)-retinyl acetate. Blood was drawn at baseline, 5 h, and 2, 4, 7, 14, 21, and 28 d following the dose. Liver biopsies were collected 7 d before and 2 d after dosing (n = 4) and at 7, 14, and 28 d (n = 4/time) after dosing. Serum and liver were analyzed by HPLC and GC-combustion-isotope ratio MS for retinol and its enrichment, respectively. Model-based compartmental analysis was applied to serum data. Lactate dehydrogenase was elevated in 50% of the monkeys. Total body reserves (TBR) of vitamin A (VA) were calculated at 28 d. Predicted TBR (3.52 +/- 2.01 mmol VA) represented measured liver stores (4.56 +/- 1.38 mmol VA; P = 0.124). Predicted liver VA concentrations (13.3 +/- 9.7 micromol/g) were similar to measured liver VA concentrations (16.4 +/- 5.3 micromol/g). The kinetic models predict that 27-52% of extravascular VA is exchanging with serum in hypervitaminotic A monkeys. The test correctly diagnosed hypervitaminosis A in all monkeys, i.e. 100% sensitivity. Stable isotope techniques have important public health potential for the classification of VA status, including hypervitaminosis, because no other technique besides invasive liver biopsies, correctly identifies excessive liver VA stores.

Longitudinal Liver Stiffness Assessment in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

PubMed Central

Martinez, Stella M.; Foucher, Juliette; Combis, Jean-Marc; Métivier, Sophie; Brunetto, Maurizia; Capron, Dominique; Bourlière, Marc; Bronowicki, Jean-Pierre; Dao, Thong; Maynard-Muet, Marianne; Lucidarme, Damien; Merrouche, Wassil; Forns, Xavier; de Lédinghen, Victor

2012-01-01

Background/Aims Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC). Methods TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC. Results 323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥9.5 and ≥7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change −16%, −10% and −2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement. Conclusions LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage. PMID:23082200

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis.

PubMed

Kanda, Tatsuo; Yasui, Shin; Nakamura, Masato; Nakamoto, Shingo; Takahashi, Koji; Wu, Shuang; Sasaki, Reina; Haga, Yuki; Ogasawara, Sadahisa; Saito, Tomoko; Kobayashi, Kazufumi; Kiyono, Soichiro; Ooka, Yoshihiko; Suzuki, Eiichiro; Chiba, Tetsuhiro; Maruyama, Hitoshi; Imazeki, Fumio; Moriyama, Mitsuhiko; Kato, Naoya

2018-02-20

Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease.

PubMed

Pervez, Muhammad Amjad; Khan, Dishad Ahmet; Ijaz, Aamir; Khan, Shamrez

2018-03-01

Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD. The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed. Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported. δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.

Redox-Dependent HMGB1 Isoforms as Pivotal Co-Ordinators of Drug-Induced Liver Injury: Mechanistic Biomarkers and Therapeutic Targets.

PubMed

Lea, Jonathan D; Clarke, Joanna I; McGuire, Niamh; Antoine, Daniel J

2016-04-20

High-mobility group box 1 (HMGB1) is a critical protein in the coordination of the inflammatory response in drug-induced liver injury (DILI). HMGB1 is released from necrotic hepatocytes and activated immune cells. The extracellular function of HMGB1 is dependent upon redox modification of cysteine residues that control chemoattractant and cytokine-inducing properties. Existing biomarkers of DILI such as alanine aminotransferase (ALT) have limitations such as lack of sensitivity and tissue specificity that can adversely affect clinical intervention. HMGB1 isoforms have been shown to be more sensitive biomarkers than ALT for predicting DILI development and the requirement for liver transplant following acetaminophen (APAP) overdose. Hepatocyte-specific conditional knockout of HMGB1 has demonstrated the pivotal role of HMGB1 in DILI and liver disease. Tandem mass spectrometry (MS/MS) enables the characterization and quantification of different mechanism-dependent post-translationally modified isoforms of HMGB1. HMGB1 shows great promise as a biomarker of DILI. However, current diagnostic assays are either too time-consuming to be clinically applicable (MS/MS) or are unable to distinguish between different redox and acetyl isoforms of HMGB1 (ELISA). Additionally, HMGB1 is not liver specific, so while it outperforms ALT (also not liver specific) as a biomarker for the prediction of DILI development, it should be used in a biomarker panel along with liver-specific markers such as miR-122. A point-of-care test for HMGB1 and the development of redox and acetyl isoform-targeting antibodies will advance clinical utility. Work is ongoing to validate baseline levels of circulating HMGB1 in healthy volunteers.

Threshold doses for focal liver reaction after stereotactic ablative body radiation therapy for small hepatocellular carcinoma depend on liver function: evaluation on magnetic resonance imaging with Gd-EOB-DTPA.

PubMed

Sanuki, Naoko; Takeda, Atsuya; Oku, Yohei; Eriguchi, Takahisa; Nishimura, Shuichi; Aoki, Yosuke; Mizuno, Tomikazu; Iwabuchi, Shogo; Kunieda, Etsuo

2014-02-01

Focal liver reaction (FLR) appears on radiographic images after stereotactic ablative body radiation therapy (SABR) in patients with hepatocellular carcinoma (HCC) and chronic liver disease. We investigated the threshold dose (TD) of FLR and possible factors affecting the TD on gadoxetate acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). In 50 patients who were treated with SABR for small HCC and followed up by MRI for >6 months, FLR, seen as a hypointense area, was evaluated on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. The follow-up MRI with the largest extent of FLR was fused to the planning computed tomography (CT) image, and patients with good image fusion concordance were eligible. After delineating the border of the FLR manually, a dose-volume histogram was used to identify the TD for the FLR. Clinical and volumetric factors were analyzed for correlation with the TD. A total of 45 patients were eligible for analysis with a median image fusion concordance of 84.9% (range, 71.6-95.4%). The median duration between SABR and subsequent hepatobiliary phase MRI with the largest extent of FLR was 3 months (range, 1-6 months). The median TD for FLR was 28.0 Gy (range, 22.3-36.4 Gy). On univariate analysis, pre-treatment Child-Pugh (CP) score and platelet count were significantly correlated with the TD. On multiple linear regression analysis, CP score was the only parameter that predicted TD. Median TDs were 30.5 Gy (range, 26.2.3-36.4 Gy) and 25.2 Gy (range, 22.3-27.5 Gy) for patients with CP-A and CP-B disease, respectively. The TD was significantly correlated with baseline liver function. We propose 30 Gy for CP-A disease and 25 Gy for CP-B disease in 5 fractions as TDs for FLR after SABR for patients with HCC and chronic liver disease. Use of these TDs will help to predict potential loss of liver tissue after SABR. Copyright © 2014 Elsevier Inc. All rights reserved.

Predictive value of liver and spleen stiffness in advanced alcoholic cirrhosis with refractory ascites.

PubMed

Lindner, Franziska; Mühlberg, Reinhard; Wiegand, Johannes; Tröltzsch, Michael; Hoffmeister, Albrecht; Keim, Volker; Karlas, Thomas

2018-06-01

 Recurrent ascitic decompensation is a frequent complication of advanced alcoholic liver disease. Ascites can be controlled by transjugular intrahepatic portosystemic shunt (TIPS) implantation, but specific pre-procedural outcome predictors are not well established. Liver and spleen stiffness measurement (LSM, SSM) correlate with outcome of compensated liver disease, but data for decompensated cirrhosis disease are scarce. Therefore, the predictive value of LSM and SSM was evaluated in patients with refractory ascites treated with TIPS insertion or receiving conservative therapy.  Patients with alcoholic liver cirrhosis and recurrent or refractory ascites were stratified according to TIPS eligibility. LSM was prospectively assessed by transient elastography (TE, XL probe) and point shear wave elastography (pSWE). pSWE was also used for SSM. The primary study endpoint was transplant-free survival after 12 months. In addition, correlation of LSM and SSM with TIPS complications was analyzed.  43 patients (16 % female, age 55.5 [28.6 - 79.6] years) were recruited, n = 20 underwent TIPS and n = 23 were treated with repeated paracenteses only. 15 patients died and five underwent liver transplantation during follow-up. LSM and SSM at baseline did not predict the patients' outcome in the TIPS cohort and in patients with conservative therapy. SSM was increased in two cases with spontaneous TIPS occlusion and declined after revision.  LSM and SSM cannot be recommended for risk stratification in cirrhotic patients with refractory ascites. SSM may be useful in monitoring TIPS function during follow-up. © Georg Thieme Verlag KG Stuttgart · New York.

A novel thyroid function index associated with opposite therapeutic outcomes in advanced hepatocellular carcinoma patients receiving chemotherapy or sorafenib.

PubMed

Chu, Yu-De; Lin, Kwang-Huei; Huang, Ya-Hui; Lin, Chen-Chun; Hung, Chien-Fu; Yeh, Ta-Sen; Lee, Wei-Chen; Yeh, Chau-Ting

2018-05-21

A sustained proportion of advanced hepatocellular carcinoma (HCC) patients worldwide received either chemotherapy or sorafenib. However, to date, effective and convenient biomarkers to predict their therapeutic outcomes remained elusive. Hypothyroidism was associated with favorable anticancer treatment outcomes in several advanced cancers. Here, we aimed to investigate the potential of using thyroid-stimulating hormone (TSH) and free T4 (FT4) levels as biomarkers to predict clinical outcomes in HCC patients receiving chemotherapy or sorafenib. Total 123 advanced HCC patients at Barcelona Clinical Liver Cancer Stage C were included. They were separated into two cohorts, one treated by sorafenib (n = 62) and the other by chemotherapy (n = 61). Clinical data including TSH and FT4 were retrieved and correlated with treatment outcomes. Because of restriction in local insurance policy, the baseline liver function reserve was better in patients receiving sorafenib. Therefore, the two cohorts were analyzed separately. The results showed that a higher (> median) TSH × FT4 value was independently associated with favorable time-to-tumor progression (P = 0.006) and overall survival (P = 0.002) if chemotherapy was provided; whereas it was associated with unfavorable time-to-tumor progression (P = 0.017) and overall survival (P = 0.001) if sorafenib was administrated. These opposite associations remained valid when patients with Child-Pugh class A liver function from either cohort were included for analysis. A novel thyroid function index, TSH × FT4, significantly predicted opposite clinical outcomes in advanced HCC patients receiving sorafenib or chemotherapy treatment. © 2018 John Wiley & Sons Australia, Ltd.

Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, C. David; Bajt, Mary Lynn; Sharpe, Matthew R.

2014-03-01

Following acetaminophen (APAP) overdose there is an inflammatory response triggered by the release of cellular contents from necrotic hepatocytes into the systemic circulation which initiates the recruitment of neutrophils into the liver. It has been demonstrated that neutrophils do not contribute to APAP-induced liver injury, but their role and the role of NADPH oxidase in injury resolution are controversial. C57BL/6 mice were subjected to APAP overdose and neutrophil activation status was determined during liver injury and liver regeneration. Additionally, human APAP overdose patients (ALT: > 800 U/L) had serial blood draws during the injury and recovery phases for the determinationmore » of neutrophil activation. Neutrophils in the peripheral blood of mice showed an increasing activation status (CD11b expression and ROS priming) during and after the peak of injury but returned to baseline levels prior to complete injury resolution. Hepatic sequestered neutrophils showed an increased and sustained CD11b expression, but no ROS priming was observed. Confirming that NADPH oxidase is not critical to injury resolution, gp91{sup phox}−/− mice following APAP overdose displayed no alteration in injury resolution. Peripheral blood from APAP overdose patients also showed increased neutrophil activation status after the peak of liver injury and remained elevated until discharge from the hospital. In mice and humans, markers of activation, like ROS priming, were increased and sustained well after active liver injury had subsided. The similar findings between surviving patients and mice indicate that neutrophil activation may be a critical event for host defense or injury resolution following APAP overdose, but not a contributing factor to APAP-induced injury. - Highlights: • Neutrophil (PMN) function increases during liver repair after acetaminophen overdose. • Liver repair after acetaminophen (APAP)-overdose is not dependent on NADPH oxidase. • Human PMNs do not appear to contribute to acetaminophen (APAP)-induced injury. • Human PMNs have enhanced activation during the resolution of liver injury after APAP.« less

Prognostic durability of liver fibrosis tests and improvement in predictive performance for mortality by combining tests.

PubMed

Bertrais, Sandrine; Boursier, Jérôme; Ducancelle, Alexandra; Oberti, Frédéric; Fouchard-Hubert, Isabelle; Moal, Valérie; Calès, Paul

2017-06-01

There is currently no recommended time interval between noninvasive fibrosis measurements for monitoring chronic liver diseases. We determined how long a single liver fibrosis evaluation may accurately predict mortality, and assessed whether combining tests improves prognostic performance. We included 1559 patients with chronic liver disease and available baseline liver stiffness measurement (LSM) by Fibroscan, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, Hepascore, and FibroMeter V2G . Median follow-up was 2.8 years during which 262 (16.8%) patients died, with 115 liver-related deaths. All fibrosis tests were able to predict mortality, although APRI (and FIB-4 for liver-related mortality) showed lower overall discriminative ability than the other tests (differences in Harrell's C-index: P < 0.050). According to time-dependent AUROCs, the time period with optimal predictive performance was 2-3 years in patients with no/mild fibrosis, 1 year in patients with significant fibrosis, and <6 months in cirrhotic patients even in those with a model of end-stage liver disease (MELD) score <15. Patients were then randomly split in training/testing sets. In the training set, blood tests and LSM were independent predictors of all-cause mortality. The best-fit multivariate model included age, sex, LSM, and FibroMeter V2G with C-index = 0.834 (95% confidence interval, 0.803-0.862). The prognostic model for liver-related mortality included the same covariates with C-index = 0.868 (0.831-0.902). In the testing set, the multivariate models had higher prognostic accuracy than FibroMeter V2G or LSM alone for all-cause mortality and FibroMeter V2G alone for liver-related mortality. The prognostic durability of a single baseline fibrosis evaluation depends on the liver fibrosis level. Combining LSM with a blood fibrosis test improves mortality risk assessment. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score-matched cohort study.

PubMed

Hong, Namki; Yoon, Han Gyul; Seo, Da Hea; Park, Seho; Kim, Seung Il; Sohn, Joo Hyuk; Rhee, Yumie

2017-09-01

Management of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters. Among 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography. Among 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m 2 ), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol-lowering effect of TMX. TMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast-enhanced Magnetic Resonance Imaging.

PubMed

Lenhard, Stephen C; Lev, Mally; Webster, Lindsey O; Peterson, Richard A; Goulbourne, Christopher N; Miller, Richard T; Jucker, Beat M

2016-01-01

To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established. © The Author(s) 2015.

Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis.

PubMed

Singh, Siddharth; Facciorusso, Antonio; Loomba, Rohit; Falck-Ytter, Yngve T

2018-01-01

We performed a systematic review and meta-analysis to estimate the decrease in liver stiffness, measured by vibration-controlled transient elastrography (VCTE), in patients with hepatitis C virus infection who achieved a sustained virologic response (SVR). We searched the literature through October 2016 for observational studies or randomized controlled trials of adults with hepatitis C virus infection who received antiviral therapy (either direct-acting antiviral agents or interferon-based therapies), underwent liver stiffness measurement using VCTE before starting therapy, and had at least 1 follow-up VCTE after completion of therapy; studies also provided data on mean or median liver stiffness measurements for patients who did and did not achieve an SVR. We identified 24 studies, and estimated weighted mean difference (and 95% confidence interval) in liver stiffness in patients with versus without SVR using random-effects meta-analysis. In patients who achieved SVR, liver stiffness decreased by 2.4 kPa at the end of therapy (95% CI, -1.7 to -3.0), by 3.1 kPa 1-6 months after therapy (95% CI, -1.6 to -4.7), by 3.2 kPa 6-12 months after therapy (90% CI, -2.6 to -3.9), and 4.1 kPa 12 months or more after therapy (95% CI, -3.3 to -4.9) (median decrease, 28.2%; interquartile range, 21.8-34.8). In contrast, there was no significant change in liver stiffness in patients who did not achieve an SVR (at 6-12 months after therapy, decrease of 0.6 kPa; 95% CI, -1.7 to 0.5). Decreases in liver stiffness were significantly greater in patients treated with direct-acting antiviral agents than with interferon-based therapy (decrease of 4.5 kPa vs decrease of 2.6 kPa; P = .03), cirrhosis at baseline (decrease of 5.1 kPa vs decrease of 2.8 kPa in patients with no cirrhosis; P = .02), or high pretreatment levels of alanine aminotransferase (P < .01). Among patients with baseline liver stiffness >9.5 kPa, 47% (95% CI, 27%-68%) achieved posttreatment liver stiffness of <9.5 kPa. In a systematic review and meta-analysis, we associated eradication of hepatitis C virus infection (SVR) with significant decreases in liver stiffness, particularly in patients with high baseline level of inflammation or patients who received direct-acting antiviral agents. Almost half the patients considered to have advanced fibrosis, based on VCTE, before therapy achieved posttreatment liver stiffness levels <9.5 kPa. Clinical Trial Registration no: CRD42016051034. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1-13 C]Alanine.

PubMed

Park, Jae Mo; Khemtong, Chalermchai; Liu, Shie-Chau; Hurd, Ralph E; Spielman, Daniel M

2017-05-01

The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD + ]. In this study, we assessed the use of hyperpolarized [1- 13 C]alanine and the subsequent detection of the intracellular products of [1- 13 C]pyruvate and [1- 13 C]lactate as a useful substrate for assessing redox levels in the liver in vivo. Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1- 13 C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of 13 C MRS spectra. In vivo rat liver spectra showed peaks from [1- 13 C] alanine and the products of [1- 13 C]lactate, [1- 13 C]pyruvate, and 13 C-bicarbonate. A significantly increased 13 C-lactate/ 13 C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in 13 C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes. A method to measure in vivo tissue redox using hyperpolarized [1- 13 C]alanine is presented, with the validity of the proposed 13 C-pyruvate/ 13 C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies.

PubMed

Bonnet, Fabrice; Gastaldelli, Amalia; Pihan-Le Bars, Florence; Natali, Andrea; Roussel, Ronan; Petrie, John; Tichet, Jean; Marre, Michel; Fromenty, Bernard; Balkau, Beverley

2017-03-01

We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07-2.22); P = 0.02]. Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension.

Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients.

PubMed

Turner, Alice M; Stolk, Jan; Bals, Robert; Lickliter, Jason D; Hamilton, James; Christianson, Dawn R; Given, Bruce D; Burdon, Jonathan G; Loomba, Rohit; Stoller, James K; Teckman, Jeffery H

2018-03-21

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. NCT02363946. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Preliminary study on liver function changes after trisectionectomy with versus without prior portal vein embolization.

PubMed

Malinowski, Maciej; Lock, Johan Friso; Seehofer, Daniel; Gebauer, Bernhard; Schulz, Antje; Demirel, Lina; Bednarsch, Jan; Stary, Victoria; Neuhaus, Peter; Stockmann, Martin

2016-09-01

Post-hepatectomy liver failure (PHLF) is the major risk factor for mortality after hepatectomy. Preoperative planning of the future liver remnant volume reduces PHLF rates; however, future liver remnant function (FLR-F) might have an even stronger predictive value. In this preliminary study, we used a new method to calculate FLR-F by the LiMAx test and computer tomography-assisted volumetric-analysis to visualize liver function changes after portal vein embolization (PVE) before extended hepatectomy. The subjects included patients undergoing extended right hepatectomy either directly (NO-PVE group) or after PVE (PVE group). Computed tomography (CT) scan and liver function tests (LiMAx) were done before PVE and preoperatively. FLR-F was calculated and correlated with the postoperative liver function. There were 12 patients in the NO-PVE group and 19 patients in the PVE group. FLR-F and postoperative liver function correlated significantly in both groups (p = 0.036, p = 0.011), although postoperative liver function was slightly overestimated, at 32 and 45 µg/kg/min, in the NO-PVE and PVE groups, respectively. LiMAx value did not change after PVE. Volume-function analysis using LiMAx and CT scan enables us to reliably predict early postoperative liver function. Global enzymatic liver function measured by the LiMAx test did not change after PVE, confirming that liver function distribution in the liver stays constant after PVE. An overestimation of FLR-F is needed to compensate for the intraoperative liver injury that occurs in patients undergoing extended hepatectomy.

All That Glitters Yellow Is Not Gold: Presentation and Pathophysiology of Bile Cast Nephropathy.

PubMed

Pitlick, Mitchell; Rastogi, Prerna

2017-10-01

Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice. It is characterized by the presence of bile casts in renal tubules, which can possibly cause tubular injury through obstructive and direct toxic effects. Thus, AKI in patients with liver disease may have a structural component in addition to a functional one. In this study, we describe 2 patients with severe hyperbilirubinemia who developed AKI and underwent a kidney biopsy that revealed bile casts in tubular lumens, consistent with bile cast nephropathy. One patient was treated aggressively for alcoholic hepatitis and required hemodialysis for AKI. The second patient was treated conservatively for drug-induced liver injury and did not require dialysis. Both patients saw a reduction in their bilirubin and creatinine toward baseline. Bile cast nephropathy is an important pathological entity that may account for the renal dysfunction in some patients with liver disease. It requires kidney biopsy for diagnosis and may often be overlooked given the scarcity of kidney biopsy in this particular clinical setting. The etiology is multifactorial, and it is often difficult to predict without the aid of a renal biopsy.

Clamp-crushing vs. radiofrequency-assisted liver resection:changes in liver function tests.

PubMed

Palibrk, Ivan; Milicic, Biljana; Stojiljkovic, Ljuba; Manojlovic, Nebojsa; Dugalic, Vladimir; Bumbasirevic, Vesna; Kalezic, Nevena; Zuvela, Marinko; Milicevic, Miroslav

2012-05-01

Liver resection is the gold standard in managing patients with metastatic or primary liver cancer. The aim of our study was to compare the traditional clamp-crushing technique to the radiofrequency- assisted liver resection technique in terms of postoperative liver function. Liver function was evaluated preoperatively and on postoperative days 3 and 7. Liver synthetic function parameters (serum albumin level, prothrombin time and international normalized ratio), markers of hepatic injury and necrosis (serum alanine aminotransferase, aspartate aminotransferase and total bilirubin level) and microsomal activity (quantitative lidocaine test) were compared. Forty three patients completed the study (14 had clamp-crushing and 29 had radiofrequency assisted liver resection). The groups did not differ in demographic characteristics, pre-operative liver function, operative time and perioperative transfusion rate. In postoperative period, there were similar changes in monitored parameters in both groups except albumin levels, that were higher in radiofrequency-assisted liver resection group (p=0.047). Both, traditional clamp-crushing technique and radiofrequency assisted liver resection technique, result in similar postoperative changes of most monitored liver function parameters.

Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics.

PubMed

Gu, Wen-Yi; Xu, Bao-Yan; Zheng, Xin; Chen, Jinjun; Wang, Xian-Bo; Huang, Yan; Gao, Yan-Hang; Meng, Zhong-Ji; Qian, Zhi-Ping; Liu, Feng; Lu, Xiao-Bo; Shang, Jia; Li, Hai; Wang, Shao-Yang; Sun, Xin; Li, Hai

2018-05-14

Definitions and descriptions of acute-on-chronic liver failure (ACLF) vary between Western and Eastern types, and alcoholism and hepatitis B virus(HBV) are the main etiologies, respectively. To determine whether there are unified diagnostic criteria and common treatment programs for different etiologies of ACLF, a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European CANONIC (Chronic liver failure-ACLF in Cirrhosis) study is urgently needed in Asia, where the prevalence of HBV is high. Fourteen nationwide liver centers from tertiary university hospitals in China were included, and 2,600 hospitalized patients with chronic liver disease (both cirrhotic and non-cirrhotic) of various etiologies with acute decompensation or acute hepatic injury were continuously recruited from January 2015 to December 2016. Data were collected during hospitalization and continuous follow-ups were performed once a month until 36 months after hospital discharge. A multicenter prospective cohort of 2,600 patients was designed (NCT no. NCT02457637). Of these patients, 71.5% had HBV-related disease, 1,833 had cirrhotic disease, and 767 had non-cirrhotic disease. The numbers and proportions of enrolled patients from each participating center and the baseline characteristics of the patients with or without cirrhosis are presented.

The Effect of Symbiotic Supplementation on Liver Enzymes, C-reactive Protein and Ultrasound Findings in Patients with Non-alcoholic Fatty Liver Disease: A Clinical Trial.

PubMed

Asgharian, Atefe; Askari, Gholamreza; Esmailzade, Ahmad; Feizi, Awat; Mohammadi, Vida

2016-01-01

Regarding to the growing prevalence of nonalcoholic fatty liver disease (NAFLD), concentrating on various strategies to its prevention and management seems necessary. The aim of this study was to determine the effects of symbiotic on C-reactive protein (CRP), liver enzymes, and ultrasound findings in patients with NAFLD. Eighty NAFLD patients were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Participants received symbiotic in form of a 500 mg capsule (containing seven species of probiotic bacteria and fructooligosaccharides) or a placebo capsule daily for 8 weeks. Ultrasound grading, CRP, and liver enzymes were evaluated at the baseline and the end of the study. In the symbiotic group, ultrasound grade decreased significantly compared to baseline (P < 0.005) but symbiotic supplementation was not associated with changes in alanine aminotransferase (ALT) and aspartate transaminase (AST) levels. In the placebo group, there was no significant change in steatosis grade whereas ALT and AST levels were significantly increased (P = 0.002, P = 0.02, respectively). CRP values remained static in either group. Symbiotic supplementation improved steatosis in NAFLD patients and might be useful in the management of NAFLD or protective against its progression.

The Effect of Symbiotic Supplementation on Liver Enzymes, C-reactive Protein and Ultrasound Findings in Patients with Non-alcoholic Fatty Liver Disease: A Clinical Trial

PubMed Central

Asgharian, Atefe; Askari, Gholamreza; Esmailzade, Ahmad; Feizi, Awat; Mohammadi, Vida

2016-01-01

Background: Regarding to the growing prevalence of nonalcoholic fatty liver disease (NAFLD), concentrating on various strategies to its prevention and management seems necessary. The aim of this study was to determine the effects of symbiotic on C-reactive protein (CRP), liver enzymes, and ultrasound findings in patients with NAFLD. Methods: Eighty NAFLD patients were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Participants received symbiotic in form of a 500 mg capsule (containing seven species of probiotic bacteria and fructooligosaccharides) or a placebo capsule daily for 8 weeks. Ultrasound grading, CRP, and liver enzymes were evaluated at the baseline and the end of the study. Results: In the symbiotic group, ultrasound grade decreased significantly compared to baseline (P < 0.005) but symbiotic supplementation was not associated with changes in alanine aminotransferase (ALT) and aspartate transaminase (AST) levels. In the placebo group, there was no significant change in steatosis grade whereas ALT and AST levels were significantly increased (P = 0.002, P = 0.02, respectively). CRP values remained static in either group. Conclusions: Symbiotic supplementation improved steatosis in NAFLD patients and might be useful in the management of NAFLD or protective against its progression. PMID:27076897

Functional restoration of cirrhotic liver after partial hepatectomy in the rat.

PubMed

Hashimoto, Masaji; Watanabe, Goro

2005-01-01

Although cirrhosis is the terminal stage of various liver diseases, thanks to recent advances one might eliminate some causes of liver damage. Liver has a potent regeneration capacity. It is important to evaluate the regenerating cirrhotic liver after partial hepatectomy, morphologically and functionally, in the long term. We evaluated the functional capacity of the rat liver rendered cirrhotic by orally administered thioacetamide, and examined the correlation between morphological and functional restoration after 2/3 hepatectomy in comparison with hepatectomized normal rats and sham-operated cirrhotic rats. Morphological restoration was evaluated by remnant liver weight, proliferating cell nuclear antigen labeling index, and fibrosis ratio. Functional restoration was evaluated by the indocyanine green disappearance rate and aminopyrine clearance. Cirrhotic rats were functionally deteriorated in comparison with the normal rats. Morphological restoration in cirrhotic rats was delayed in comparison with normal rats. Functional restoration after 2/3 hepatectomy was advanced in comparison with morphological restoration. In comparison with sham-operated cirrhotic rats, functional restoration of the cirrhotic liver was accelerated by partial hepatectomy. In cirrhotic rats, functional restoration of the liver after 2/3 hepatectomy was advanced in comparison with morphological restoration. Partial hepatectomy seemed to promote functional restoration of the cirrhotic liver.

Multi organ assessment of Compensated Cirrhosis Patients using quantitative Magnetic Resonance Imaging.

PubMed

Bradley, Christopher R; Cox, Eleanor F; Scott, Robert A; James, Martin W; Kaye, Phillip; Aithal, Guruprasad P; Francis, Susan T; Guha, Indra Neil

2018-06-07

Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit versus harm for therapies. Our aim was to establish the feasibility of Magnetic Resonance Imaging to assess changes in compensated cirrhosis (CC), and relate this to disease severity and future liver related outcomes (LROs). 60 CC patients, 40 healthy volunteers and 7 decompensated cirrhotics were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T 1 longitudinal relaxation time and volume assessment of liver, spleen and kidneys, heart rate and cardiac index. We explore MRI parameters with disease severity and differences in baseline MRI parameters in those 11 (18%) of CC patients who had future LROs. In the liver compositional changes were reflected by increased T 1 in progressive disease (p<0.001) and an increase in liver volume in CC (p=0.006), with associated progressive reduction in liver (p < 0.001) and splenic (p<0.001) perfusion. A significant reduction in renal cortex T 1 and increase in cardiac index and superior mesenteric arterial (SMA) blood flow was seen with increasing disease severity. Baseline liver T 1 (p=0.01) and perfusion (p< 0.01), and renal cortex T 1 (p<0.01) were significantly different in CC patients who subsequently developed negative LROs. MRI allows the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement of contrast agent. MRI parameters of liver T 1, renal T 1, hepatic and splenic perfusion, and SMA blood flow were related to risk of LROs. This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (compensated cirrhosis). Those MRI measures which change with disease severity and are related to negative liver related clinical outcomes are described. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

PubMed

Schall, Joan I; Mascarenhas, Maria R; Maqbool, Asim; Dougherty, Kelly A; Elci, Okan; Wang, Dah-Jyuu; Altes, Talissa A; Hommel, Kevin A; Shaw, Walter; Moore, Jeff; Stallings, Virginia A

2016-04-01

Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. A total of 110 subjects were enrolled (age 10.4 ± 3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.

Choline Supplementation with a Structured Lipid in Children with Cystic Fibrosis: A Randomized Placebo-Controlled Trial

PubMed Central

Schall, Joan I.; Mascarenhas, Maria R.; Maqbool, Asim; Dougherty, Kelly A.; Elci, Okan; Wang, Dah-Jyuu; Altes, Talissa A.; Hommel, Kevin A.; Shaw, Walter; Moore, Jeff; Stallings, Virginia A.

2015-01-01

Background Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency (PI) in spite of enzyme treatment and may result in liver, fatty acid and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. Methods Children with CF and PI were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption (CFA), pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared to a healthy comparison group matched for age, sex and body size. Results 110 subjects were enrolled (age 10.4±3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P=0.007). Plasma lysophosphatidylcholine and phosphatidylcholine (PC) increased and fecal PC/phosphatidylethanolamine ratio decreased (P≤0.05) in LXS only, accompanied by a 6% CFA increase (P=0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. Conclusions LXS had improved choline intake, plasma choline status and muscle choline stores, compared with placebo. The choline-rich supplement was safe, accepted by participants and improved choline status in children with CF. PMID:26465792

Differential effect of Pistacia vera extracts on experimental atherosclerosis in the rabbit animal model: an experimental study

PubMed Central

2010-01-01

Background Lipid-enriched diets and oxidative stress are risk factors for the development of atherosclerosis. The effects of the methanolic (ME) and cyclohexane (CHE) extracts of the Pistacia vera nut, often included in the Mediterranean diet, were studied in the rabbit model of atherosclerosis. Methods and results Twenty-four New Zealand White rabbits received atherogenic diet (Control Group), supplemented with ME (Group ME) or CHE (Group CHE) for 3 months. Previously, a GC-MS and a UHPLC LC-DAD-ESI(-)-HRMS/MS method were developed to investigate the extracts' chemical profiles. Blood samples at baseline and monthly determined lipid profile, lipid peroxidation and liver function. The aorta, myocardium and liver were examined histologically at 3 months. Groups ME and CHE had significantly higher HDL- and non-significantly lower LDL-cholesterol median % changes from baseline than the Control Group. Triacylglycerol was significantly higher in Group CHE vs. Control. MDA values were significantly lower in Group ME vs. Control and CHE. ALT and AST were significantly higher in Group CHE vs. Control. γ-GT was lower in Group ME vs. Control. Aortic intimal thickness was significantly less in Groups ME and CHE vs. Control; Group ME atherosclerotic lesions were significantly less extensive vs. Groups Control and CHE. Only Group CHE had significant liver fatty infiltration. Conclusions During short-term administration concomitantly with atherogenic diet, both P. vera extracts were beneficial on HDL-, LDL-cholesterol and aortic intimal thickness. The ME additionally presented an antioxidant effect and significant decrease of aortic surface lesions. These results indicate that P. vera dietary inclusion, in particular its ME, is potentially beneficial in atherosclerosis management. PMID:20633299

Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis VI) Clinical Surveillance Program (CSP).

PubMed

Hendriksz, Christian J; Giugliani, Roberto; Harmatz, Paul; Lampe, Christina; Martins, Ana Maria; Pastores, Gregory M; Steiner, Robert D; Leão Teles, Elisa; Valayannopoulos, Vassili

2013-03-01

To outline the design, baseline data, and 5-year follow-up data of patients with mucopolysaccharidosis (MPS) VI enrolled in the Clinical Surveillance Program (CSP), a voluntary, multinational, observational program. The MPS VI CSP was opened in 2005 to collect, for at least 15 years, observational data from standard clinical and laboratory assessments of patients with MPS VI. Baseline and follow-up data are documented by participating physicians in electronic case report forms. Between September 2005 and March 2010 the CSP enrolled 132 patients, including 123 who received enzyme replacement therapy (ERT) with galsulfase. Median age at enrolment was 13 years (range 1-59). Mean baseline data showed impaired growth, hepatosplenomegaly, and reduced endurance and pulmonary function. The most common findings were heart valve disease (90%), reduced visual acuity (79%), impaired hearing (59%), and hepatosplenomegaly (54%). Follow-up data up to 5 years in patients with pre- and post-ERT measurements showed a decrease in urinary glycosaminoglycans and increases in height and weight in patients <16 years and suggested reductions in liver and spleen size and improvements in endurance and pulmonary function after ERT was started. Vision, hearing, and cardiac function were unchanged. Safety data were in line with previous reports. The CSP represents the largest cross-sectional study of MPS VI to date. This first report provides information on the design and implementation of the program and population statistics for several clinical variables in patients with MPS VI. Data collected over 5 years suggest that ERT provides clinical benefit and is well-tolerated with no new safety concerns.

Mathematical Modeling of Serum 13C-Retinol in Captive Rhesus Monkeys Provides New Insights on Hypervitaminosis A1–3

PubMed Central

Escaron, Anne L.; Green, Michael H.; Howe, Julie A.; Tanumihardjo, Sherry A.

2009-01-01

Hypervitaminosis A is increasingly a public health concern, and thus noninvasive quantitative methods merit exploration. In this study, we applied the 13C-retinol isotope dilution test to a nonhuman primate model with excessive liver stores. After baseline serum chemistries, rhesus macaques (Macaca mulatta; n = 16) were administered 3.5 μmol 13C2-retinyl acetate. Blood was drawn at baseline, 5 h, and 2, 4, 7, 14, 21, and 28 d following the dose. Liver biopsies were collected 7 d before and 2 d after dosing (n = 4) and at 7, 14, and 28 d (n = 4/time) after dosing. Serum and liver were analyzed by HPLC and GC-combustion-isotope ratio MS for retinol and its enrichment, respectively. Model-based compartmental analysis was applied to serum data. Lactate dehydrogenase was elevated in 50% of the monkeys. Total body reserves (TBR) of vitamin A (VA) were calculated at 28 d. Predicted TBR (3.52 ± 2.01 mmol VA) represented measured liver stores (4.56 ± 1.38 mmol VA; P = 0.124). Predicted liver VA concentrations (13.3 ± 9.7 μmol/g) were similar to measured liver VA concentrations (16.4 ± 5.3 μmol/g). The kinetic models predict that 27–52% of extravascular VA is exchanging with serum in hypervitaminotic A monkeys. The test correctly diagnosed hypervitaminosis A in all monkeys, i.e. 100% sensitivity. Stable isotope techniques have important public health potential for the classification of VA status, including hypervitaminosis, because no other technique besides invasive liver biopsies, correctly identifies excessive liver VA stores. PMID:19710158

Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

PubMed Central

Thiel, Karolin; Klingert, Wilfried; Klingert, Kathrin; Morgalla, Matthias H; Schuhmann, Martin U; Leckie, Pamela; Sharifi, Yalda; Davies, Nathan A; Jalan, Rajiv; Peter, Andreas; Grasshoff, Christian; Königsrainer, Alfred; Schenk, Martin; Thiel, Christian

2017-01-01

AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose. METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy. RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 103/µL ± 34 × 103/µL) of intoxicated animals declined slowly to values of 145 × 103/µL ± 46 × 103/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/µL ± 3 × 103/µL preceding fatality within few hours which was significant (P > 0.01). CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model. PMID:28321158

The Association Between Liver and Tumor [18F]FDG Uptake in Patients with Diffuse Large B Cell Lymphoma During Chemotherapy.

PubMed

Wu, Xingchen; Bhattarai, Abhisek; Korkola, Pasi; Pertovaara, Hannu; Eskola, Hannu; Kellokumpu-Lehtinen, Pirkko-Liisa

2017-10-01

The aim of this study was to explore the association between liver, mediastinum and tumor 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) uptake during chemotherapy in diffuse large B cell lymphoma (DLBCL). Nineteen patients with proven DLBCL underwent positron emission tomography (PET)/X-ray computed tomography scan at baseline, 1 week and 2 cycles after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy, and again after chemotherapy completion. The mean and maximal standardized uptake value (SUVmean and SUVmax) of the liver and mediastinum were measured and correlated with the tumor SUVmax, SUVsum, whole-body metabolic tumor volume (MTVwb), and total lesion glycolysis (TLG). At baseline, both the liver and mediastinum SUVmean and SUVmax correlated inversely with the tumor MTVwb or TLG (p < 0.01 or 0.001). The liver SUVmean and SUVmax increased significantly after 1 week of R-CHOP therapy and remained at the high level until chemotherapy completion. The mediastinum SUVmean and SUVmax remained stable during chemotherapy. The tumor SUVmax, SUVsum, MTVwb, and TLG decreased significantly after 1 week of R-CHOP therapy. The change of the liver SUVmean correlated inversely with the change of tumor MTVwb and TLG after 1 week of chemotherapy (p < 0.05, respectively). The intersubject variability of liver and mediastinum [ 18 F]FDG uptake ranged from 11 to 26 %. The liver [ 18 F]FDG uptake increased significantly after R-CHOP therapy. One of the possible reasons is the distribution of a greater fraction of the tracer to healthy tissues rather than tumor after effective chemotherapy. The variability of the liver [ 18 F]FDG uptake during chemotherapy might affect the visual analysis of the interim PET scan and this needs to be confirmed in future studies with a large patient cohort. In addition, the intersubject variability of the liver and mediastinum [ 18 F]FDG uptake should be considered.

Improvement of liver stiffness measurement, acoustic radiation force impulse measurements, and noninvasive fibrosis markers after direct-acting antivirals for hepatitis C virus G4 recurrence post living donor liver transplantation: Egyptian cohort.

PubMed

Alem, Shereen Abdel; Said, Mohamed; Anwar, Ismail; Abdellatif, Zeinab; Elbaz, Tamer; Eletreby, Rasha; AbouElKhair, Mahmoud; El-Serafy, Magdy; Mogawer, Sherif; El-Amir, Mona; El-Shazly, Mostafa; Hosny, Adel; Yosry, Ayman

2018-05-02

Progression of recurrent hepatitis C is accelerated in liver transplant (LT) recipients. Direct-acting antivirals (DAAs) have recently emerged as a promising therapeutic regimen for the treatment of hepatitis C virus infection. Rates of sustained virological response (SVR) have drastically improved since the introduction of DAAs. The aim is to elucidate the changes in liver stiffness measurement (LSM) by transient elastography (TE) as well as acoustic radiation force impulse (ARFI) elastography and fibrosis scores after DAA treatment in LT recipients with hepatitis C virus recurrence. A single-center, prospective study including 58 LT recipients with hepatitis C recurrence who received different sofosbuvir-based treatment regimens. Transient elastography and ARFI elastography values were recorded as well as fibrosis 4 score (FIB-4) and aspartate aminotransferase-to-platelet ratio index were calculated at baseline and SVR at week 24 (SVR24). The outcome was improvement in LSM and at least a 20% decrease in LSM at SVR24 compared with baseline. The sustained virological response was 98.1%. There was improvement of platelet counts, alanine aminotransferase, and aspartate aminotransferase, which in turn caused improvement in fibrosis scores at SVR24. LSM by TE and ARFI elastography decreased from the baseline median value of 6.3 kPa (interquartile range [IQR]; 4.6 to 8.8 kPa) and 1.28 m/s (IQR; 1.07 to 1.53 m/s) to an SVR24 median value of 6.2 kPa (IQR; 4.85 to 8.9 kPa) and 1.12 (IQR; 0.97 to 1.30 m/s), respectively. Logistic regression analysis showed that baseline viral load was the only significant predictor of improvement in LS after DAA therapy at SVR24. Sofosbuvir-based treatment resulted in an early improvement in parameters of liver fibrosis in post-LT patients with hepatitis C recurrence. © 2018 Wiley Periodicals, Inc.

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis

PubMed Central

Kanda, Tatsuo; Yasui, Shin; Nakamura, Masato; Nakamoto, Shingo; Takahashi, Koji; Wu, Shuang; Sasaki, Reina; Haga, Yuki; Ogasawara, Sadahisa; Saito, Tomoko; Kobayashi, Kazufumi; Kiyono, Soichiro; Ooka, Yoshihiko; Suzuki, Eiichiro; Chiba, Tetsuhiro; Maruyama, Hitoshi; Imazeki, Fumio; Moriyama, Mitsuhiko; Kato, Naoya

2018-01-01

Background Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. Results All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Conclusions Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Methods Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed. PMID:29545925

Liver Function Tests

MedlinePlus

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Changes in Regional Adiposity and Cardio-Metabolic Function Following a Weight Loss Program with Sibutramine in Obese Men with Obstructive Sleep Apnea

PubMed Central

Phillips, Craig L.; Yee, Brendon J.; Trenell, Mike I.; Magnussen, John S.; Wang, David; Banerjee, Dev; Berend, Norbert; Grunstein, Ronald R.

2009-01-01

Background: Although obstructive sleep apnea (OSA) is strongly linked with obesity, both conditions have been associated with increased cardiovascular risk including glucose intolerance, dyslipidemia, and hypertension independent of one another. Weight loss is known to improve both cardiovascular risk and OSA severity. The aim of this study was to evaluate cardiovascular and metabolic changes, including compartment-specific fat loss in obese OSA subjects undergoing a weight loss program. Design: Observational study. Participants: 93 men with moderate-severe OSA. Interventions: 6-month open-label weight loss trial combining sibutramine (a serotonin and noradrenaline reuptake inhibitor) with a 600-kcal deficit diet and exercise. Measurements and Results: At baseline and following 6 months of weight loss, OSA was assessed together with CT-quantified intra-abdominal and liver fat and markers of metabolic and cardiovascular function. At 6 months, weight loss and improvements in OSA were accompanied by improved insulin resistance (HOMA), increased HDL cholesterol, and reduced total cholesterol/HDL ratio. There were also reductions in measures of visceral and subcutaneous abdominal fat and liver fat. Reductions in liver fat and sleep time spent below 90% oxyhemoglobin saturation partly explained the improvement in HOMA (R2 = 0.18). In contrast, arterial stiffness (aortic augmentation index), heart rate, blood pressure, and total cholesterol did not change. Conclusions: Weight loss with sibutramine was associated with improvements in metabolic and body composition risk factors but not blood pressure or arterial stiffness. Improved insulin resistance was partly associated with reductions in liver fat and hypoxemia associated with sleep apnea. Citation: Phillips CL; Yee BJ; Trenell MI; Magnussen JS; Wang D; Banerjee D; Berend N; Grunstein RR. Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea. J Clin Sleep Med 2009;5(5):416-421. PMID:19961024

Hepatitis C Virus Resistance Testing in Genotype 1: The Changing Role in Clinical Utility.

PubMed

Molino, Suzanne; Martin, Michelle T

2017-09-01

To review the role and utility of baseline resistance testing with currently available and pipeline genotype 1 hepatitis C virus (HCV) treatment. Authors reviewed liver meeting abstracts for data on currently-available and pipeline genotype 1 retreatment regimens from January 1, 2015, to March 23, 2017. Additional trials were identified from a review of clinicaltrials.gov using the pipeline medication names. Authors identified reports of current and pipeline genotype 1 retreatment regimens. Seven references were clinical study results presented at the meetings of the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, and 2 studies were from clinicaltrials.gov . Retreatment trial data of currently available salvage regimens indicate that baseline NS5A resistance-associated substitutions (RASs) may decrease sustained virological response (SVR) rates when retreating with ledipasvir/sofosbuvir but are not affected when using elbasvir/grazoprevir + sofosbuvir + ribavirin, paritaprevir/ritonavir/ombitasvir + dasabuvir + sofosbuvir, or sofosbuvir/velpatasvir + ribavirin. Pipeline data indicate that baseline NS5A RASs do not affect SVR rates when retreating with sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir. Baseline resistance testing was used for decisional support for 3 clinical scenarios in patients with HCV genotype 1 infection at the time of manuscript submission. Pending the approval of 2 new direct-acting antiviral regimens in the third quarter of 2017, the rapidly evolving HCV treatment guidelines will likely reflect a decreased clinical utility for resistance testing.

Enzymatic liver function capacity correlates with disease severity of patients with liver cirrhosis: a study with the LiMAx test.

PubMed

Malinowski, Maciej; Jara, Maximilian; Lüttgert, Katja; Orr, James; Lock, Johan Friso; Schott, Eckart; Stockmann, Martin

2014-12-01

Assessment and quantification of actual liver function is crucial in patients with chronic liver disease to monitor disease progression and predict individual prognosis. Mathematical models, such as model for end-stage liver disease, are used for risk stratification of patients with chronic liver disease but do not include parameters that reflect the actual functional state of the liver. We aimed to evaluate the potential of a (13)C-based liver function test as a stratification tool by comparison with other liver function tests and clinical parameters in a large sample of healthy controls and cirrhotic patients. We applied maximum liver function capacity (LiMAx) to evaluate actual liver function in 347 patients with cirrhosis and in 86 controls. LiMAx showed strong negative correlation with Child-Pugh Score (r = -0.707; p < 0.001), MELD (r = -0.686; p < 0.001) and liver function tests. LiMAx was lower in patients with liver cirrhosis compared to healthy controls [99 (57-160) µg/kg/h vs. 412 (365-479) µg/kg/h, p < 0.001] and differed among Child-Pugh classes [a: 181 (144-227) µg/kg/h, b: 96 (62-132) µg/kg/h and c: 52 (37-81) µg/kg/h; p < 0.001]. When stratified patients according to disease severity, LiMAx results were not different between cirrhotic patients and cirrhotic patients with transjugular intrahepatic portosystemic shunt. LiMAx appears to provide reliable information on remnant enzymatic liver function in chronic liver disease and allows graduation of disease severity.

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier.

PubMed

Zhou, Da; Pan, Qin; Xin, Feng-Zhi; Zhang, Rui-Nan; He, Chong-Xin; Chen, Guang-Yu; Liu, Chang; Chen, Yuan-Wen; Fan, Jian-Gao

2017-01-07

To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation- or metabolism-associated genes were quantified by real-time PCR. NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae , Blautia and Lactobacillus . These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group. NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.

PubMed

Mauro, Ezequiel; Crespo, Gonzalo; Montironi, Carla; Londoño, Maria-Carlota; Hernández-Gea, Virginia; Ruiz, Pablo; Sastre, Lydia; Lombardo, Julissa; Mariño, Zoe; Díaz, Alba; Colmenero, Jordi; Rimola, Antoni; Garcia-Pagán, Juan Carlos; Brunet, Mercé; Forns, Xavier; Navasa, Miquel

2018-05-01

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694). © 2017 by the American Association for the Study of Liver Diseases.

Biliary drainage strategy of unresectable malignant hilar strictures by computed tomography volumetry.

PubMed

Takahashi, Ei; Fukasawa, Mitsuharu; Sato, Tadashi; Takano, Shinichi; Kadokura, Makoto; Shindo, Hiroko; Yokota, Yudai; Enomoto, Nobuyuki

2015-04-28

To identify criteria for predicting successful drainage of unresectable malignant hilar biliary strictures (UMHBS) because no ideal strategy currently exists. We examined 78 patients with UMHBS who underwent biliary drainage. Drainage was considered effective when the serum bilirubin level decreased by ≥ 50% from the value before stent placement within 2 wk after drainage, without additional intervention. Complications that occurred within 7 d after stent placement were considered as early complications. Before drainage, the liver volume of each section (lateral and medial sections of the left liver and anterior and posterior sections of the right liver) was measured using computed tomography (CT) volumetry. Drained liver volume was calculated based on the volume of each liver section and the type of bile duct stricture (according to the Bismuth classification). Tumor volume, which was calculated by using CT volumetry, was excluded from the volume of each section. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff values for drained liver volume. In addition, factors associated with the effectiveness of drainage and early complications were evaluated. Multivariate analysis showed that drained liver volume [odds ratio (OR) = 2.92, 95%CI: 1.648-5.197; P < 0.001] and impaired liver function (with decompensated liver cirrhosis) (OR = 0.06, 95%CI: 0.009-0.426; P = 0.005) were independent factors contributing to the effectiveness of drainage. ROC analysis for effective drainage showed cutoff values of 33% of liver volume for patients with preserved liver function (with normal liver or compensated liver cirrhosis) and 50% for patients with impaired liver function (with decompensated liver cirrhosis). The sensitivity and specificity of these cutoff values were 82% and 80% for preserved liver function, and 100% and 67% for impaired liver function, respectively. Among patients who met these criteria, the rate of effective drainage among those with preserved liver function and impaired liver function was 90% and 80%, respectively. The rates of effective drainage in both groups were significantly higher than in those who did not fulfill these criteria (P < 0.001 and P = 0.02, respectively). Drainage-associated cholangitis occurred in 9 patients (12%). A smaller drained liver volume was associated with drainage-associated cholangitis (P < 0.01). Liver volume drainage ≥ 33% in patients with preserved liver function and ≥ 50% in patients with impaired liver function correlates with effective biliary drainage in UMHBS.

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

PubMed

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

2013-02-28

To study whether the severity of liver fibrosis estimated by the nonalcoholic fatty liver disease (NAFLD) fibrosis score can predict all-cause mortality, cardiac complications, and/or liver complications of patients with NAFLD over long-term follow-up. A cohort of well-characterized patients with NAFLD diagnosed during the period of 1980-2000 was identified through the Rochester Epidemiology Project. The NAFLD fibrosis score (NFS) was used to separate NAFLD patients with and without advanced liver fibrosis. We used the NFS score to classify the probability of fibrosis as < -1.5 for low probability, > -1.5 to < 0.67 for intermediate probability, and > 0.67 for high probability. Primary endpoints included all-cause death and cardiovascular- and/or liver-related mortality. From the 479 patients with NAFLD assessed, 302 patients (63%) greater than 18 years old were included. All patients were followed, and medical charts were reviewed until August 31, 2009 or the date when the first primary endpoint occurred. By using a standardized case record form, we recorded a detailed history and physical examination and the use of statins and metformin during the follow-up period. A total of 302/479 (63%) NAFLD patients (mean age: 47 ± 13 year) were included with a follow-up period of 12.0 ± 3.9 year. A low probability of advanced fibrosis (NFS < -1.5 at baseline) was found in 181 patients (60%), while an intermediate or high probability of advanced fibrosis (NSF > -1.5) was found in 121 patients (40%). At the end of the follow-up period, 55 patients (18%) developed primary endpoints. A total of 39 patients (13%) died during the follow-up. The leading causes of death were non-hepatic malignancy (n = 13/39; 33.3%), coronary heart disease (CHD) (n = 8/39; 20.5%), and liver-related mortality (n = 5/39; 12.8%). Thirty patients had new-onset CHD, whereas 8 of 30 patients (27%) died from CHD-related causes during the follow-up. In a multivariate analysis, a higher NFS at baseline and the presence of new-onset CHD were significantly predictive of death (OR = 2.6 and 9.2, respectively; P < 0.0001). Our study showed a significant, graded relationship between the NFS, as classified into 3 subgroups (low, intermediate and high probability of liver fibrosis), and the occurrence of primary endpoints. The use of metformin or simvastatin for at least 3 mo during the follow-up was associated with fewer deaths in patients with NAFLD (OR = 0.2 and 0.03, respectively; P < 0.05). Additionally, the rate of annual NFS change in patients with an intermediate or high probability of advanced liver fibrosis was significantly lower than those patients with a low probability of advanced liver fibrosis (0.06 vs 0.09, P = 0.004). The annual NFS change in patients who died was significantly higher than those in patients who survived (0.14 vs 0.07, P = 0.03). At the end of the follow-up, we classified the patients into 3 subgroups according to the progression pattern of liver fibrosis by comparing the NFS at baseline to the NFS at the end of the follow-up period. Most patients were in the stable-fibrosis (60%) and progressive-fibrosis (37%) groups, whereas only 3% were in the regressive fibrosis. A higher NAFLD fibrosis score at baseline and a new onset of CHD were significantly predictive of death in patients with NAFLD.

Impact of effective versus sham continuous positive airway pressure on liver injury in obstructive sleep apnoea: Data from randomized trials.

PubMed

Jullian-Desayes, Ingrid; Tamisier, Renaud; Zarski, Jean-Pierre; Aron-Wisnewsky, Judith; Launois-Rollinat, Sandrine H; Trocme, Candice; Levy, Patrick; Joyeux-Faure, Marie; Pepin, Jean-Louis

2016-02-01

Obstructive sleep apnoea (OSA) could be an independent risk factor for non-alcoholic fatty liver disease (NAFLD) occurrence and progression. The impact of continuous positive airway pressure (CPAP) treatment on non-invasive markers of NAFLD has not been studied. The aim of this study was to evaluate the effect of 6-12 weeks of effective CPAP on the FibroMax test (comprising components including the SteatoTest, NashTest and FibroTest) through three randomized sham controlled studies. The FibroMax test was performed in 103 obstructive sleep apnoea patients (apnoea + hypopnoea index > 15/h) enrolled in a randomized study comparing sham versus effective CPAP. At baseline, 40.4% of patients in the sham CPAP group and 45.5% in the CPAP group exhibited liver steatosis. Furthermore, 39.6% of patients in the sham CPAP group and 58.4% in the CPAP group displayed borderline or possible non-alcoholic steatohepatitis (NASH). Six to twelve weeks of effective CPAP did not demonstrate any impact on reducing steatosis, NASH or liver fibrosis even after adjustment for gender, BMI, baseline apnoea + hypopnoea index and severity of liver injury. A number of non-invasive markers of liver damage are increased in untreated obstructive sleep apnoea patients, potentially contributing to cardiometabolic risk, but they do not improve after 6-12 weeks of effective CPAP treatment. NCT01196845 (ADISAS), NCT00464659 (MneSAS) and NCT00669695 (StatinflaSAS) at ClinicalTrials.gov. © 2015 Asian Pacific Society of Respirology.

A fourth dimension in decision making in hepatology.

PubMed

Ilan, Yaron

2010-12-01

Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders. © 2010 The Japan Society of Hepatology.

Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind, placebo-controlled trial.

PubMed

Kimer, Nina; Pedersen, Julie Steen; Busk, Troels Malte; Gluud, Lise Lotte; Hobolth, Lise; Krag, Aleksander; Møller, Søren; Bendtsen, Flemming

2017-02-01

Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double-blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty-five patients were male, mean age 56 years (±8.4), average Child score 8.3 (±1.3), and Model for End-Stage Liver Disease score 11.7 (±3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 ± 3.8 mm Hg at baseline versus 16.6 ± 5.3 mm Hg at follow-up, compared to the placebo, mean 16.4 ± 4 mm Hg at baseline versus 16.3 ± 4.4 mm Hg at follow-up, P = 0.94. No effect was found on cardiac output, mean 6.9 ± 1.7 L/min at baseline versus 6.9 ± 2.3 L/min at follow-up, compared to placebo, mean 6.6 ± 1.9 L/min at baseline compared to 6.5 ±2.1 L/min at follow-up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes × s/cm 5 ) revealed no effect of rifaximin. Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017;65:592-603). © 2016 by the American Association for the Study of Liver Diseases.

Differences in Peripheral Blood Lymphocytes between Brand-Name and Generic Tacrolimus Used in Stable Liver Transplant Recipients.

PubMed

Kim, Jong Man; Kwon, Choon Hyuck David; Joh, Jae-Won; Sinn, Dong Hyun; Choi, Gyu-Seong; Park, Jae Berm; Kang, Eun-Suk; Lee, Suk-Koo

2017-01-01

In this study, peripheral blood lymphocytes were compared between a brand-name and a generic tacrolimus group in stable liver transplant recipients. Sixteen patients who underwent ABO-compatible living donor liver transplants between 2012 and 2013 and had stable graft function were included in this study. Ten patients received brand-name tacrolimus and 6 patients received generic tacrolimus. CD3, CD4, CD8, γδ, CD4+FoxP3+, and CD3-CD56+ T cells were analyzed in peripheral blood obtained preoperatively and 4, 8, 12, and 24 weeks after liver transplantation. Categorical variables were compared using a χ2 test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. Regarding the baseline and perioperative characteristics, there were no statistically significant differences between the 2 groups. Immunosuppression also was not different. Subtype analysis of T-cell populations carried out in parallel showed similar levels of CD3, CD4, CD8, and γδT cells with brand-name tacrolimus and generic tacrolimus in stable liver transplant recipients. However, the levels of CD4+Foxp3+ and CD3-CD56+ T cells were higher in the brand-name tacrolimus group than in the generic tacrolimus group 8 weeks after transplantation (p < 0.05). The level of CD4+Foxp3+ T cells was higher in the brand-name tacrolimus group than in the generic tacrolimus group after transplantation. This finding showed that brand-name tacrolimus could have more potential immunosuppressive activity than generic tacrolimus regarding the contribution of CD4+Foxp3+ T cells to graft tolerance in liver transplant recipients. © 2017 S. Karger AG, Basel.

Liver function tests

MedlinePlus

Liver function tests are common tests that are used to see how well the liver is working. Tests include: ... E, Bowne WB, Bluth MH. Evaluation of liver function. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

Liver Function Tests

MedlinePlus

... food, store energy, and remove poisons. Liver function tests are blood tests that check to see how well your liver ... hepatitis and cirrhosis. You may have liver function tests as part of a regular checkup. Or you ...

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease.

PubMed

Vichinsky, Elliott; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Eckman, James; Lane, Peter; Files, Beatrice; Hassell, Kathryn; Kelly, Patrick; Wilson, Felicia; Bernaudin, Françoise; Forni, Gian Luca; Okpala, Iheanyi; Ressayre-Djaffer, Catherine; Alberti, Daniele; Holland, Jaymes; Marks, Peter; Fung, Ellen; Fischer, Roland; Mueller, Brigitta U; Coates, Thomas

2007-02-01

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11.4%) and deferoxamine (11.1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

Alternative Therapy and Abnormal Liver Function During Adjuvant Chemotherapy in Breast Cancer Patients

PubMed Central

Ahn, Jin-Hee; Kim, Sung-Bae; Yun, Mi Ra; Lee, Jung-Shin; Kang, Yoon-Koo

2004-01-01

Although hepatotoxicity has been rarely reported during adjuvant chemotherapy in breast cancer patients, we observed a high frequency in our patients who were also taking alternative agents. We therefore sought to determine the association between hepatotoxicity and alternative agents during adjuvant chemotherapy in breast cancer patients. All breast cancer patients were treated with the same chemotherapeutic regimen and had normal baseline liver function test (LFT). LFT was checked repeatedly during each cycle of chemotherapy. Patients showing LFT abnormalities were asked about use of alternative agents, and, after the end of chemotherapy, a questionnaire was administered to each patient on their use of alternative agents. Of 178 patients, 65 (36.5%) admitted using alternative therapy, and significantly more patients in this group developed LFT abnormalities (37/65, 56.9%) than those who denied taking alternative therapy (25/113, 22.1%, p=0.001). Although LFT abnormalities were mild to moderate and normalized in most patients after cessation of alternative agents, it remained a serious problem in one patient. In conclusion, alternative therapy may be one of the etiologies for abnormal LFT in breast cancer patients receiving adjuvant chemotherapy. PMID:15201506

Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxemia in non-infected cirrhotic patients.

PubMed

Weil, Delphine; Pais de Barros, Jean-Paul; Mourey, Guillaume; Laheurte, Caroline; Cypriani, Benoit; Badet, Nicolas; Delabrousse, Eric; Grandclément, Emilie; Di Martino, Vincent; Saas, Philippe; Lagrost, Laurent; Thévenot, Thierry

2018-06-22

The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. Plasma from 90 non-infected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by High Performance Liquid Chromatography coupled with Mass Spectrometry. 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, p=0.005). Patients with severe acute alcoholic hepatitis (n=16; 113 vs 74 ng/mL,p=0.012), diabetic patients (n=22; 99 vs 70 ng/mL, p=0.028) and those not receiving beta-blockers (n=44; 98 vs 72 ng/mL, p=0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n=7; 144 vs 76 ng/mL, p=0.45) or SIRS (n=10; 106 vs 75 ng/mL, p=0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR=4.39; 95%CI=1.79-10.76) or MELD (OR=8.24; 95%CI=3.19-21.32) scores. Patients dying from liver insufficiency (n=6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, p=0.089). In non-infected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, non-use of beta-blockers, and a trend towards poorer outcome is also observed. The direct mass-measurement of LPS using 3-HM appears reliable to detect transient endotoxemia and promising to manage the follow-up of cirrhotic patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Profile, risk factors and outcome of acute kidney injury in paediatric acute-on-chronic liver failure.

PubMed

Lal, Bikrant B; Alam, Seema; Sood, Vikrant; Rawat, Dinesh; Khanna, Rajeev

2018-01-11

There are no studies on acute kidney injury in paediatric acute-on-chronic liver failure. This study was planned with aim to describe the clinical presentation and outcome of acute kidney injury among paediatric acute-on-chronic liver failure patients. Data of all children 1-18 years of age presenting with acute chronic liver failure (Asia pacific association for the study of the liver definition) was reviewed. Acute kidney injury was defined as per Kidney Diseases-Improving Global Outcomes guidelines. Poor outcome was defined as death or need for liver transplant within 3 months of development of acute kidney injury. A total of 84 children with acute-on-chronic liver failure were presented to us in the study period. Acute kidney injury developed in 22.6% of patients with acute-on-chronic liver failure. The median duration from acute-on-chronic liver failure to development of acute kidney injury was 4 weeks (Range: 2-10 weeks). The causes of acute kidney injury were hepatorenal syndrome (31.6%), sepsis (31.6%), nephrotoxic drugs (21%), dehydration (10.5%) and bile pigment related acute tubular necrosis in one patient. On univariate analysis, higher baseline bilirubin, higher international normalized ratio, higher paediatric end stage liver disease, presence of systemic inflammatory response syndrome and presence of spontaneous bacterial peritonitis had significant association with presence of acute kidney injury. On logistic regression analysis, presence of systemic inflammatory response syndrome (adjusted OR: 8.659, 95% CI: 2.18-34.37, P = .002) and higher baseline bilirubin (adjusted OR: 1.07, 95% CI: 1.008-1.135, P = .025) were independently associated with presence of acute kidney injury. Of the patients with acute kidney injury, 5(26.3%) survived with native liver, 10(52.6%) died and 4 (21.1%) underwent liver transplantation. Acute kidney injury developed in 22.6% of children with acute-on-chronic liver failure. Bilirubin more than 17.7 mg/dL and presence of systemic inflammatory response syndrome were high risk factors for acute kidney injury. Development of acute kidney injury in a child with acute-on-chronic liver failure suggests poor outcome and need for early intervention. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Liver function testing with nuclear medicine techniques is coming of age.

PubMed

Bennink, Roelof J; Tulchinsky, Mark; de Graaf, Wilmar; Kadry, Zakiyah; van Gulik, Thomas M

2012-03-01

Liver function is a broad term, as the organ participates in a multitude of different physiological and biochemical processes, including metabolic, synthetic, and detoxifying functions. However, it is the function of the hepatocyte that is central to sustaining normal life and dealing with disease states. When the liver begins to fail in severely ill patients, it forecasts a terminal outcome. However, unlike the glomerular filtration rate which clearly quantifies the key renal function, at most practice sites, there is no clinically available quantitative test for liver function. Although it is commonplace to assess indirect evidence of that function (by measuring blood levels of its end products and by-products) and to detect an acute injury (by following rising transaminases), a widely available test that would directly measure hepatocellular function is lacking. This article reviews current knowledge on liver function studies and focuses on those nuclear medicine tests available to study the whole liver and regional liver function. The clinical application driving these tests, prediction of remnant liver function after partial hepatectomy for primary liver malignancy or metastatic disease, is addressed here in detail. The test was recently validated for this specific application and was shown to be better than the current standard of practice (computed tomography volumetry), particularly in patients with hepatic comorbidities like cirrhosis, steatosis, or cholestasis. Furthermore, early assessment of regional liver function increase after preoperative portal vein embolization becomes possible with this technology. The limiting factor to a wider acceptance of this test is based on the lack of clinical software that would allow calculation of liver function parameters. This article provides information that enables a clinical nuclear medicine facility to provide this test using readily available equipment. Furthermore, it addresses emerging clinical applications that are under investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans.

PubMed

Sevastianova, Ksenia; Kotronen, Anna; Gastaldelli, Amalia; Perttilä, Julia; Hakkarainen, Antti; Lundbom, Jesper; Suojanen, Laura; Orho-Melander, Marju; Lundbom, Nina; Ferrannini, Eleuterio; Rissanen, Aila; Olkkonen, Vesa M; Yki-Järvinen, Hannele

2011-07-01

The rs738409 C→G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([(2)H(5)]glycerol infusion) were measured before and after the diet. At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 ± 0.5 kg; PNPLA3-148II: -3.1 ± 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775.

Liver failure in total artificial heart therapy.

PubMed

Dimitriou, Alexandros Merkourios; Dapunt, Otto; Knez, Igor; Wasler, Andrae; Oberwalder, Peter; Koerfer, Reiner; Tenderich, Gero; Spiliopoulos, Sotirios

2016-07-01

Congestive hepatopathy (CH) and acute liver failure (ALF) are common among biventricular heart failure patients. We sought to evaluate the impact of total artificial heart (TAH) therapy on hepatic function and associated clinical outcomes. A total of 31 patients received a Syncardia Total Artificial Heart. Preoperatively 17 patients exhibited normal liver function or mild hepatic derangements that were clinically insignificant and did not qualify as acute or chronic liver failure, 5 patients exhibited ALF and 9 various hepatic derangements owing to CH. Liver associated mortality and postoperative course of liver values were prospectively documented and retrospectively analyzed. Liver associated mortality in normal liver function, ALF and CH cases was 0%, 20% (P=0.03) and 44.4% (P=0.0008) respectively. 1/17 (5.8%) patients with a normal liver function developed an ALF, 4/5 (80%) patients with an ALF experienced a markedly improvement of hepatic function and 6/9 (66.6%) patients with CH a significant deterioration. TAH therapy results in recovery of hepatic function in ALF cases. Patients with CH prior to surgery form a high risk group with increased liver associated mortality.

Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C.

PubMed

Langhans, Bettina; Nischalke, Hans Dieter; Krämer, Benjamin; Hausen, Annekristin; Dold, Leona; van Heteren, Peer; Hüneburg, Robert; Nattermann, Jacob; Strassburg, Christian P; Spengler, Ulrich

2017-05-01

CD4 + regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination. We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 + CD25 + CD4 + T cells were studied by multi-color flow cytometry and co-culture inhibition assays. Frequencies and activation status of Foxp3 + CD25 + CD4 + T cells remained elevated above those of normal controls in both treatment groups even long-term after HCV elimination. Co-culture assays indicated a dose-response relationship for functional inhibition of autologous CD4 + effector T cells and confirmed that activation of Tregs remained largely unchanged over the observation period. Unlike IFN-free regimens, SOF plus IFN/ribavirin induced a transiently increased frequency of Foxp3 + CD25 + CD4 + T cells at EOT (5.0% at baseline to 6.1% at EOT; p=0.001). These Foxp3 + CD25 + CD4 + T cells co-expressed the activation markers glycoprotein A repetitions predominant (GARP; p=0.012) and tumor necrosis factor receptor superfamily, member 4 (OX-40; p=0.001) but showed unchanged in vitro inhibitory activity. Although IFN-based DAA therapy induced transient expansion of activated Foxp3 + CD25 + CD4 + T cells, neither IFN-based nor IFN-free DAA regimens normalized frequencies and activation status of Tregs one year after viral elimination. Persistence of immunosuppressive Tregs may thus contribute to complications of liver disease even long-term after HCV cure. In chronic hepatitis C virus (HCV) infection, CD4 + regulatory T cells (Tregs) can reduce antiviral immune responses, promote liver fibrosis and may increase the risk for liver cancer, because they gradually expand during disease. Modern direct-acting antiviral agents (DAA) can "cure" hepatitis C in almost all treated patients. However, our study shows that DAA do not normalize the increased frequency and activation status of Tregs even long-term after HCV elimination. Tregs may persistently modulate functions of the immune system even after "cure" of hepatitis C. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

PubMed Central

Kyriakides, Michael; Hardwick, Rhiannon N.; Jin, Zhaosheng; Goedken, Michael J.; Holmes, Elaine; Cherrington, Nathan J.; Coen, Muireann

2014-01-01

Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs. PMID:25145655

Hepatic Fibrosis Progression in HIV-Hepatitis C Virus Co-Infection--The Effect of Sex on Risk of Significant Fibrosis Measured by Aspartate-to-Platelet Ratio Index.

PubMed

Rollet-Kurhajec, Kathleen C; Moodie, Erica E M; Walmsley, Sharon; Cooper, Curtis; Pick, Neora; Klein, Marina B

2015-01-01

In Hepatitis C virus (HCV) mono-infection, male sex is associated with faster liver fibrosis progression but the effects of sex have not been well studied in HIV-HCV co-infected patients. We examined the influence of sex on progression to significant liver fibrosis in HIV-HCV co-infected adults receiving antiretroviral therapy (ART) using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate biomarker of liver fibrosis. We evaluated 308 HIV infected, HCV RNA positive participants of a Canadian multicentre prospective cohort receiving antiretrovirals and without significant liver fibrosis or end-stage liver disease at baseline. We used multivariate discrete-time proportional hazards models to assess the effect of sex on time to significant fibrosis (APRI≥1.5) adjusting for baseline age, alcohol use, cigarette smoking, HCV duration, and APRI and time-updated CD4 count and HIV RNA. Overall, 55 (18%) participants developed an APRI ≥ 1.5 over 544 person-years of at-risk follow-up time; 18 (21%) women (incidence rate (IR)=14.0/100 PY; 7.5-20.4) and 37 (17%) men (IR=8.9/100 PY; 6.0-11.8). Women had more favourable profiles with respect to traditional risk factors for liver disease progression (younger, shorter duration of HCV infection and less alcohol use). Despite this, female sex was associated with a greater than two-fold increased risk of fibrosis progression (adjusted hazard rate (HR) =2.23; 1.22-4.08). HIV-HCV co-infected women receiving antiretroviral therapy were at significantly greater risk of progressing to liver fibrosis as measured by APRI compared with men. Enhanced efforts to engage and treat co-infected women for HCV are needed.

Burden of Liver Abscess and Survival Risk Score in Thailand: A Population-Based Study

PubMed Central

Poovorawan, Kittiyod; Pan-ngum, Wirichada; Soonthornworasiri, Ngamphol; Kulrat, Chotipa; Kittitrakul, Chatporn; Wilairatana, Polrat; Treeprasertsuk, Sombat; Kitsahawong, Bubpha; Phaosawasdi, Kamthorn

2016-01-01

In Thailand, the burden of liver abscess, a life-threatening infectious disease, has not been thoroughly evaluated. We developed a predictive scoring system to estimate survival of patients with liver abscess using information from the 2008–2013 Nationwide Hospital Admission Data to evaluate the burden of liver abscess in Thailand. All patients with primary diagnosis of pyogenic liver abscess (PLA) and amoebic liver abscess (ALA) were included. Epidemiological data, baseline characteristics, hospital course, and survival were analyzed. Overall, 11,296 admissions comprising 8,423 patients from 844 hospitals across Thailand were eligible for analysis. The mean age was 52 ± 17 years and 66.1% of patients were male. ALA was significantly prevalent in southern and western border regions of Thailand, and PLA occurred nationwide. The highest incidence of liver abscess occurred in the rainy season (June–November, P < 0.01). The median length of hospital stay was 8 days (interquartile range = 4–13 days), and mean direct cost of hospitalization was 846 ± 1,574 USD. The overall inhospital mortality rate was 2.8%. Incidence of ALA decreased over the 5-year study period, whereas PLA incidence increased (P < 0.01). Using multivariable Cox regression methods with stepwise variable selection, we developed a final model with five highly significant baseline parameters associated with increased 60-day mortality: older age, PLA, underlying chronic kidney disease, cirrhosis, and human immunodeficiency virus infection. Range of estimated probability of 60-day survival was 95–16% at cumulative risk score 0–13. This simplified score is practical, and may help clinicians prioritize patients requiring more intensive care. PMID:27325801

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

PubMed

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

2016-04-01

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

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a case cohort study.

PubMed

Carr, Brian I; Buch, Shama C; Kondragunta, Venkateswarlu; Pancoska, Petr; Branch, Robert A

2008-08-01

A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end-point for all analyses. We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient subgroups based on poor liver function and aggressive tumor characteristics. In subgroup analysis based on these subsets, there was clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant, independent but modest risk factors. The results of this large dataset show that amongst nonsurgical HCC patients, there are clear subsets with longer survival than other subsets. This data also supports the concept of heterogeneity of HCC.

Dynamic gadoxetate-enhanced MRI for the assessment of total and segmental liver function and volume in primary sclerosing cholangitis.

PubMed

Nilsson, Henrik; Blomqvist, Lennart; Douglas, Lena; Nordell, Anders; Jacobsson, Hans; Hagen, Karin; Bergquist, Annika; Jonas, Eduard

2014-04-01

To evaluate dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) for the assessment of global and segmental liver volume and function in patients with primary sclerosing cholangitis (PSC), and to explore the heterogeneous distribution of liver function in this patient group. Twelve patients with primary sclerosing cholangitis (PSC) and 20 healthy volunteers were examined using DHCE-MRI with Gd-EOB-DTPA. Segmental and total liver volume were calculated, and functional parameters (hepatic extraction fraction [HEF], input relative blood-flow [irBF], and mean transit time [MTT]) were calculated in each liver voxel using deconvolutional analysis. In each study subject, and incongruence score (IS) was constructed to describe the mismatch between segmental function and volume. Among patients, the liver function parameters were correlated to bile duct obstruction and to established scoring models for liver disease. Liver function was significantly more heterogeneously distributed in the patient group (IS 1.0 versus 0.4). There were significant correlations between biliary obstruction and segmental functional parameters (HEF rho -0.24; irBF rho -0.45), and the Mayo risk score correlated significantly with the total liver extraction capacity of Gd-EOB-DTPA (rho -0.85). The study demonstrates a new method to quantify total and segmental liver function using DHCE-MRI in patients with PSC. Copyright © 2013 Wiley Periodicals, Inc.

Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

PubMed

Ward, C; Lucas, M; Piris, J; Collier, J; Chapel, H

2008-09-01

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

Future remnant liver function as predictive factor for the hypertrophy response after portal vein embolization.

PubMed

Cieslak, Kasia P; Huisman, Floor; Bais, Thomas; Bennink, Roelof J; van Lienden, Krijn P; Verheij, Joanne; Besselink, Marc G; Busch, Olivier R C; van Gulik, Thomas M

2017-07-01

Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99m Tc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre-portal vein embolization and post-portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre-portal vein embolization future remnant liver function was performed to identify patients who would meet the post-portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m 2 ). Mean pre-portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m 2 and increased to 2.89% ± 0.97%/min/m 2 post-portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre-portal vein embolization future remnant liver function of ≥1.72%/min/m 2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post-portal vein embolization future remnant liver function below the cutoff value for safe resection. When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of liver volume and liver function on posthepatectomy liver failure after portal vein embolization- A multivariable cohort analysis.

PubMed

Alizai, Patrick H; Haelsig, Annabel; Bruners, Philipp; Ulmer, Florian; Klink, Christian D; Dejong, Cornelis H C; Neumann, Ulf P; Schmeding, Maximilian

2018-01-01

Liver failure remains a life-threatening complication after liver resection, and is difficult to predict preoperatively. This retrospective cohort study evaluated different preoperative factors in regard to their impact on posthepatectomy liver failure (PHLF) after extended liver resection and previous portal vein embolization (PVE). Patient characteristics, liver function and liver volumes of patients undergoing PVE and subsequent liver resection were analyzed. Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2). Factors associated with the primary end point PHLF (according to ISGLS definition) were identified through multivariable analysis. Secondary end points were 30-day mortality and morbidity. 95 patients received PVE, of which 64 patients underwent major liver resection. PHLF occurred in 7 patients (11%). Calculated postoperative liver function was significantly lower in patients with PHLF than in patients without PHLF (67 vs. 109 μg/kg/h; p = 0.01). Other factors associated with PHLF by univariable analysis were age, future liver remnant, MELD score, ASA score, renal insufficiency and heart insufficiency. By multivariable analysis, future liver remnant was the only factor significantly associated with PHLF (p = 0.03). Mortality and morbidity rates were 4.7% and 29.7% respectively. Future liver remnant is the only preoperative factor with a significant impact on PHLF. Assessment of preoperative liver function may additionally help identify patients at risk for PHLF.

Standardized added metabolic activity (SAM) IN ¹⁸F-FDG PET assessment of treatment response in colorectal liver metastases.

PubMed

Mertens, Jeroen; De Bruyne, S; Van Damme, N; Smeets, P; Ceelen, W; Troisi, R; Laurent, S; Geboes, K; Peeters, M; Goethals, I; Van de Wiele, C

2013-08-01

Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC). (18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (∆SUVmax) and SAM (∆SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS). A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ∆SUVmax of 25.3% and ∆SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ∆SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ∆SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS). (18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ∆SAM were found to be significant prognostic factors for PFS and OS.

A low-glycemic-load versus low-fat diet in the treatment of fatty liver in obese children.

PubMed

Ramon-Krauel, Marta; Salsberg, Sandra L; Ebbeling, Cara B; Voss, Stephan D; Mulkern, Robert V; Apura, Margaret M; Cooke, Emily A; Sarao, Karen; Jonas, Maureen M; Ludwig, David S

2013-06-01

Fatty liver is highly prevalent among obese children and represents a major risk factor for chronic liver diseases and severe metabolic complications. We randomly assigned 17 obese children 8-17 years of age with fatty liver to either an experimental low-glycemic-load or conventional low-fat diet for 6 months. Participants in both groups received nutrition education and behavioral counseling of equal intensity. The primary outcome was hepatic lipid content measured by proton magnetic resonance spectroscopy. Secondary outcomes included change in visceral fat, BMI, anthropometrics, alanine aminotransferase (ALT), and insulin resistance. A total of 16 participants completed the study. Reported glycemic load decreased in the low-glycemic-load group and reported dietary fat decreased in the low-fat group. At baseline, liver fat was 23.8% [standard deviation (SD) 12.2] in the low-glycemic-load group and 29.3% (14.1) in the low-fat group. Liver fat decreased substantially in both groups at 6 months expressed as absolute percentage change, with no between-group differences [-8.8 (standard error (SE) 4.1) vs. -10.5 (3.7)%, respectively, p=0.76 for group×time interaction]. Secondary outcomes also improved on both diets, with no between-group differences. Baseline and change in ALT were strongly associated with hepatic fat content. Weight-reducing diets focused either on glycemic load or dietary fat improved hepatic steatosis over 6 months. Additional research is needed to determine whether these diets differ in effectiveness over the long term. clinicaltrials.gov Identifier: NCT00480922.

An innovative method to accommodate Chinese medicine pattern diagnosis within the framework of evidence-based medical research.

PubMed

Berle, Christine; Cobbin, Deirdre; Smith, Narelle; Zaslawski, Christopher

2011-11-01

Pattern diagnosis is an integral aspect of Chinese medicine (CM). CM differentiates biomedical diseases into patterns, based upon the patient's symptoms and signs. Pattern identification (PI) is used to diagnose, direct the treatment principle and determine the treatment protocol. Most CM research has used fixed formula treatments for Western-defined diseases with outcomes measured using objective biomedical markers. This article presents an innovative method used in a randomised controlled pilot study using acupuncture for participants with hepatitis C virus. Each participant's CM patterns were identified and quantified at baseline which directed the treatment protocol for the treatment group. Data identified that while each participant expressed different patterns at baseline all participants displayed multiple patterns. Six patterns showed some expression by all 16 participants; Liver (Gan) yin vacuity expressing a group aggregate mean percentage of 47.2, binding depression of Liver qi 46.9, and Liver Kidney (Shen) yin vacuity 45.1. Further sub category gender grouping revealed that pattern ranking changed with gender; Liver yin vacuity (male 53.4%, female 51.93%), binding depression of Liver qi (male 50.0%, female 42.86%) and Liver Kidney yin vacuity (male 42.9%, female 47.96%). The quantification of CM patterns described in this article permitted statistical evaluation of presenting CM patterns. Although this methodology is in its infancy it may have potential use in the integration of PI with rigorous evidence based clinical research. Biomedical markers often do not relate to symptom/signs and therefore this innovative measure may offer an additional CM evaluation methodology and further CM PI understanding.

Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity.

PubMed

Stockmann, Martin; Lock, Johan F; Riecke, Björn; Heyne, Karsten; Martus, Peter; Fricke, Michael; Lehmann, Sina; Niehues, Stefan M; Schwabe, Michael; Lemke, Arne-Jörn; Neuhaus, Peter

2009-07-01

To validate the LiMAx test, a new bedside test for the determination of maximal liver function capacity based on C-methacetin kinetics. To investigate the diagnostic performance of different liver function tests and scores including the LiMAx test for the prediction of postoperative outcome after hepatectomy. Liver failure is a major cause of mortality after hepatectomy. Preoperative prediction of residual liver function has been limited so far. Sixty-four patients undergoing hepatectomy were analyzed in a prospective observational study. Volumetric analysis of the liver was carried out using preoperative computed tomography and intraoperative measurements. Perioperative factors associated with morbidity and mortality were analyzed. Cutoff values of the LiMAx test were evaluated by receiver operating characteristic. Residual LiMAx demonstrated an excellent linear correlation with residual liver volume (r = 0.94, P < 0.001) after hepatectomy. The multivariate analysis revealed LiMAx on postoperative day 1 as the only predictor of liver failure (P = 0.003) and mortality (P = 0.004). AUROC for the prediction of liver failure and liver failure related death by the LiMAx test was both 0.99. Preoperative volume/function analysis combining CT volumetry and LiMAx allowed an accurate calculation of the remnant liver function capacity prior to surgery (r = 0.85, P < 0.001). Residual liver function is the major factor influencing the outcome of patients after hepatectomy and can be predicted preoperatively by a combination of LiMAx and CT volumetry.

The Role of Akt in Chronic Liver Disease and Liver Regeneration.

PubMed

Morales-Ruiz, Manuel; Santel, Ansgar; Ribera, Jordi; Jiménez, Wladimiro

2017-02-01

The liver is continuously exposed to diverse insults, which may culminate in pathological processes causing liver disease. An effective therapeutic strategy for chronic liver disease should control the causal factors of the disease and stimulate functional liver regeneration. Preclinical studies have shown that interventions aimed at maintaining Akt activity in a dysfunctional liver meet most of the criteria. Although the central function of Akt is cell survival, other cellular aspects such as glucose uptake, glycogen synthesis, cell-cycle progression, and lipid metabolism have been shown to be prominent functions of Akt in the context of hepatic physiology. In this review, the authors describe the benefits of the Akt signaling pathway, emphasizing its importance in coordinating proper cellular growth and differentiation during liver regeneration, hepatic function, and liver disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The effect of a low fructose and low glycemic index/load (FRAGILE) dietary intervention on indices of liver function, cardiometabolic risk factors, and body composition in children and adolescents with nonalcoholic fatty liver disease (NAFLD).

PubMed

Mager, Diana R; Iñiguez, Ingrid Rivera; Gilmour, Susan; Yap, Jason

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in obese children. Diets high in added fructose (high fructose corn syrup; HFCS) and glycemic index (GI)/glycemic load (GL) are associated with increased risk of NAFLD. Lifestyle modification is the main treatment, but no guidelines regarding specific dietary interventions for childhood NAFLD exist. We hypothesized that reductions in dietary fructose (total, free, and HFCS)/GI/GL over 6 months would result in improvements in body composition and markers of liver dysfunction and cardiometabolic risk in childhood NAFLD. Children and adolescents with NAFLD (n = 12) and healthy controls (n = 14) 7-18 years were studied at baseline and 3 and 6 months post-dietary intervention. Plasma markers of liver dysfunction (ALT, AST, γGT), cardiometabolic risk (TG, total cholesterol, LDL-HDL cholesterol, Apo-B100, Apo-B48, Apo-CIII, insulin, homeostasis model of assessment of insulin resistance [HOMA-IR]), inflammation (TNF-α, IL-6, IL-10), anthropometric, and blood pressure (BP) were studied using validated methodologies. Significant reductions in systolic BP (SBP), percentage body fat (BF), and plasma concentrations of ALT (P = .04), Apo-B100 (P < .001), and HOMA-IR were observed in children with NAFLD at 3 and 6 months (P < .05). Dietary reductions in total/free fructose/HFCS and GL were related to reductions in SBP (P = .01), ALT (P = .004), HOMA-IR (P = .03), and percentage BF in children with NAFLD. Reductions in dietary GI were associated with reduced plasma Apo-B100 (P = .02) in both groups. With the exception of Apo-B100, no changes in laboratory variables were observed in the control group. Modest reductions in fructose (total/free, HFCS) and GI/GL intake result in improvements of plasma markers of liver dysfunction and cardiometabolic risk in childhood NAFLD. © 2013 American Society for Parenteral and Enteral Nutrition.

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

PubMed

Larsen, Fin Stolze; Schmidt, Lars Ebbe; Bernsmeier, Christine; Rasmussen, Allan; Isoniemi, Helena; Patel, Vishal C; Triantafyllou, Evangelos; Bernal, William; Auzinger, Georg; Shawcross, Debbie; Eefsen, Martin; Bjerring, Peter Nissen; Clemmesen, Jens Otto; Hockerstedt, Krister; Frederiksen, Hans-Jørgen; Hansen, Bent Adel; Antoniades, Charalambos G; Wendon, Julia

2016-01-01

Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis.

PubMed

Al-Fayoumi, Suliman; Hashiguchi, Taishi; Shirakata, Yuka; Mascarenhas, John; Singer, Jack W

2018-01-01

Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling. To investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease. Pacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured. Pacritinib-treated mice had significantly ( P <0.01) reduced fibrotic areas in liver compared to vehicle control and significantly ( P <0.05) lower levels of CK18. The antifibrotic effect of pacritinib was comparable to that of telmisartan, but without significant effects on fat accumulation. These results, the first to demonstrate hepatic antifibrotic effects for pacritinib in an animal model of liver disease, provide preliminary support for potential clinical applications of pacritinib in fibrotic diseases other than myelofibrosis.

Computational Modeling in Liver Surgery

PubMed Central

Christ, Bruno; Dahmen, Uta; Herrmann, Karl-Heinz; König, Matthias; Reichenbach, Jürgen R.; Ricken, Tim; Schleicher, Jana; Ole Schwen, Lars; Vlaic, Sebastian; Waschinsky, Navina

2017-01-01

The need for extended liver resection is increasing due to the growing incidence of liver tumors in aging societies. Individualized surgical planning is the key for identifying the optimal resection strategy and to minimize the risk of postoperative liver failure and tumor recurrence. Current computational tools provide virtual planning of liver resection by taking into account the spatial relationship between the tumor and the hepatic vascular trees, as well as the size of the future liver remnant. However, size and function of the liver are not necessarily equivalent. Hence, determining the future liver volume might misestimate the future liver function, especially in cases of hepatic comorbidities such as hepatic steatosis. A systems medicine approach could be applied, including biological, medical, and surgical aspects, by integrating all available anatomical and functional information of the individual patient. Such an approach holds promise for better prediction of postoperative liver function and hence improved risk assessment. This review provides an overview of mathematical models related to the liver and its function and explores their potential relevance for computational liver surgery. We first summarize key facts of hepatic anatomy, physiology, and pathology relevant for hepatic surgery, followed by a description of the computational tools currently used in liver surgical planning. Then we present selected state-of-the-art computational liver models potentially useful to support liver surgery. Finally, we discuss the main challenges that will need to be addressed when developing advanced computational planning tools in the context of liver surgery. PMID:29249974

Optimizing global liver function in radiation therapy treatment planning

NASA Astrophysics Data System (ADS)

Wu, Victor W.; Epelman, Marina A.; Wang, Hesheng; Romeijn, H. Edwin; Feng, Mary; Cao, Yue; Ten Haken, Randall K.; Matuszak, Martha M.

2016-09-01

Liver stereotactic body radiation therapy (SBRT) patients differ in both pre-treatment liver function (e.g. due to degree of cirrhosis and/or prior treatment) and radiosensitivity, leading to high variability in potential liver toxicity with similar doses. This work investigates three treatment planning optimization models that minimize risk of toxicity: two consider both voxel-based pre-treatment liver function and local-function-based radiosensitivity with dose; one considers only dose. Each model optimizes different objective functions (varying in complexity of capturing the influence of dose on liver function) subject to the same dose constraints and are tested on 2D synthesized and 3D clinical cases. The normal-liver-based objective functions are the linearized equivalent uniform dose (\\ell \\text{EUD} ) (conventional ‘\\ell \\text{EUD} model’), the so-called perfusion-weighted \\ell \\text{EUD} (\\text{fEUD} ) (proposed ‘fEUD model’), and post-treatment global liver function (GLF) (proposed ‘GLF model’), predicted by a new liver-perfusion-based dose-response model. The resulting \\ell \\text{EUD} , fEUD, and GLF plans delivering the same target \\ell \\text{EUD} are compared with respect to their post-treatment function and various dose-based metrics. Voxel-based portal venous liver perfusion, used as a measure of local function, is computed using DCE-MRI. In cases used in our experiments, the GLF plan preserves up to 4.6 % ≤ft(7.5 % \\right) more liver function than the fEUD (\\ell \\text{EUD} ) plan does in 2D cases, and up to 4.5 % ≤ft(5.6 % \\right) in 3D cases. The GLF and fEUD plans worsen in \\ell \\text{EUD} of functional liver on average by 1.0 Gy and 0.5 Gy in 2D and 3D cases, respectively. Liver perfusion information can be used during treatment planning to minimize the risk of toxicity by improving expected GLF; the degree of benefit varies with perfusion pattern. Although fEUD model optimization is computationally inexpensive and often achieves better GLF than \\ell \\text{EUD} model optimization does, the GLF model directly optimizes a more clinically relevant metric and can further improve fEUD plan quality.

Extracorporeal Bioartificial Liver for Treating Acute Liver Diseases

PubMed Central

Kumar, Ashok; Tripathi, Anuj; Jain, Shivali

2011-01-01

Abstract: Liver is a vital organ of the human body performing myriad of essential functions. Liver-related ailments are often life-threatening and dramatically deteriorate the quality of life of patients. Management of acute liver diseases requires adequate support of various hepatic functions. Thus far, liver transplantation has been proven as the only effective solution for acute liver diseases. However, broader application of liver transplantation is limited by demand for lifelong immunosuppression, shortage of organ donors, relative high morbidity, and high cost. Therefore, research has been focused on attempting to develop alternative support systems to treat liver diseases. Earlier attempts have been made to use nonbiological therapies based on the use of conventional detoxification procedures such as filtration and dialysis. However, the absence of liver cells in such techniques reduced the overall survival rate of the patients and led to inadequate essential liver-specific functions. As a result, there has been growing interest in the development of biological therapy-based extracorporeal liver support systems as a bridge to liver transplantation or to support the ailing liver. A bioartificial liver support is an extracorporeal device through which plasma is circulated over living and functionally active hepatocytes packed in a bioreactor with the aim to aid the diseased liver until it regenerates or until a suitable graft for transplantation is available. This review article gives a brief overview of efficacy of various liver support systems that are currently available. Also, the development of advanced liver support systems, which has been analyzed for improving the important system component such as cell source and other culture and circulation conditions for the maintenance of the liver-specific functions, have been described. PMID:22416599

Dynamics of liver stiffness values by means of transient elastography in patients with HCV liver cirrhosis undergoing interferon free treatment.

PubMed

Sporea, Ioan; Lupușoru, Raluca; Mare, Ruxandra; Popescu, Alina; Gheorghe, Liana; Iacob, Speranța; Șirli, Roxana

2017-06-01

Liver stiffness (LS) measurement by Transient Elastography (TE) has been widely accepted as a tool for fibrosis assessment. The aim of this study was to assess LS dynamics in a group of patients with HCV liver cirrhosis after interferon free treatment (IFT). This two-center clinical trial included 225 patients with compensated HCV cirrhosis (all genotype 1b), who received IFT for 12 weeks. All patients were evaluated by means of TE at the beginning and at the end of treatment (EOT), and a subgroup (170 patients) also 12 weeks after EOT; all of them had sustained viral response (SVR). Reliable LS measurements (LSM) were defined as a median value of 10 valid LSM, with IQR <30% and SR >/=60%. Both M and XL probes were used. For diagnosing cirrhosis we used a cut-off value of 12kPa as proposed by the Tsochatzis meta-analysis. We considered a decrease or increase of more than 10% in LSM as being significant. Out of 225 subjects, reliable measurements were obtained in 93.7%, so that the final analysis included 211 patients. The mean LS values decreased significantly after IFT: 26.4+/-11.7 vs. 23.5+/-13.3 kPa (p=0.01). Most patients, 59.2% (125/211) presented more than 10% decrease in LS values, 24.1% (51/211) had stable LS values, while in 16.4% (35/211) cases, the LS values increased. In the subgroup of 170 patients with LSM also performed 12 weeks after EOT (SVR), the mean LS values were significantly lower as compared to baseline: 21.3+/-11 kPa vs. 27.4+/-11.9 kPa (p<0.0001) and also as compared to EOT: 21.3+/-11 kPa vs. 23.7+/-13.3 kPa (p<0.0001). In our patients with HCV liver cirrhosis, the mean LS values evaluated by TE significantly decreased after antiviral treatment at EOT and also 12 weeks after EOT as compared to baseline. Overall, about 60% of patients had LS values at EOT lower than at baseline, while 12 weeks after EOT about 75% of patients had LS values lower than at baseline.

TH-A-9A-04: Incorporating Liver Functionality in Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, V; Epelman, M; Feng, M

2014-06-15

Purpose: Liver SBRT patients have both variable pretreatment liver function (e.g., due to degree of cirrhosis and/or prior treatments) and sensitivity to radiation, leading to high variability in potential liver toxicity with similar doses. This work aims to explicitly incorporate liver perfusion into treatment planning to redistribute dose to preserve well-functioning areas without compromising target coverage. Methods: Voxel-based liver perfusion, a measure of functionality, was computed from dynamic contrast-enhanced MRI. Two optimization models with different cost functions subject to the same dose constraints (e.g., minimum target EUD and maximum critical structure EUDs) were compared. The cost functions minimized were EUDmore » (standard model) and functionality-weighted EUD (functional model) to the liver. The resulting treatment plans delivering the same target EUD were compared with respect to their DVHs, their dose wash difference, the average dose delivered to voxels of a particular perfusion level, and change in number of high-/low-functioning voxels receiving a particular dose. Two-dimensional synthetic and three-dimensional clinical examples were studied. Results: The DVHs of all structures of plans from each model were comparable. In contrast, in plans obtained with the functional model, the average dose delivered to high-/low-functioning voxels was lower/higher than in plans obtained with its standard counterpart. The number of high-/low-functioning voxels receiving high/low dose was lower in the plans that considered perfusion in the cost function than in the plans that did not. Redistribution of dose can be observed in the dose wash differences. Conclusion: Liver perfusion can be used during treatment planning potentially to minimize the risk of toxicity during liver SBRT, resulting in better global liver function. The functional model redistributes dose in the standard model from higher to lower functioning voxels, while achieving the same target EUD and satisfying dose limits to critical structures. This project is funded by MCubed and grant R01-CA132834.« less

Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity.

PubMed

Schwarz, Jean-Marc; Noworolski, Susan M; Erkin-Cakmak, Ayca; Korn, Natalie J; Wen, Michael J; Tai, Viva W; Jones, Grace M; Palii, Sergiu P; Velasco-Alin, Moises; Pan, Karen; Patterson, Bruce W; Gugliucci, Alejandro; Lustig, Robert H; Mulligan, Kathleen

2017-09-01

Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). Children (9-18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%-14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm 3 (IQR, 85-145 cm 3 ) to 110 cm 3 (IQR, 84-134 cm 3 ) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat. Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

HIV/HCV Co-infection, Liver Disease Progression, and Age-Related IGF-1 Decline.

PubMed

Quinn, Jeffrey; Astemborski, Jacquie; Mehta, Shruti H; Kirk, Gregory D; Thomas, David L; Balagopal, Ashwin

2017-01-01

We have previously reported that persons co-infected with HIV and hepatitis C virus (HCV) had liver disease stages similar to HIV-uninfected individuals who were approximately 10 years older. Insulin-like growth factor 1(IGF-1) levels have long been known to decline with advancing age in humans and non-humans alike. We examined whether HIV infection affects the expected decline in IGF-1 in persons with chronic hepatitis C virus (HCV) infection and if that alteration in IGF-1 decline contributes to the link between HIV, aging, and liver disease progression. A total of 553 individuals with HCV infection were studied from the AIDS Linked to the Intravenous Experience (ALIVE) cohort for whom more than 10 years of follow-up was available. Serum IGF-1 levels were determined by ELISA and evaluated according to baseline characteristics and over time by HIV status and liver disease progression. Linear regression with generalized estimating equations was used to determine whether IGF-1 decline over time was independently associated with liver disease progression. Baseline IGF-1 levels were strongly associated with age ( P < 0.0001) but not with gender or HIV infection. Levels of IGF-1 declined at a rate of -1.75 ng/mL each year in HCV mono-infected individuals and at a rate of -1.23 ng/mL each year in HIV/HCV co-infected individuals ( P < 0.05). In a multivariable linear regression model, progression of liver fibrosis was associated with HIV infection and age, as well as with a slower rate of IGF-1 decline ( P = 0.001); however, the rate of IGF-1 decline did not alter the strength of the associations between HIV, liver disease, and age. The normal decline in IGF-1 levels with age was attenuated in HIV/HCV co-infected individuals compared to those with HCV mono-infection, and slower IGF-1 decline was independently associated with liver disease progression.

Liver Function Assessment Using Technetium 99m-Galactosyl Single-Photon Emission Computed Tomography/CT Fusion Imaging: A Prospective Trial.

PubMed

Okabayashi, Takehiro; Shima, Yasuo; Morita, Sojiro; Shimada, Yasuhiro; Sumiyoshi, Tatsuaki; Sui, Kenta; Iwata, Jun; Iiyama, Tatsuo

2017-12-01

The prediction of postoperative liver function remains a largely subjective practice based on CT volumetric analysis. However, future liver volume after a hepatectomy is not the only factor that contributes to postoperative liver function and outcomes. In this prospective trial, 185 consecutive patients who underwent liver operations between 2014 and 2015 were studied. Volumetric and functional rates of remnant liver were measured using technetium 99m-galactosyl human serum albumin single-photon emission computed tomography/CT fusion imaging to evaluate post-hepatectomy remnant liver function. Remnant indocyanine green clearance rate using galactosyl (KGSA) (KGSA × functional rate) was used to predict future remnant liver function. Hepatectomy was considered safe for patients with remnant KGSA values ≥0.05, and the primary end point was to determine the accuracy and reliability of this criteria. The prediction of the 90-day major complication and mortality rates was assessed. Median hospital stay was 9 days and median ICU stay was 1 day, with only 1 in-hospital death (90-day mortality rate 0.5%). Overall morbidity rate evaluated according to the Clavien-Dindo classification was 9%. For post-hepatectomy liver failure definitions, the International Study Group of Liver Surgery definition was fulfilled in 14 patients (8%), with the majority being grade B (50%), compared with 2 patients (1%) fulfilling the "50-50" criteria, and 0 patients (0%) fulfilling the Peak Bili >7 criteria. Results of this study showed that remnant KGSA provided information that allowed us to predict remnant liver function. This information will be important for surgeons when deciding on a treatment plan for patients with liver diseases. (ClinicalTrials.gov ID: NCT02013895). Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy.

PubMed

Matesan, Manuela M; Bowen, Stephen R; Chapman, Tobias R; Miyaoka, Robert S; Velez, James W; Wanner, Michele F; Nyflot, Matthew J; Apisarnthanarax, Smith; Vesselle, Hubert J

2017-07-01

A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation. Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage. We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration

PubMed Central

Mukherjee, Sarmistha; Chellappa, Karthikeyani; Moffitt, Andrea; Ndungu, Joan; Dellinger, Ryan W.; Davis, James G.; Agarwal, Beamon; Baur, Joseph A.

2016-01-01

The regenerative capacity of the liver is essential for recovery from surgical resection or injuries induced by trauma or toxins. During liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls, at least in part due to metabolic competition for precursors. To test whether NAD availability restricts the rate of liver regeneration, we supplied nicotinamide riboside (NR), an NAD precursor, in the drinking water of mice subjected to partial hepatectomy. NR increased DNA synthesis, mitotic index, and mass restoration in the regenerating livers. Intriguingly, NR also ameliorated the steatosis that normally accompanies liver regeneration. To distinguish the role of hepatocyte NAD levels from any systemic effects of NR, we generated mice overexpressing Nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme for NAD synthesis, specifically in the liver. Nampt overexpressing mice were mildly hyperglycemic at baseline and, similarly to the mice treated with NR, exhibited enhanced liver regeneration and reduced steatosis following partial hepatectomy. Conversely, mice lacking Nampt in hepatocytes exhibited impaired regenerative capacity that was completely rescued by administering NR. Conclusion NAD availability is limiting during liver regeneration and supplementation with precursors such as NR may be therapeutic in settings of acute liver injury. PMID:27809334

Epidemiology and mortality of liver abscess in end-stage renal disease dialysis patients: Taiwan national cohort study.

PubMed

Hong, Chon-Seng; Chung, Kun-Ming; Huang, Po-Chang; Wang, Jhi-Joung; Yang, Chun-Ming; Chu, Chin-Chen; Chio, Chung-Ching; Chang, Fu-Lin; Chien, Chih-Chiang

2014-01-01

To determine the incidence rates and mortality of liver abscess in ESRD patients on dialysis. Using Taiwan's National Health Insurance Research Database, we collected data from all ESRD patients who initiated dialysis between 2000 and 2006. Patients were followed until death, end of dialysis, or December 31, 2008. Predictors of liver abscess and mortality were identified using Cox models. Of the 53,249 incident dialysis patients identified, 447 were diagnosed as having liver abscesses during the follow-up period (224/100,000 person-years). The cumulative incidence rate of liver abscess was 0.3%, 1.1%, and 1.5% at 1 year, 5 years, and 7 years, respectively. Elderly patients and patients on peritoneal dialysis had higher incidence rates. The baseline comorbidities of diabetes mellitus, polycystic kidney disease, malignancy, chronic liver disease, biliary tract disease, or alcoholism predicted development of liver abscess. Overall in-hospital mortality was 10.1%. The incidence of liver abscess is high among ESRD dialysis patients. In addition to the well known risk factors of liver abscess, two other important risk factors, peritoneal dialysis and polycystic kidney disease, were found to predict liver abscess in ESRD dialysis patients.

Changes in liver stiffness measurement using acoustic radiation force impulse elastography after antiviral therapy in patients with chronic hepatitis C.

PubMed

Chen, Sheng-Hung; Lai, Hsueh-Chou; Chiang, I-Ping; Su, Wen-Pang; Lin, Chia-Hsin; Kao, Jung-Ta; Chuang, Po-Heng; Hsu, Wei-Fan; Wang, Hung-Wei; Chen, Hung-Yao; Huang, Guan-Tarn; Peng, Cheng-Yuan

2018-01-01

To compare on-treatment and off-treatment parameters acquired using acoustic radiation force impulse elastography, the Fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI) in patients with chronic hepatitis C (CHC). Patients received therapies based on pegylated interferon or direct-acting antiviral agents. The changes in paired patient parameters, including liver stiffness (LS) values, the FIB-4 index, and APRI, from baseline to sustained virologic response (SVR) visit (24 weeks after the end of treatment) were compared. Multiple regression models were used to identify significant factors that explained the correlations with LS, FIB-4, and APRI values and SVR. A total of 256 patients were included, of which 219 (85.5%) achieved SVR. The paired LS values declined significantly from baseline to SVR visit in all groups and subgroups except the nonresponder subgroup (n = 10). Body mass index (P = 0.0062) and baseline LS (P < 0.0001) were identified as independent factors that explained the LS declines. Likewise, the baseline FIB-4 (P < 0.0001) and APRI (P < 0.0001) values independently explained the declines in the FIB-4 index and APRI, respectively. Moreover, interleukin-28B polymorphisms, baseline LS, and rapid virologic response were identified as independent correlates with SVR. Paired LS measurements in patients treated for CHC exhibited significant declines comparable to those in FIB-4 and APRI values. These declines may have correlated with the resolution of necroinflammation. Baseline LS values predicted SVR.

Serial Liver Stiffness Measurements and Monitoring of Liver-Transplanted Patients in a Real-Life Clinical Practice

PubMed Central

Rinaldi, Luca; Valente, Giovanna; Piai, Guido

2016-01-01

Background Liver transplanted patients need close surveillance for early signs of graft disease. Objectives Transient elastography can safely be repeated over time, offering serial liver stiffness measurement values. Serial stiffness measurements were compared to single baseline stiffness measurements in predicting the appearance of liver-related clinical events and guiding subsequent clinical decisions. Methods One hundred and sixty liver transplanted patients were observed for three years in our real-life practice. Results Liver stiffness measurements were stable in 75% of patients, decreased in 4% of patients, and increased in 21% of patients. The pattern of increased stiffness measurements was associated with both HCV-RNA positive status and the presence of an active biliary complication of liver transplantation and was more predictive of a clinically significant event resulting from any disease of the transplanted liver when compared to a stable pattern or to a single liver stiffness measurement. The procedures that were consequently performed were often diagnostic for unexpected situations, both in HCV-RNA positive and HCV-RNA negative patients. Conclusions The pattern of longitudinally increased liver stiffness measurements efficiently supported clinical decisions for individualized management strategies. Repeated transient elastography in real-life clinical practice appears to have a practical role in monitoring liver transplanted patients. PMID:28123442

[Definition of surgical degree of freedom by functional anatomy in liver resection surgery].

PubMed

Kraus, T W; Golling, M; Klar, E

2001-07-01

Liver resections have developed to very complex and differentiated operations, clearly adapted to individual anatomical and physiological conditions. In parallel, perioperative morbidity has been dramatically reduced. Intraoperative strict consideration of various details of hepatic anatomy, particularly of functional liver anatomy, has proved to be of particular importance when liver surgery reaches indication and technical limits. The term "functional anatomy" stands for a form of hepatic substructurization, which is primarily based on the existence of hemodynamically independent regions of liver parenchyma. A selection of some of the most important details and facts of functional liver anatomy and secondary derived guidelines for surgical strategy and technique is presented in an overview, with special focus on liver resection.

Liver Function Assessment by Magnetic Resonance Imaging.

PubMed

Ünal, Emre; Akata, Deniz; Karcaaltincaba, Musturay

2016-12-01

Liver function assessment by hepatocyte-specific contrast-enhanced magnetic resonance imaging is becoming a new biomarker. Liver function can be assessed by T1 mapping (reduction rate) and signal intensity measurement (relative enhancement ratio) before and after GD-EOB-DTPA (gadoxetic acid) administration, as alternative to Tc-99m galactosyl serum albumin scintigraphy, 99m Tc-labeled mebrofenin scintigraphy, and indocyanine green clearance test. Magnetic resonance imaging assessment of liver function can enable diagnosis of cirrhosis, nonalcoholic fatty liver disease associated fibrosis and steatohepatitis, primary sclerosing cholangitis, toxic hepatitis, and chemotherapy and radiotherapy-related changes, which may be only visible on hepatobiliary phase images. Simple visual assessment of signal intensity at hepatobiliary phase images is important for the diagnosis of different patterns of liver dysfunction including diffuse, lobar, segmental, and subsegmental forms. Furthermore, preoperative assessment of liver function is feasible before oncologic hepatic surgery, which may be important to prevent posthepatectomy liver failure and to estimate future remnant volume. Functional magnetic resonance cholangiography obtained by T1-weighted images at hepatobiliary phase can allow diagnosis of acalculous cholecystitis, biliary leakage, bile reflux to the stomach, sphincter of oddi dysfunction, and lesions with communication to biliary tree. Functional information can be easily obtained when Gd-EOB-DTPA is used for liver magnetic resonance imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo.

PubMed

Zahr, Natalie M; Sullivan, Edith V; Rohlfing, Torsten; Mayer, Dirk; Collins, Amy M; Luong, Richard; Pfefferbaum, Adolf

2016-07-01

Serious neurological concomitants of alcoholism include Wernicke's encephalopathy (WE), Korsakoff's syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.

Non-invasive assessment of the liver using imaging

NASA Astrophysics Data System (ADS)

Thorling Thompson, Camilla; Wang, Haolu; Liu, Xin; Liang, Xiaowen; Crawford, Darrell H.; Roberts, Michael S.

2016-12-01

Chronic liver disease causes 2,000 deaths in Australia per year and early diagnosis is crucial to avoid progression to cirrhosis and end stage liver disease. There is no ideal method to evaluate liver function. Blood tests and liver biopsies provide spot examinations and are unable to track changes in function quickly. Therefore better techniques are needed. Non-invasive imaging has the potential to extract increased information over a large sampling area, continuously tracking dynamic changes in liver function. This project aimed to study the ability of three imaging techniques, multiphoton and fluorescence lifetime imaging microscopy, infrared thermography and photoacoustic imaging, in measuring liver function. Collagen deposition was obvious in multiphoton and fluorescence lifetime imaging in fibrosis and cirrhosis and comparable to conventional histology. Infrared thermography revealed a significantly increased liver temperature in hepatocellular carcinoma. In addition, multiphoton and fluorescence lifetime imaging and photoacoustic imaging could both track uptake and excretion of indocyanine green in rat liver. These results prove that non-invasive imaging can extract crucial information about the liver continuously over time and has the potential to be translated into clinic in the assessment of liver disease.

Association of Transcatheter Aortic Valve Replacement With 30-Day Renal Function and 1-Year Outcomes Among Patients Presenting With Compromised Baseline Renal Function: Experience From the PARTNER 1 Trial and Registry.

PubMed

Beohar, Nirat; Doshi, Darshan; Thourani, Vinod; Jensen, Hanna; Kodali, Susheel; Zhang, Feifan; Zhang, Yiran; Davidson, Charles; McCarthy, Patrick; Mack, Michael; Kapadia, Samir; Leon, Martin; Kirtane, Ajay

2017-07-01

The frequency of baseline renal impairment among high-risk and inoperable patients with severe aortic stenosis undergoing a transcatheter aortic valve replacement (TAVR) and the effect of TAVR on subsequent renal function are, to our knowledge, unknown. To determine the effect of TAVR among patients with baseline renal impairment. This substudy of patients with baseline renal impairment (estimated glomerular filtration rate [eGFR] ≤ 60 mL/min) and paired baseline and 30-day measures of renal function undergoing TAVR in the PARTNER 1 trial and continued access registries was conducted in 25 centers in the United States and Canada. Patients were categorized with improved eGFR (30-day follow-up eGFR≥10% higher than baseline pre-TAVR), worsened eGFR (≥10% lower), or no change in renal function (neither). Baseline characteristics, 30-day to 1-year all-cause mortality, and repeat hospitalization were compared. Multivariable models were constructed to identify predictors of 1-year mortality and of improvement/worsening in eGFR. Of the 821 participants, 401 (48.8%) were women and the mean (SD) age for participants with improved, unchanged, or worsening eGFR was 84.90 (6.91) years, 84.37 (7.13) years, and 85.39 (6.40) years, respectively. The eGFR was 60 mL/min or lower among 821 patients (72%), of whom 345 (42%) improved, 196 (24%) worsened, and 280 (34%) had no change at 30 days. There were no differences in baseline age, body mass index, diabetes, chronic obstructive pulmonary disease, coronary artery disease, peripheral arterial disease, hypertension, pulmonary hypertension, renal or liver disease, New York Heart Association III/IV symptoms, transaortic gradient, left ventricular ejection fraction, or procedural characteristics. The group with improved eGFR had more women, nonsmokers, and a lower cardiac index. Those with worsening eGFR had a higher median Society of Thoracic Surgeons score and left ventricle mass. From 30 days to 1 year, those with improved eGFR had no difference in mortality or repeat hospitalization. Those with worsening eGFR had increased mortality (25.5% vs 19.1%, P = .07) but no significant increases in repeat hospitalization or dialysis. Predictors of improved eGFR were being female (odds ratio [OR], 1.38; 95% CI, 1.03-1.85; P = .03) and nonsmoking status (OR, 1.49; 95% CI, 1.11-1.01; P = .01); predictors of worsening eGFR were baseline left ventricle mass (OR, 1.00; 95% CI, 1.00-1.01; P = .01), smoking (OR, 1.51; 95% CI, 1.06-2.14; P = .02), and age (OR, 1.03; 95% CI, 1.00-1.05; P = .05); and predictors of 1-year mortality were baseline left ventricular ejection fraction (OR, 0.98; 95% CI, 0.97-0.99; P = .003), baseline eGFR (OR, 0.98; 95% CI, 0.96-0.99; P < .001), and worsening eGFR vs no change in eGFR (OR, 1.51; 95% CI, 1.02-2.24; P = .04). Baseline renal impairment was frequent among patients who underwent TAVR. While improved eGFR did not improve 1-year outcomes, worsening eGFR was associated with increased mortality. clinicaltrials.gov Identifier: NCT00530894.

Risk factors for stent graft thrombosis after transjugular intrahepatic portosystemic shunt creation.

PubMed

Jahangiri, Younes; Kerrigan, Timothy; Li, Lei; Prosser, Dominik; Brar, Anantnoor; Righetti, Johnathan; Schenning, Ryan C; Kaufman, John A; Farsad, Khashayar

2017-12-01

To identify risk factors of stent graft thrombosis after transjugular intrahepatic portosystemic shunt (TIPS) creation. Patients who underwent TIPS creation between June 2003 and January 2016 and with follow-up assessing stent graft patency were included (n=174). Baseline comorbidities, liver function, procedural details and follow-up liver function tests were analyzed in association with hazards of thrombosis on follow-up. Competing risk cox regression models were used considering liver transplant after TIPS creation as the competing risk variable. One-, 2- and 5-year primary patency rates were 94.1%, 91.7% and 78.2%, respectively. Patient age [sub-hazard ratio (sHR): 1.13; P=0.001], body mass index (BMI) <30 (sHR: 33.08; P=0.008) and a higher post-TIPS portosystemic pressure gradient (sHR: 1.14; P=0.023) were significantly associated with TIPS thrombosis in multivariate analysis. A higher rate of TIPS thrombosis was observed in those for whom the procedure was clinically unsuccessful (P=0.014). A significant increase in incidence of thrombosis was noted with increasing tertiles of post-TIPS portosystemic gradients (P value for trend=0.017). Older age, lower BMI and higher post-TIPS portosystemic gradients were associated with higher hazards of shunt thrombosis after TIPS creation using stent grafts. Higher rates of shunt thrombosis were seen in patients for whom TIPS creation was clinically unsuccessful. The association between TIPS thrombosis and higher post-TIPS portosystemic gradients may indicate impaired flow through the shunt, a finding which may be technical or anatomic in nature and should be assessed before procedure completion.

[Effect of fenicaberan on liver function in patients with chronic noncalculous cholecystitis].

PubMed

Skroban, N V

1989-06-01

The author studied the effect of fenicaberan on the functional state of the liver in 34 patients with chronic noncalculous cholecystitis. It was found that fenicaberan favours improvement of the functional state of the liver but complete normalization of all liver values indicates necessity continuation of treatment in outpatient conditions.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.

PubMed

Valayannopoulos, Vassili; Malinova, Vera; Honzík, Tomas; Balwani, Manisha; Breen, Catherine; Deegan, Patrick B; Enns, Gregory M; Jones, Simon A; Kane, John P; Stock, Eveline O; Tripuraneni, Radhika; Eckert, Stephen; Schneider, Eugene; Hamilton, Gavin; Middleton, Michael S; Sirlin, Claude; Kessler, Bruce; Bourdon, Christopher; Boyadjiev, Simeon A; Sharma, Reena; Twelves, Chris; Whitley, Chester B; Quinn, Anthony G

2014-11-01

Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184). Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Short-Term Hypocaloric High-Fiber and High-Protein Diet Improves Hepatic Steatosis Assessed by Controlled Attenuation Parameter

PubMed Central

Arslanow, Anita; Teutsch, Melanie; Walle, Hardy; Grünhage, Frank; Lammert, Frank; Stokes, Caroline S

2016-01-01

OBJECTIVES: Non-alcoholic fatty liver disease is one of the most prevalent liver diseases and increases the risk of fibrosis and cirrhosis. Current standard treatment focuses on lifestyle interventions. The primary aim of this study was to assess the effects of a short-term low-calorie diet on hepatic steatosis, using the controlled attenuation parameter (CAP) as quantitative tool. METHODS: In this prospective observational study, 60 patients with hepatic steatosis were monitored during a hypocaloric high-fiber, high-protein diet containing 1,000 kcal/day. At baseline and after 14 days, we measured hepatic fat contents using CAP during transient elastography, body composition with bioelectrical impedance analysis, and serum liver function tests and lipid profiles using standard clinical–chemical assays. RESULTS: The median age was 56 years (25–78 years); 51.7% were women and median body mass index was 31.9 kg/m2 (22.4–44.8 kg/m2). After 14 days, a significant CAP reduction (14.0% P<0.001) was observed from 295 dB/m (216–400 dB/m) to 266 dB/m (100–353 dB/m). In parallel, body weight decreased by 4.6% (P<0.001), of which 61.9% was body fat. In addition, liver stiffness (P=0.002), γ-GT activities, and serum lipid concentrations decreased (all P<0.001). CONCLUSIONS: This study shows for the first time that non-invasive elastography can be used to monitor rapid effects of dietary treatment for hepatic steatosis. CAP improvements occur after only 14 days on short-term low-calorie diet, together with reductions of body composition parameters, serum lipids, and liver enzymes, pointing to the dynamics of hepatic lipid turnover. PMID:27311064

Short-Term Hypocaloric High-Fiber and High-Protein Diet Improves Hepatic Steatosis Assessed by Controlled Attenuation Parameter.

PubMed

Arslanow, Anita; Teutsch, Melanie; Walle, Hardy; Grünhage, Frank; Lammert, Frank; Stokes, Caroline S

2016-06-16

Non-alcoholic fatty liver disease is one of the most prevalent liver diseases and increases the risk of fibrosis and cirrhosis. Current standard treatment focuses on lifestyle interventions. The primary aim of this study was to assess the effects of a short-term low-calorie diet on hepatic steatosis, using the controlled attenuation parameter (CAP) as quantitative tool. In this prospective observational study, 60 patients with hepatic steatosis were monitored during a hypocaloric high-fiber, high-protein diet containing 1,000 kcal/day. At baseline and after 14 days, we measured hepatic fat contents using CAP during transient elastography, body composition with bioelectrical impedance analysis, and serum liver function tests and lipid profiles using standard clinical-chemical assays. The median age was 56 years (25-78 years); 51.7% were women and median body mass index was 31.9 kg/m(2) (22.4-44.8 kg/m(2)). After 14 days, a significant CAP reduction (14.0%; P<0.001) was observed from 295 dB/m (216-400 dB/m) to 266 dB/m (100-353 dB/m). In parallel, body weight decreased by 4.6% (P<0.001), of which 61.9% was body fat. In addition, liver stiffness (P=0.002), γ-GT activities, and serum lipid concentrations decreased (all P<0.001). This study shows for the first time that non-invasive elastography can be used to monitor rapid effects of dietary treatment for hepatic steatosis. CAP improvements occur after only 14 days on short-term low-calorie diet, together with reductions of body composition parameters, serum lipids, and liver enzymes, pointing to the dynamics of hepatic lipid turnover.

Nadolol for lithium tremor in the presence of liver damage.

PubMed

Dave, M; Langbart, M M

1994-03-01

Lithium-induced tremor classically responds to treatment with propranolol. Since it is metabolized in the liver, propranolol may not be the drug of choice in those patients who have compromised liver function or who are recovering from prior liver diseases. Another nonselective beta-adrenergic blocker, nadolol, has no hepatic biotransformation. We present here the first case report of successful treatment of lithium-induced tremor with nadolol, which was selected because the patient had compromised liver function. The patient's liver function tests remained stable with the therapy.

Liver Ischemic Preconditioning (IPC) Improves Intestinal Microbiota Following Liver Transplantation in Rats through 16s rDNA-Based Analysis of Microbial Structure Shift

PubMed Central

Lu, Haifeng; Chen, Xinhua; Jiang, Jianwen; Liu, Hui; He, Yong; Ding, Songming; Hu, Zhenhua; Wang, Weilin; Zheng, Shusen

2013-01-01

Background Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The “gut-liver axis” closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). Methods The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-α. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Principal Findings Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-α decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Conclusion Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the “gut-liver axis”. PMID:24098410

Liver ischemic preconditioning (IPC) improves intestinal microbiota following liver transplantation in rats through 16s rDNA-based analysis of microbial structure shift.

PubMed

Ren, Zhigang; Cui, Guangying; Lu, Haifeng; Chen, Xinhua; Jiang, Jianwen; Liu, Hui; He, Yong; Ding, Songming; Hu, Zhenhua; Wang, Weilin; Zheng, Shusen

2013-01-01

Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The "gut-liver axis" closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-α. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-α decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the "gut-liver axis".

High serum carotenoids are associated with lower risk for developing elevated serum alanine aminotransferase among Japanese subjects: the Mikkabi cohort study.

PubMed

Sugiura, Minoru; Nakamura, Mieko; Ogawa, Kazunori; Ikoma, Yoshinori; Yano, Masamichi

2016-04-01

Many recent studies have shown that antioxidant vitamins and/or carotenoids may reduce liver disease, but this association has not been well established with thorough longitudinal cohort studies. The objective of this study was to longitudinally investigate whether serum carotenoids at baseline are associated with the risk of developing elevated serum alanine aminotransferase (ALT) among Japanese subjects. We conducted a follow-up study of 1073 males and females aged between 30 and 79 years at baseline from the Mikkabi prospective cohort study. Those who participated in the baseline study and completed follow-up surveys were examined longitudinally. Exclusions included excessive alcohol consumption (≥60 g alcohol/d), hepatitis B and C and having a history of medication use for liver disease. A cohort of 213 males and 574 females free of elevated serum ALT (>30 IU/ml) at baseline was studied. Over a mean follow-up period of 7·4 (sd 3·1) years, thirty-one males and forty-nine females developed new elevated serum ALT. After adjustments for confounders, the hazard ratios for elevated serum ALT in the highest tertiles of basal serum β-carotene, β-cryptoxanthin and total provitamin A carotenoids against the lowest tertiles were 0·43 (95 % CI 0·22, 0·81), 0·51 (CI 0·27, 0·94) and 0·52 (CI 0·28, 0·97), respectively. For α-carotene and lycopene, borderline reduced risks were also observed; however, these were not significant. Our results further support the hypothesis that antioxidant carotenoids, especially provitamin A carotenoids, might help prevent earlier pathogenesis of non-alcoholic liver disease in Japanese subjects.

Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study.

PubMed

Bawden, S J; Stephenson, M C; Ciampi, E; Hunter, K; Marciani, L; Macdonald, I A; Aithal, G P; Morris, P G; Gowland, P A

2016-06-01

Impaired homeostasis of hepatic ATP has been associated with NAFLD. An intravenous fructose infusion has been shown to be an effective challenge to monitor the depletion and subsequent recovery of hepatic ATP reserves using (31)P MRS. The purpose of this study was to evaluate the effects of an oral rather than intravenous fructose challenge on hepatic ATP reserves in healthy subjects. Self-reported healthy males were recruited. Following an overnight fast, baseline liver glycogen and lipid levels were measured using Magnetic Resonance Spectroscopy (MRS). Immediately after consuming a 500 ml 75 g fructose drink (1275 kJ) subjects were scanned continuously for 90 min to acquire dynamic (31)P MRS measurements of liver ATP reserves. A significant effect on ATP reserves was observed across the time course (P < 0.05). Mean ATP levels reached a minimum at 50 min which was markedly lower than baseline (80 ± 17% baseline, P < 0.05). Subsequently, mean values tended to rise but did not reach statistical significance above minimum. The time to minimum ATP levels across subjects was negatively correlated with BMI (R(2) = 0.74, P < 0.005). Rates of ATP recovery were not significantly correlated with BMI or liver fat levels, but were negatively correlated with baseline glycogen levels (R(2) = 0.7, P < 0.05). Depletion of ATP reserves can be measured non-invasively following an oral fructose challenge using (31)P MRS. BMI is the best predictor of postprandial ATP homeostasis following fructose consumption. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Effects of Synthetic Androgens on Liver Function Using the Rabbit as a Model*†

PubMed Central

Hild, Sheri Ann; Attardi, Barbara J.; Koduri, Sailaja; Till, Bruce A.; Reel, Jerry R.

2010-01-01

The objective of this study was to determine if the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT), as a positive control, and testosterone (T), as a negative control, to validate this model. Synthetic androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7 and 14, were determined. As expected, T (10 mg/kg/day) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/day) increased BSP retention, and AST, ALT, GGT, and SDH levels indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/day), increased BSP retention, and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/day did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/day. For the androgens that exhibited liver toxicity at 10 mg/kg/day (MT, DMAU, and MENT), a no observed effect level (NOEL) of 1 mg/kg/day was established. Overall ranking of the synthetic androgens from most to least hepatotoxic based on %BSP retention was: MT ≫ DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury. PMID:20378929

A Low-Glycemic-Load versus Low-Fat Diet in the Treatment of Fatty Liver in Obese Children

PubMed Central

Ramon-Krauel, Marta; Salsberg, Sandra L.; Ebbeling, Cara B.; Voss, Stephan D.; Mulkern, Robert V.; Apura, Margaret M.; Cooke, Emily A.; Sarao, Karen; Jonas, Maureen M.

2013-01-01

Abstract Background Fatty liver is highly prevalent among obese children and represents a major risk factor for chronic liver diseases and severe metabolic complications. Methods We randomly assigned 17 obese children 8–17 years of age with fatty liver to either an experimental low-glycemic-load or conventional low-fat diet for 6 months. Participants in both groups received nutrition education and behavioral counseling of equal intensity. The primary outcome was hepatic lipid content measured by proton magnetic resonance spectroscopy. Secondary outcomes included change in visceral fat, BMI, anthropometrics, alanine aminotransferase (ALT), and insulin resistance. Results A total of 16 participants completed the study. Reported glycemic load decreased in the low-glycemic-load group and reported dietary fat decreased in the low-fat group. At baseline, liver fat was 23.8% [standard deviation (SD) 12.2] in the low-glycemic-load group and 29.3% (14.1) in the low-fat group. Liver fat decreased substantially in both groups at 6 months expressed as absolute percentage change, with no between-group differences [−8.8 (standard error (SE) 4.1) vs. −10.5 (3.7)%, respectively, p=0.76 for group×time interaction]. Secondary outcomes also improved on both diets, with no between-group differences. Baseline and change in ALT were strongly associated with hepatic fat content. Conclusions Weight-reducing diets focused either on glycemic load or dietary fat improved hepatic steatosis over 6 months. Additional research is needed to determine whether these diets differ in effectiveness over the long term. Trial Registration clinicaltrials.gov Identifier: NCT00480922 PMID:23705885

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

PubMed Central

Vichinsky, Elliott; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Eckman, James; Lane, Peter; Files, Beatrice; Hassell, Kathryn; Kelly, Patrick; Wilson, Felicia; Bernaudin, Françoise; Forni, Gian Luca; Okpala, Iheanyi; Ressayre-Djaffer, Catherine; Alberti, Daniele; Holland, Jaymes; Marks, Peter; Fung, Ellen; Fischer, Roland; Mueller, Brigitta U; Coates, Thomas

2007-01-01

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease. PMID:17233848

The utility of uric acid assay in dogs as an indicator of functional hepatic mass.

PubMed

Hill, J M; Leisewitz, A L; Goddard, A

2011-06-01

Uric acid was used as a test for liver disease before the advent of enzymology. Three old studies criticised uric acid as a test of liver function. Uric acid, as an end-product of purine metabolism in the liver, deserved re-evaluation as a liver function test. Serum totalbile acids are widely accepted as the most reliable liver function test. This study compared the ability of serum uric acid concentration to assess liver function with that of serum pre-prandial bile acids in dogs. In addition, due to the renal excretion of uric acid the 2 assays were also compared in a renal disease group. Using a control group of healthy dogs, a group of dogs with congenital vascular liver disease, a group of dogs with non-vascular parenchymal liver diseases and a renal disease group, the ability of uric acid and pre-prandial bile acids was compared to detect reduced functional hepatic mass overall and in the vascular or parenchymal liver disease groups separately. Sensitivities, specificities and predictive value parameters were calculated for each test. The medians of uric acid concentration did not differ significantly between any of the groups, whereas pre-prandial bile acids medians were significantly higher in the liver disease groups compared with the normal and renal disease group of dogs. The sensitivity of uric acid in detecting liver disease overall was 65% while the specificity of uric acid in detecting liver disease overall was 59%. The sensitivity and specificity of uric acid in detecting congenital vascular liver disease was 68% and 59%, respectively. The sensitivity and specificity of uric acid in detecting parenchymal liver disease was 63% and 60%, respectively. The overall positive and negative predictive values for uric acid in detecting liver disease were poor and the data in this study indicated uric acid to be an unreliable test of liver function. In dogs suffering from renal compromise serum uric acid concentrations may increase into the abnormal range due to its renal route of excretion.

Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration.

PubMed

Mukherjee, Sarmistha; Chellappa, Karthikeyani; Moffitt, Andrea; Ndungu, Joan; Dellinger, Ryan W; Davis, James G; Agarwal, Beamon; Baur, Joseph A

2017-02-01

The regenerative capacity of the liver is essential for recovery from surgical resection or injuries induced by trauma or toxins. During liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls, at least in part due to metabolic competition for precursors. To test whether NAD availability restricts the rate of liver regeneration, we supplied nicotinamide riboside (NR), an NAD precursor, in the drinking water of mice subjected to partial hepatectomy. NR increased DNA synthesis, mitotic index, and mass restoration in the regenerating livers. Intriguingly, NR also ameliorated the steatosis that normally accompanies liver regeneration. To distinguish the role of hepatocyte NAD levels from any systemic effects of NR, we generated mice overexpressing nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for NAD synthesis, specifically in the liver. Nicotinamide phosphoribosyltransferase overexpressing mice were mildly hyperglycemic at baseline and, similar to mice treated with NR, exhibited enhanced liver regeneration and reduced steatosis following partial hepatectomy. Conversely, mice lacking nicotinamide phosphoribosyltransferase in hepatocytes exhibited impaired regenerative capacity that was completely rescued by administering NR. NAD availability is limiting during liver regeneration, and supplementation with precursors such as NR may be therapeutic in settings of acute liver injury. (Hepatology 2017;65:616-630). © 2016 by the American Association for the Study of Liver Diseases.

Laboratory-Based Biomarkers and Liver Metastases in Metastatic Castration-Resistant Prostate Cancer.

PubMed

Cotogno, Patrick M; Ranasinghe, Lahiru K; Ledet, Elisa M; Lewis, Brian E; Sartor, Oliver

2018-04-26

Metastatic castrate-resistant prostate cancer (mCRPC) patients with liver metastases have a poor prognosis. No large studies have investigated the clinical and biochemical parameters associated with liver metastases in this population. Patient data made available via Project Data Sphere were collected from 1,281 men with mCRPC who were enrolled on to three phase III clinical trials for the treatment of their disease. Multiple logistic regression was performed on eight clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline radiographic imaging. Variables of interest included prior docetaxel exposure, Eastern Cooperative Oncology Group performance status, albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase (AST), hemoglobin (HGB), lactate dehydrogenase (LDH), prostate-specific antigen, and total bilirubin. Final models were compared when treating the variables as either continuous or categorized. Multiple variable analysis demonstrated that an increasing serum AST or LDH or a decreasing HGB was associated with an increased probability of having documented radiographic liver metastases ( p  < .0001). The area under the curve for the continuous model was 0.6842 and 0.6890 for the categorical one, with the latter model containing a dichotomized AST and LDH based on the upper limit of normal and tertile ranges of HGB based on the distribution of the outcome. Our analysis demonstrated a significant association between the presence of liver metastases and laboratory levels of AST, LDH, and HGB. These have implications for patient management. More research is needed to validate these biomarkers and prospectively determine their application in the clinical setting. The purpose of this study was to evaluate biochemical and clinical biomarkers associated with the presence of liver metastases in men diagnosed with metastatic castrate-resistant prostate cancer. The results indicate that quantitative assessments of aspartate transaminase, lactate dehydrogenase, and hemoglobin are significantly associated with an increased probability of having documented radiographic liver metastases. Analysis of these simple variables can alert clinicians to those at high risk for prostate cancer that has spread to the liver, a finding of clear importance for clinical management. © AlphaMed Press 2018.

Association of sustained virologic response with reduced progression to liver cirrhosis in elderly patients with chronic hepatitis C.

PubMed

Tseng, Chih-Wei; Chang, Ting-Tsung; Tzeng, Shinn-Jia; Hsieh, Yu-Hsi; Hung, Tsung-Hsing; Huang, Hsiang-Ting; Wu, Shu-Fen; Tseng, Kuo-Chih

2016-01-01

We studied the effect of sustained virologic response (SVR) after treatment with pegylated-interferon (PEG-IFN) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis C (CHC). This retrospective study enrolled 145 elderly CHC patients (aged ≥65 years) who were treatment-naïve and were treated with PEG-IFN plus ribavirin for 6 months between January 2005 and December 2011. Abdominal sonography was performed and liver biochemistry was studied at baseline, at the end of treatment, and every 3-6 months thereafter. The development of liver cirrhosis and related complications was evaluated at the follow-ups. The aspartate aminotransferase-to-platelet ratio index was used as a noninvasive maker for fibrosis. The mean patient age was 69.1±3.3 years, and the average follow-up time was 5.5 years (standard deviation: 2.5 years, range: 1.1-12.3 years). Ninety-five patients (65.5%) achieved SVR, and 26 (17.9%) discontinued treatment. Twenty-seven patients (18.6%) developed liver cirrhosis after treatment. Patients without SVR had significantly greater risk of liver cirrhosis than those with SVR (hazard ratio [HR]: 3.39, 95% confidence interval [CI]: 1.312-8.761, P=0.012). The difference in 3-year cumulative incidence of liver cirrhosis was 24.8% greater for patients without SVR (35.2%, 95% CI: 13.0-57.5, P=0.012) compared with those with SVR (10.4%, 95% CI: 3.1-17.7). There was a trend of a higher baseline aspartate aminotransferase-to-platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress (2.1±1.2 vs 1.6±1.3, P=0.055), but the difference failed to reach significance by Cox regression (adjusted HR: 1.285, 95% CI: 0.921-1.791, P=0.14). An SVR following PEG-IFN combination treatment can reduce the risk of liver cirrhosis in elderly CHC patients.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levine, E.; Cook, L.T.; Grantham, J.J.

Hepatic CT findings were analyzed in 44 patients with autosomal-dominant polycystic kidney disease and were correlated with liver and renal function tests and liver, splenic, and renal CT volume measurements. CT showed many large liver cysts in 31.8% of patients, small liver cysts in 25%, and no liver cysts in 43.2%. Patients with many large cysts often showed increased liver volumes. There was no correlation between severity of liver involvement and extent of renal cystic disease as determined from urea nitrogen and creatinine levels and renal volumes. Liver function tests were normal except in two patients, one with a cholangiocarcinoma,more » which may have arisen from a cyst, and the other with an infected liver cyst and chronic active hepatitis. Accordingly, if liver function tests are abnormal, an attempt should be made to identify complications of polycystic liver disease such as tumor cyst infection, and biliary obstruction. CT is a useful method for detecting liver cysts and identifying patients at risk for these complications.« less

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

PubMed

Cortes, Miriam; Pareja, Eugenia; García-Cañaveras, Juan C; Donato, M Teresa; Montero, Sandra; Mir, Jose; Castell, José V; Lahoz, Agustín

2014-09-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Optimization of Lyophilized Plasma for Use in Combat Casualties

DTIC Science & Technology

2016-03-01

during which a baseline MAP was recorded and pre-weighed laparotomy sponges were placed in both paracolic gutters and in the pelvis for blood...period, the liver was packed tightly with laparotomy sponges . Swine were randomized to receive either LP reconstituted to 50% (50%LP, n=10) or 100...continuously recorded throughout the study. Blood loss following liver injury was carefully recorded with the use of pre-weighed laparotomy sponges and

Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.

PubMed

Sangro, Bruno; Carpanese, Livio; Cianni, Roberto; Golfieri, Rita; Gasparini, Daniele; Ezziddin, Samer; Paprottka, Philipp M; Fiore, Francesco; Van Buskirk, Mark; Bilbao, Jose Ignacio; Ettorre, Giuseppe Maria; Salvatori, Rita; Giampalma, Emanuela; Geatti, Onelio; Wilhelm, Kai; Hoffmann, Ralf Thorsten; Izzo, Francesco; Iñarrairaegui, Mercedes; Maini, Carlo Ludovico; Urigo, Carlo; Cappelli, Alberta; Vit, Alessandro; Ahmadzadehfar, Hojjat; Jakobs, Tobias Franz; Lastoria, Secondo

2011-09-02

A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium-90-labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole-liver (45.2%) or right-lobe (38.5%) infusions. Typically, patients were Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one-quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9-15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6-38.1 months]; BCLC B, 16.9 months [95% CI, 12.8-22.8 months]; BCLC C, 10.0 months [95% CI, 7.7-10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options. Copyright © 2011 American Association for the Study of Liver Diseases.

Rapid liver and spleen stiffness improvement in compensated advanced chronic liver disease patients treated with oral antivirals.

PubMed

Pons, Mònica; Santos, Begoña; Simón-Talero, Macarena; Ventura-Cots, Meritxell; Riveiro-Barciela, Mar; Esteban, Rafael; Augustin, Salvador; Genescà, Joan

2017-08-01

We aimed to investigate the early changes in liver and spleen stiffness measurement (LSM, SSM) in hepatitis C virus (HCV) patients with compensated advanced chronic liver disease (cACLD) treated with new antivirals (DAA) to elucidate factors determining the initial change in stiffness and its implications for the long-term follow up of HCV-cured patients. A total of 41 patients with cACLD who started DAA therapy underwent LSM and SSM at baseline, week 4, end of treatment (EOT), 24 and 48 weeks of follow up using transient elastography. LSM improved rapidly during the first 4 weeks of treatment (baseline: 20.8kPa; week 4: 17.5kPa, p = 0.002), with no significant changes between week 4 and EOT (18.3kPa, p = 0.444) and between EOT and 48-week follow up (14.3kPa, p = 0.148). Likewise, SSM improved rapidly (baseline: 45.7kPa; week 4: 33.8kPa, p = 0.047), with no significant changes between week 4 and EOT (30.8kPa, p = 0.153) and between EOT and 48-week follow up (31.2kPa, p = 0.317). A higher decrease in LSM was observed in patients with baseline ALT ⩾ twofold upper limit normal (2 × ULN) than in those with ALT < 2 × ULN (-5.7kPa versus -1.6kPa). Patients who presented a decrease in LSM ⩾ 10% during treatment compared with those with LSM < 10% decrease, showed lower SSM values, higher platelet counts and lower bilirubin levels at 24-week follow up. Those with decrease in SSM ⩾ 10%, presented a higher increase in platelets than those with SSM < 10% change ( p = 0.015). LSM and SSM decrease very rapidly during DAA treatment in cACLD patients suggesting that it most probably reflects a reduction in inflammation rather than in fibrosis. cACLD patients should be maintained under surveillance independently of stiffness changes, because advanced fibrosis can still be present.

Unilobar Versus Bilobar Biliary Drainage: Effect on Quality of Life and Bilirubin Level Reduction

PubMed Central

Gamanagatti, Shivanand; Singh, Tejbir; Sharma, Raju; Srivastava, Deep N; Dash, Nihar Ranjan; Garg, Pramod Kumar

2016-01-01

Background: Percutaneous biliary drainage is an accepted palliative treatment for malignant biliary obstruction. Purpose: To assess the effect on quality of life (QOL) and bilirubin level reduction in patients with inoperable malignant biliary obstruction treated by unilobar or bilobar percutaneous transhepatic biliary drainage (PTBD). Materials and Methods: Over a period of 2 years, 49 patients (age range, 22–75 years) of inoperable malignant biliary obstruction were treated by PTBD. Technical and clinical success rates, QOL, patency rates, survival rates, and complications were recorded. Clinical success rates, QOL, and bilirubin reduction were compared in patients treated with complete (n = 21) versus partial (n = 28) liver parenchyma drainage. QOL before and 1 month after biliary drainage were analyzed retrospectively between these two groups. Results: Biliary drainage was successful in all 49 patients, with an overall significant reduction of the postintervention bilirubin levels (P < 0.001) resulting in overall clinical success rate of 89.97%. Clinical success rates were similar in patients treated with whole-liver drainage versus partial-liver drainage. Mean serum bilirubin level before PTBD was 19.85 mg/dl and after the procedure at 1 month was 6.02 mg/dl. The mean baseline functional score was 39.35, symptom scale score was 59.55, and global health score was 27.45. At 1 month, mean functional score was 61.25, symptom scale score was 36.0 4, and global health score was 56.33, with overall significant improvement in QOL (<0.001). There was a statistically significant difference in the improvement of the QOL scores (P = 0.002), among patients who achieved clinical success, compared with those patients who did not achieve clinical success at 1 month. We did not find any significant difference in the QOL scores in patients according to the amount of liver drained (unilateral or bilateral drainage), the type of internalization used (ring biliary or stent). Overall, minor and major complications rates were 14.3% and 8.1%, respectively. Conclusion: Percutaneous biliary drainage provides good palliation of malignant obstructive jaundice. Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level. PMID:26962281

Enzyme activities in plasma, kidney, liver, and muscle of five avian species

USGS Publications Warehouse

Franson, J.C.; Murray, H.C.; Bunck, C.

1985-01-01

Activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) were determined in plasma, kidney, liver, and muscle from five species of captive birds. Few differences occurred in plasma activities between sexes but considerable differences occurred between species. All five enzymes were detected in each of the tissues sampled. Relative enzyme activities in liver, kidney, and muscle were similar for each species. CPK activity was much higher in muscle than in liver or kidney and, of the five enzymes studied, may be the best indicator of muscle damage. Most of the other enzymes were more evenly distributed among the three tissues, and no organ-specific enzyme could be identified for liver or kidney. Because of interspecific variations in plasma enzyme activities, it is important to establish baseline values for each species to ensure accurate interpretation of results.

Lack of Siglec-7 expression identifies a dysfunctional natural killer cell subset associated with liver inflammation and fibrosis in chronic HCV infection.

PubMed

Varchetta, Stefania; Mele, Dalila; Lombardi, Andrea; Oliviero, Barbara; Mantovani, Stefania; Tinelli, Carmine; Spreafico, Marta; Prati, Daniele; Ludovisi, Serena; Ferraioli, Giovanna; Filice, Carlo; Aghemo, Alessio; Lampertico, Pietro; Facchetti, Floriana; Bernuzzi, Francesca; Invernizzi, Pietro; Mondelli, Mario U

2016-12-01

Sialic-acid-binding immunoglobulin-like lectin-7 (Siglec-7) is a natural killer (NK) cell inhibitory receptor associated with NK phenotypic and functional abnormalities in HIV-1 infection. We investigated the significance of NK-expressed and serum soluble Siglec-7 in relation to NK functional ability and parameters of liver necroinflammation and fibrosis in chronic HCV infection. NK-expressed and serum Siglec-7 were evaluated in 130 and 166 HCV-infected individuals by flow cytometry and ELISA, respectively. NK cell degranulation and cytokine secretion were determined by flow cytometry. 65 patients with chronic HBV infection, 84 with chronic biliary disorders and 168 healthy donors served as controls. Expression of Siglec-7 was significantly decreased on NK cells from HCV-infected and HBV-infected patients and, conversely, serum Siglec-7 was significantly increased in these patients compared with controls. The frequency of Siglec-7pos NK cells was significantly higher at baseline in sustained virological responders to pegylated interferon-α/ribavirin treatment than in non-responders. Activating receptor expression was significantly higher in Siglec-7pos NK cells and was associated with increased degranulation and cytokine secretion compared with Siglec-7 neg cells. In chronic HCV infection, there was an inverse correlation between Siglec-7 expression and serum aminotransferases, γ-glutamyl transpeptidase, liver stiffness, aspartate aminotransferase to platelet ratio index and fibrosis-4 scores, and a positive correlation between serum Siglec-7 and the same clinical parameters, including histological staging. These findings identify Siglec-7 neg NK cells as a dysfunctional subpopulation associated with severe liver disease in chronic HCV infection. 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/.

Impact of pretransplant renal function on survival after liver transplantation.

PubMed

Gonwa, T A; Klintmalm, G B; Levy, M; Jennings, L S; Goldstein, R M; Husberg, B S

1995-02-15

To determine the effect of pretransplant liver function on survival following orthotopic liver transplantation and to quantify the effects of cyclosporine administration on long-term renal function in patients undergoing liver transplant, we performed an analysis of a prospectively maintained database. Data from 569 consecutive patients undergoing liver transplantation alone who were treated with CsA for immunosuppression were used for this study. Actuarial graft and patient survival rates were calculated using Kaplan-Meier statistics. Glomerular filtration rates, serum creatinine, and the use of various immunosuppressives were analyzed for this study. The initial analysis demonstrated that patients presenting for liver transplant with hepatorenal syndrome have a significantly decreased acturial patient survival after liver transplant at 5 years compared with patients without hepatorenal syndrome (60% vs. 68%, P < 0.03). Patients with hepatorenal syndrome recovered their renal function after liver transplant. Patients who had hepatorenal syndrome were sicker and required longer stays in the intensive care unit, longer hospitalizations, and more dialysis treatments after transplantation compared with patients who did not have hepatorenal syndrome. The incidence of end-stage renal disease after liver transplantation in patients who had hepatorenal syndrome was 7%, compared with 2% in patients who did not have hepatorenal syndrome. To more fully examine the effect of pretransplant renal function on posttransplant survival, the non-hepatorenal syndrome patients were divided into quartiles depending upon their pretransplant renal function. The patients with the lowest pretransplant renal function had the same survival as the patients with the highest pretransplant renal function. In addition, there was no increased incidence of acute or chronic rejection in any of the groups. The patients with the lower pretransplant renal function were treated with more azathioprine to maintain renal function and had a negligible decrease in glomerular filtration rate following transplant. Conversely, patients with the highest level of renal function pretransplant had a 40% decline in renal function in the first year, but maintained stable renal function up to 4 years after transplant. We conclude that pretransplant renal function other than hepato-renal syndrome has no effect on patient survival after orthotopic liver transplant. Renal function after liver transplant is stable after an initial decline, despite continued administration of CsA.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of abnormal liver function tests.

PubMed

Agrawal, Swastik; Dhiman, Radha K; Limdi, Jimmy K

2016-04-01

Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests. 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/

[The clinicopathological analysis of 88 patients with abnormal liver function test of unknown etiology].

PubMed

Pang, Shu-zhen; Ou, Xiao-juan; Shi, Xiao-yan; Wang, Tai-ling; Duan, Wei-jia; Jia, Ji-dong

2011-01-01

To evaluate the clinical and histological features of patients with abnormal liver tests of unknown etiology, and then to investigate the diagnosis and differential diagnosis. Patients with abnormal liver function test hospitalized and had liver biopsies during 2008 - 2009 constituted this retrospective study cohort. After excluding those patients diagnosed with hepatotropic viral hepatitis, space occupying lesions of the liver, alcoholic liver disease and obstruction of bile duct caused by stone or malignancy and AMA/AMA-M(2) positive of primary biliary cirrhosis (PBC), the clinical and histological characteristics were evaluated. Out of the 180 patients who underwent liver biopsy, 88 patients were included in the present analysis. The final diagnosis involved 15 categories of diseases, with drug-induced liver injury (DILI) [34.09% (30/88)], autoimmune liver diseases [22.73% (20/88)], and nonalcoholic fatty liver disease (NAFLD) [12.50% (11/88)] being the most common causes, following by genetic and other rare diseases. DILI, autoimmune liver disease and NAFLD were the most common causes of abnormal liver tests in these non-viral liver diseases. Some rare diseases such as hereditary metabolic liver disease also represent a considerable proportion in patients with abnormal liver function test.

Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis.

PubMed

Pembroke, Thomas; Deschenes, Marc; Lebouché, Bertrand; Benmassaoud, Amine; Sewitch, Maida; Ghali, Peter; Wong, Philip; Halme, Alex; Vuille-Lessard, Elise; Pexos, Costa; Klein, Marina B; Sebastiani, Giada

2017-10-01

Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear. The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective cohort study using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis, in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ⩾248dB/m), or transition to severe HS (CAP >292dB/m), for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM] >7.1kPa), or transition to cirrhosis (LSM >12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression. A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs. 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection. HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection. Lay summary: Fatty liver is the most frequent liver disease in Western countries. People living with HIV seem at high risk of fatty liver due to frequent metabolic disorders and the long-term effects of antiretroviral therapy. However, due to the invasiveness of liver biopsy, the traditional method of diagnosing fatty liver, there are few data regarding its frequency in people living with HIV. In this study, we used a non-invasive diagnostic tool to analyze the epidemiology of fatty liver in 726 HIV+ patients. We found that fatty liver affects over one-third of people living with HIV. When followed over time, we found that HIV+ patients without HCV co-infection develop fatty liver more frequently than those co-infected with HCV. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Kupffer Cell Metabolism and Function

PubMed Central

Nguyen-Lefebvre, Anh Thu; Horuzsko, Anatolij

2015-01-01

Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions. PMID:26937490

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

PubMed

Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T

2016-07-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.

Detection and characterization of lesions on low-radiation-dose abdominal CT images postprocessed with noise reduction filters.

PubMed

Kalra, Mannudeep K; Maher, Michael M; Blake, Michael A; Lucey, Brian C; Karau, Kelly; Toth, Thomas L; Avinash, Gopal; Halpern, Elkan F; Saini, Sanjay

2004-09-01

To assess the effect of noise reduction filters on detection and characterization of lesions on low-radiation-dose abdominal computed tomographic (CT) images. Low-dose CT images of abdominal lesions in 19 consecutive patients (11 women, eight men; age range, 32-78 years) were obtained at reduced tube currents (120-144 mAs). These baseline low-dose CT images were postprocessed with six noise reduction filters; the resulting postprocessed images were then randomly assorted with baseline images. Three radiologists performed independent evaluation of randomized images for presence, number, margins, attenuation, conspicuity, calcification, and enhancement of lesions, as well as image noise. Side-by-side comparison of baseline images with postprocessed images was performed by using a five-point scale for assessing lesion conspicuity and margins, image noise, beam hardening, and diagnostic acceptability. Quantitative noise and contrast-to-noise ratio were obtained for all liver lesions. Statistical analysis was performed by using the Wilcoxon signed rank test, Student t test, and kappa test of agreement. Significant reduction of noise was observed in images postprocessed with filter F compared with the noise in baseline nonfiltered images (P =.004). Although the number of lesions seen on baseline images and that seen on postprocessed images were identical, lesions were less conspicuous on postprocessed images than on baseline images. A decrease in quantitative image noise and contrast-to-noise ratio for liver lesions was noted with all noise reduction filters. There was good interobserver agreement (kappa = 0.7). Although the use of currently available noise reduction filters improves image noise and ameliorates beam-hardening artifacts at low-dose CT, such filters are limited by a compromise in lesion conspicuity and appearance in comparison with lesion conspicuity and appearance on baseline low-dose CT images. Copyright RSNA, 2004

Hepatic Fibrosis Progression in HIV-Hepatitis C Virus Co-Infection – The Effect of Sex on Risk of Significant Fibrosis Measured by Aspartate-to-Platelet Ratio Index

PubMed Central

Rollet-Kurhajec, Kathleen C.; Moodie, Erica E. M.; Walmsley, Sharon; Cooper, Curtis; Pick, Neora; Klein, Marina B.

2015-01-01

Background In Hepatitis C virus (HCV) mono-infection, male sex is associated with faster liver fibrosis progression but the effects of sex have not been well studied in HIV-HCV co-infected patients. We examined the influence of sex on progression to significant liver fibrosis in HIV-HCV co-infected adults receiving antiretroviral therapy (ART) using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate biomarker of liver fibrosis. Methods We evaluated 308 HIV infected, HCV RNA positive participants of a Canadian multicentre prospective cohort receiving antiretrovirals and without significant liver fibrosis or end-stage liver disease at baseline. We used multivariate discrete-time proportional hazards models to assess the effect of sex on time to significant fibrosis (APRI≥1.5) adjusting for baseline age, alcohol use, cigarette smoking, HCV duration, and APRI and time-updated CD4 count and HIV RNA. Results Overall, 55 (18%) participants developed an APRI ≥ 1.5 over 544 person-years of at-risk follow-up time; 18 (21%) women (incidence rate (IR)=14.0/100 PY; 7.5-20.4) and 37 (17%) men (IR=8.9/100 PY; 6.0-11.8). Women had more favourable profiles with respect to traditional risk factors for liver disease progression (younger, shorter duration of HCV infection and less alcohol use). Despite this, female sex was associated with a greater than two-fold increased risk of fibrosis progression (adjusted hazard rate (HR) =2.23; 1.22-4.08). Conclusions HIV-HCV co-infected women receiving antiretroviral therapy were at significantly greater risk of progressing to liver fibrosis as measured by APRI compared with men. Enhanced efforts to engage and treat co-infected women for HCV are needed. PMID:26090666

Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network.

PubMed

Shantakumar, Sumitra; Nordstrom, Beth L; Hall, Susan A; Djousse, Luc; van Herk-Sukel, Myrthe P P; Fraeman, Kathy H; Gagnon, David R; Chagin, Karen; Nelson, Jeanenne J

2017-04-20

Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines. Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring. Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing. In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease.

PubMed

Gelli, Chiara; Tarocchi, Mirko; Abenavoli, Ludovico; Di Renzo, Laura; Galli, Andrea; De Lorenzo, Antonino

2017-05-07

To determine the clinical effectiveness of nutritional counseling on reduction of non-alcoholic fatty liver disease (NAFLD) severity, weight loss, metabolic and anthropometric indexes and liver enzymes. Forty-six adults with NAFLD received a 6-mo clinical and a dietary intervention (based on Mediterranean diet) carried out respectively by a gastroenterologist and a nutritionist with counseling license. The counseling process consisted of monthly meeting (about 45 min each). The effect of the treatment was evaluated monitoring liver enzymes, metabolic parameters, cardiovascular risk indexes, NAFLD severity [assessed by ultrasound (US)] and related indexes. All parameters were assessed at baseline. Biochemistry was also assessed at mid- and end-interventions and US was repeated at end-intervention. The percentage of patients with steatosis grade equal or higher than 2 was reduced from 93% to 48% and steatosis regressed in 9 patients (20%). At the end of the treatment the end-point concerning the weight ( i.e ., a 7% weight reduction or achievement/maintenance of normal weight) was accomplished by 25 out of 46 patients ( i.e ., 54.3%). As far as the liver enzymes is concerned, all three liver enzymes significantly decrease during the treatment the normalization was particularly evident for the ALT enzyme (altered values reduced from 67% down to 11%). Several parameters, i.e ., BMI, waist circumference, waist-to-hip ratio, AST, ALT, GGT, HDL, serum glucose, Tot-Chol/HDL, LDL/HDL, TG/HDL, AIP, HOMA, FLI, Kotronen index, VAI, NAFLD liver fat score and LAP, showed a significant improvement ( P < 0.01) between baseline and end-treatment. Outcomes of this study further strengthen the hypothesis that MedDiet and more active lifestyle can be considered a safe therapeutic approach for reducing risk and severity of NAFLD and related disease states. The proposed approach may be proposed as a valid and recommended approach for improving the clinical profile of NAFLD patients.

Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer.

PubMed

Toesca, Diego A S; Osmundson, Evan C; von Eyben, Rie; Shaffer, Jenny L; Koong, Albert C; Chang, Daniel T

This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT). In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant. A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using α/β of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008). ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Epidemiology and Mortality of Liver Abscess in End-Stage Renal Disease Dialysis Patients: Taiwan National Cohort Study

PubMed Central

Huang, Po-Chang; Wang, Jhi-Joung; Yang, Chun-Ming; Chu, Chin-Chen; Chio, Chung-Ching; Chang, Fu-Lin; Chien, Chih-Chiang

2014-01-01

Background and Objectives To determine the incidence rates and mortality of liver abscess in ESRD patients on dialysis. Design, Setting, Participants, & Measurements Using Taiwan’s National Health Insurance Research Database, we collected data from all ESRD patients who initiated dialysis between 2000 and 2006. Patients were followed until death, end of dialysis, or December 31, 2008. Predictors of liver abscess and mortality were identified using Cox models. Results Of the 53,249 incident dialysis patients identified, 447 were diagnosed as having liver abscesses during the follow-up period (224/100,000 person-years). The cumulative incidence rate of liver abscess was 0.3%, 1.1%, and 1.5% at 1 year, 5 years, and 7 years, respectively. Elderly patients and patients on peritoneal dialysis had higher incidence rates. The baseline comorbidities of diabetes mellitus, polycystic kidney disease, malignancy, chronic liver disease, biliary tract disease, or alcoholism predicted development of liver abscess. Overall in-hospital mortality was 10.1%. Conclusions The incidence of liver abscess is high among ESRD dialysis patients. In addition to the well known risk factors of liver abscess, two other important risk factors, peritoneal dialysis and polycystic kidney disease, were found to predict liver abscess in ESRD dialysis patients. PMID:24551077

Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

PubMed

Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

2017-07-01

The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

The bioimpedance analysis of a parenchyma of a liver in the conditions of its extensive resection in experiment

NASA Astrophysics Data System (ADS)

Agibalov, D. Y.; Panchenkov, D. N.; Chertyuk, V. B.; Leonov, S. D.; Astakhov, D. A.

2017-01-01

The liver failure which is result of disharmony of functionality of a liver to requirements of an organism is the main reason for unsatisfactory results of an extensive resection of a liver. However, uniform effective criterion of definition of degree of a liver failure it isn’t developed now. One of data acquisition methods about a morfo-functional condition of internals is the bioimpedance analysis (BIA) based on impedance assessment (full electric resistance) of a biological tissue. Measurements of an impedance are used in medicine and biology for the characteristic of physical properties of living tissue, studying of the changes bound to a functional state and its structural features. In experimental conditions we carried out an extensive resection of a liver on 27 white laboratory rats of the Vistar line. The comparative characteristic of data of a bioimpedansometriya in intraoperative and after the operational period with the main existing methods of assessment of a functional condition of a liver was carried out. By results of the work performed by us it is possible to claim that the bioimpedance analysis of a liver on the basis of an invasive bioimpedansometriya allows to estimate morphological features and functional activity of a liver before performance of an extensive resection of a liver. The data obtained during scientific work are experimental justification for use of an impedansometriya during complex assessment of functional reserves of a liver. Preliminary data of clinical approbation at a stage of introduction of a technique speak about rather high informational content of a bioimpedansometriya. The subsequent analysis of efficiency of the invasive bioimpedance analysis of a liver requires further accumulation of clinical data. However even at this stage the method showed the prospect for further use in clinical surgical hepathology.

Chronic DON exposure and acute LPS challenge: effects on porcine liver morphology and function.

PubMed

Renner, Lydia; Kahlert, Stefan; Tesch, Tanja; Bannert, Erik; Frahm, Jana; Barta-Böszörményi, Anikó; Kluess, Jeannette; Kersten, Susanne; Schönfeld, Peter; Rothkötter, Hermann-Josef; Dänicke, Sven

2017-08-01

The aim of the present study was to examine the role of chronic deoxynivalenol (DON) exposition on the liver morphology and function in combination with pre- and post-hepatic lipopolysaccharide (LPS) stress in young pigs fed for 4 weeks with a DON-contaminated diet (4.59 mg/kg feed). At the end of the experiment, LPS (7.5 μg/kg BW) was administered for 1 h pre-hepatically (Vena portae hepatis) or post-hepatically (Vena jugularis). Liver morphology was macroscopically checked and showed haemorrhage in all LPS groups, significantly higher relative liver weights, accompanied by marked oedema in the gallbladder wall. Histological changes were judged by a modified histology activity index (HAI). Liver HAI score was significantly increased in all LPS groups compared to placebo, primarily due to neutrophil infiltration and haemorrhage. DON feed alone was without effect on the liver HAI. Liver function was characterized by (i) hepatic biochemical markers, (ii) mitochondrial respiration and (iii) Ca 2+ accumulation capacity of isolated mitochondria. Clinical chemical parameters characterizing liver function were initially (<3 h) slightly influenced by LPS. After 3 h, bilirubin and alkaline phosphatase were increased significantly, in DON-fed, jugular-infused LPS group. Respiration and Ca 2+ accumulation capacity of isolated liver mitochondria was not impaired by chronic DON exposure, acute LPS challenge or combined treatments. DON-contaminated feed did not change macroscopy and histology of the liver, but modified the function under LPS stress. The different function was not linked to modifications of liver mitochondria.

Integration of technologies for hepatic tissue engineering.

PubMed

Nahmias, Yaakov; Berthiaume, Francois; Yarmush, Martin L

2007-01-01

The liver is the largest internal organ in the body, responsible for over 500 metabolic, regulatory, and immune functions. Loss of liver function leads to liver failure which causes over 25,000 deaths/year in the United States. Efforts in the field of hepatic tissue engineering include the design of bioartificial liver systems to prolong patient's lives during liver failure, for drug toxicity screening and for the study of liver regeneration, ischemia/reperfusion injury, fibrosis, viral infection, and inflammation. This chapter will overview the current state-of-the-art in hepatology including isolated perfused liver, culture of liver slices and tissue explants, hepatocyte culture on collagen "sandwich" and spheroids, coculture of hepatocytes with non-parenchymal cells, and the integration of these culture techniques with microfluidics and reactor design. This work will discuss the role of oxygen and medium composition in hepatocyte culture and present promising new technologies for hepatocyte proliferation and function. We will also discuss liver development, architecture, and function as they relate to these culture techniques. Finally, we will review current opportunities and major challenges in integrating cell culture, bioreactor design, and microtechnology to develop new systems for novel applications.

A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation.

PubMed

McDiarmid, Sue V; Anand, Ravinder; Martz, Karen; Millis, Michael J; Mazariegos, George

2011-07-01

The purpose of this study was to identify significant, independent factors that predicted 6 month patient and graft survival after pediatric liver transplantation. The Studies of Pediatric Liver Transplantation (SPLIT) is a multicenter database established in 1995, of currently more than 4000 US and Canadian children undergoing liver transplantation. Previous published analyses from this data have examined specific factors influencing outcome. This study analyzes a comprehensive range of factors that may influence outcome from the time of listing through the peri- and postoperative period. A total of 42 pre-, peri- and posttransplant variables evaluated in 2982 pediatric recipients of a first liver transplant registered in SPLIT significant at the univariate level were included in multivariate models. In the final model combining all baseline and posttransplant events, posttransplant complications had the highest relative risk of death or graft loss. Reoperation for any cause increased the risk for both patient and graft loss by 11 fold and reoperation exclusive of specific complications by 4 fold. Vascular thromboses, bowel perforation, septicemia, and retransplantation, each independently increased the risk of patient and graft loss by 3 to 4 fold. The only baseline factor with a similarly high relative risk for patient and graft loss was recipient in the intensive care unit (ICU) intubated at transplant. A significant center effect was also found but did not change the impact of the highly significant factors already identified. We conclude that the most significant factors predicting patient and graft loss at 6 months in children listed for transplant are posttransplant surgical complications.

Toward integrated opisthorchiasis control in Northeast Thailand: The Lawa Project

PubMed Central

Sripa, Banchob; Tangkawattana, Sirikachorn; Laha, Thewarach; Kaewkes, Sasithorn; Mallory, Frank F.; Smith, John F.; Wilcox, Bruce A.

2015-01-01

Human liver fluke, Opisthorchis viverrini, a food-borne trematode is a significant public health problem in Southeast Asia, particularly in Thailand. Despite a long history of control programs in Thailand and a nationwide reduction, O. viverrini infection prevalence remains high in the Northeastern Provinces. Therefore, a new strategy for controlling the liver fluke infection using the EcoHealth/One Health approach was introduced into the Lawa Lake area in Khon Kaen province where the liver fluke is endemic. A program has been carried using anthelminthic treatment, novel intensive health education methods both in the communities and in schools, ecosystem monitoring and active community participation. As a result, the infection rate in the more than 10 villages surrounding the Lake has declined to approximate one third of the average of 50% as estimated by a baseline survey. Strikingly, the Cyprinoid fish species in the Lake, which are the intermediate host, now showed less than 1% prevalence compared to a maximum of 70% at baseline. This liver fluke control program, named “Lawa model,” is now recognized nationally and internationally, and being expanding to other parts of Thailand and neighboring Mekong countries. Challenges to O. viverrini disease control, and lessons learned in developing an integrative control program using a community-based, ecosystem approach, and scaling-up regionally based on Lawa as a model are described. PMID:25102053

Toward integrated opisthorchiasis control in northeast Thailand: the Lawa project.

PubMed

Sripa, Banchob; Tangkawattana, Sirikachorn; Laha, Thewarach; Kaewkes, Sasithorn; Mallory, Frank F; Smith, John F; Wilcox, Bruce A

2015-01-01

Human liver fluke, Opisthorchis viverrini, a food-borne trematode is a significant public health problem in Southeast Asia, particularly in Thailand. Despite a long history of control programmes in Thailand and a nationwide reduction, O. viverrini infection prevalence remains high in the northeastern provinces. Therefore, a new strategy for controlling the liver fluke infection using the EcoHealth/One Health approach was introduced into the Lawa Lake area in Khon Kaen province where the liver fluke is endemic. A programme has been carried using anthelminthic treatment, novel intensive health education methods both in the communities and in schools, ecosystem monitoring and active community participation. As a result, the infection rate in the more than 10 villages surrounding the lake has declined to approximate one third of the average of 50% as estimated by a baseline survey. Strikingly, the Cyprinoid fish species in the lake, which are the intermediate host, now showed less than 1% prevalence compared to a maximum of 70% at baseline. This liver fluke control programme, named "Lawa model," is now recognised nationally and internationally, and being expanding to other parts of Thailand and neighbouring Mekong countries. Challenges to O. viverrini disease control, and lessons learned in developing an integrative control programme using a community-based, ecosystem approach, and scaling-up regionally based on Lawa as a model are described. Copyright © 2014 Elsevier B.V. All rights reserved.

Vitamin D deficiency is a risk factor for infections in patients affected by HCV-related liver cirrhosis.

PubMed

Buonomo, Antonio Riccardo; Zappulo, Emanuela; Scotto, Riccardo; Pinchera, Biagio; Perruolo, Giuseppe; Formisano, Pietro; Borgia, Guglielmo; Gentile, Ivan

2017-10-01

To evaluate the prevalence of vitamin D deficiency and its impact on infections in HCV-related liver cirrhosis. We enrolled 291 patients affected by HCV-related liver cirrhosis. Serum vitamin D levels were dosed at enrolment. The presence of infection was assessed at baseline and during follow-up based on physical examination and laboratory analyses. Vitamin D deficiency (<20ng/mL) was diagnosed in 68.3% of patients, and a total of 102 infections were detected. Urinary tract infections were the most common infections diagnosed (41.2%). Vitamin D deficiency rates were higher in patients with decompensated cirrhosis (Child-Pugh B vs A p=0.008, and Child-Pugh C vs A p=0.024). Infection was significantly associated with vitamin D deficiency (p<0.001), MELD score >15 (p=0.003), Child-Pugh class B/C vs A (p<0.001), and active hepatocellular carcinoma (HCC) (p<0.001). At multivariate analysis, vitamin D deficiency (p<0.01), HCC (p<0.05), hospitalization (p<0.001) and exposure to immunosuppressant agents (p<0.05) were independent risk factors for infection at baseline. Vitamin D may play a role in the development of infections in patients affected by liver cirrhosis, and preventive strategies with vitamin D supplementation are to be evaluated in randomized controlled trials. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Circuit lifespan during continuous renal replacement therapy for combined liver and kidney failure.

PubMed

Chua, Horng-Ruey; Baldwin, Ian; Bailey, Michael; Subramaniam, Ashwin; Bellomo, Rinaldo

2012-12-01

To evaluate circuit lifespan (CL) and bleeding risk during continuous renal replacement therapy (CRRT), in combined liver and renal failure. Single-center retrospective analysis of adults with acute liver failure or decompensated cirrhosis who received CRRT, without anticoagulation or with heparinization in intensive care unit. Seventy-one patients with 539 CRRT circuits were evaluated. Median overall CL was 9 (6-16) hours. CL was 12 (7-24) hours in 51 patients never anticoagulated for CRRT. In 20 patients who subsequently received heparinization, CL was 7 (5-11) hours without anticoagulation, which did not improve with systemic or regional heparinization (P = .231), despite higher peri-circuit activated partial thromboplastin time (APTT) and heparin dose. Using multivariate linear regression, patients with higher baseline APTT or serum bilirubin, or who were not mechanically ventilated, had longer CL (P < .05). Additionally, peri-circuit thrombocytopenia (P < .0001) or higher international normalized ratio (P < .05) predicted longer CL. Of 71 patients, 33 had significant bleeding events. Using multivariate logistic regression, patients with higher baseline APTT, vasoactive drug use >24 hours, or thrombocytopenia, had more bleeding complications (P < .05). Decreasing platelet counts (especially <50 × 10(9)/mm(3)) had an incremental effect on CL (P < .0001). CRRT CL is short in patients with liver failure despite apparent coagulopathy. Thrombocytopenia predicts longer CL and bleeding complications. Copyright © 2012 Elsevier Inc. All rights reserved.

Causes of altered liver function tests - the role of alpha-1 antitrypsin.

PubMed

Stollenwerk, J; Schepke, M; Biecker, E

2016-09-01

Altered liver function tests are a common finding in clinical practice. Our retrospective study aimed to identify the diagnoses in a non-selected cohort of patients with altered liver tests and to investigate whether alpha-1 antitrypsin genotyping should be part of the diagnostic workup. 501 patients who were admitted to our outpatient clinic for further evaluation of altered liver function tests were included in the study. The patients underwent a standardized diagnostic program with history taking, physical examination, laboratory tests and ultrasonography. Liver biopsy was performed if appropriate. More than 50 % of the patients had nonalcoholic fatty liver disease. Alcoholic and drug-induced liver injury were found in 8.6 % and 7 % of patients, respectively. Chronic hepatitis B and C, autoimmune liver disease and inherited causes of liver disease made up for approximately 16 % of the diagnoses. The remaining patients were diagnosed with kryptogenic liver disease or had miscellaneous diagnoses. In 3.7 % of the genotyped patients, the alpha-1 antitrypsin genotype PiMZ was found. Nonalcoholic fatty liver disease is nowadays the most frequent cause of altered liver tests. Alcoholic liver disease might be underrepresented in our study since these patients less often seek medical attention or the diagnosis is already made by the primary care physician. Drug-induced liver injury was found in more patients than expected and might therefore be underdiagnosed in practice. The alpha-1 antitrypsin genotype PiMZ was found in absence of other possible causes of liver disease, indicating that the PiMZ genotype is itself a risk factor for liver disease. Genotyping for alpha-1 antitrypsin should therefore be done when other causes for altered liver function tests have been ruled out. © Georg Thieme Verlag KG Stuttgart · New York.

Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study.

PubMed

TruneČka, P; Klempnauer, J; Bechstein, W O; Pirenne, J; Friman, S; Zhao, A; Isoniemi, H; Rostaing, L; Settmacher, U; Mönch, C; Brown, M; Undre, N; Tisone, G

2015-07-01

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable. © 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.

Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response

PubMed Central

Aydinok, Yesim; Evans, Patricia; Manz, Chantal Y.; Porter, John B.

2012-01-01

Background Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone. Design and Methods Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year. Results Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months. Conclusions The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662. PMID:22180427

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

PubMed

Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

2015-07-07

To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group. These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve MetS within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

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

PubMed

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

2016-09-14

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

Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system.

PubMed

Kudo, Masashi; Gotohda, Naoto; Sugimoto, Motokazu; Kobayashi, Tatsushi; Kojima, Motohiro; Takahashi, Shinichiro; Konishi, Masaru; Hayashi, Ryuichi

2018-06-02

Magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) is a diagnostic modality for liver tumors. Three-dimensional (3D) volumetric analysis systems using EOB-MRI data are used to simulate liver anatomy for surgery. This study was conducted to investigate clinical utility of a 3D volumetric analysis system on EOB-MRI to evaluate liver function. Between August 2014 and December 2015, 181 patients underwent laboratory and radiological exams as standardized preoperative evaluation for liver surgery. The liver-spleen contrast-enhanced ratio (LSR) was measured by a semi-automated 3D volumetric analysis system on EOB-MRI. First, the inter-evaluator variability of the calculated LSR was evaluated. Additionally, a subset of liver surgical specimens was evaluated histologically by using immunohistochemical staining. Finally, the correlations between the LSR and grading systems of liver function, laboratory data, or histological findings were analyzed. The inter-evaluator correlation coefficient of the measured LSR was 0.986. The mean LSR was significantly correlated with the Child-Pugh score (p = 0.014) and the ALBI score (p < 0.001). Significant correlations were also observed between the LSR and indocyanine green retention rate at 15 min (r = - 0.601, p < 0.001), between the LSR and liver fibrosis stage (r = - 0.556, p < 0.001), and between the LSR and liver steatosis grade (r = - 0.396, p < 0.001). The LSR calculated by a 3D volumetric analysis system on EOB-MRI was highly reproducible and was shown to be correlated with liver function parameters and liver histology. These data suggest that this imaging modality can be a reliable tool to evaluate liver function.

Laparoscopic splenectomy for patients with liver cirrhosis: Improvement of liver function in patients with Child-Pugh class B.

PubMed

Yamamoto, Naoki; Okano, Keiichi; Oshima, Minoru; Akamoto, Shitaro; Fujiwara, Masao; Tani, Joji; Miyoshi, Hisaaki; Yoneyama, Hirohito; Masaki, Tsutomu; Suzuki, Yasuyuki

2015-12-01

We aimed to assess the short-term outcomes of laparoscopic splenectomy (LS) and liver function at 1 year after splenectomy in the patients with liver cirrhosis. Forty-five patients with liver cirrhosis and hypersplenism underwent LS. We reviewed electronic medical records regarding the liver functional reserve, the etiology of liver cirrhosis, and the presence of hepatocellular carcinoma and esophago-gastric varices. Prospectively collected data of perioperative variables, postoperative complications, and long-term liver function were analyzed. Forty-five patients had a chronic liver disease classified into Child-Pugh classes (A/B/C: 23/20/2). The etiologies of disease were hepatitis C virus infection in 34 patients, hepatitis B virus infection in 4, and others in 7. Fourteen patients underwent procedures in addition to LS, including hepatectomy (n = 7) and devascularization for esophagogastric varices (n = 8). Postoperative complications occurred in 11 patients (24%). Neither postoperative liver failure nor in-hospital mortality occurred. White blood cell and platelet counts determined 7 days, 1 month, and 1 year after LS doubled or increased more than twice compared with the preoperative values (P < .001). One year after LS, patients who had been classified preoperatively into Child-Pugh class B had decreased total serum bilirubin levels (P = .03), and increased prothrombin activity (P = 003) and decreased Child-Pugh scores (P = .001). The Child-Pugh classifications improved in 14 of 18 patients (78%) who had Child-Pugh class B preoperatively. LS is a safe and feasible procedure for hypersplenism in patients with liver cirrhosis. In addition, LS most likely ameliorates liver function at 1 year after LS in patients with Child-Pugh class B liver cirrhosis. Copyright © 2015 Elsevier Inc. All rights reserved.

TU-F-12A-04: Differential Radiation Avoidance of Functional Liver Regions Defined by 99mTc-Sulfur Colloid SPECT/CT with Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, S; Miyaoka, R; Kinahan, P

2014-06-15

Purpose: Radiotherapy for hepatocellular carcinoma patients is conventionally planned without consideration of spatial heterogeneity in hepatic function, which may increase risk of radiation-induced liver disease. Pencil beam scanning (PBS) proton radiotherapy (pRT) plans were generated to differentially decrease dose to functional liver volumes (FLV) defined on [{sup 99m}Tc]sulfur colloid (SC) SPECT/CT images (functional avoidance plans) and compared against conventional pRT plans. Methods: Three HCC patients underwent SC SPECT/CT scans for pRT planning acquired 15 min post injection over 24 min. Images were reconstructed with OSEM following scatter, collimator, and exhale CT attenuation correction. Functional liver volumes (FLV) were defined bymore » liver:spleen uptake ratio thresholds (43% to 90% maximum). Planning objectives to FLV were based on mean SC SPECT uptake ratio relative to GTV-subtracted liver and inversely scaled to mean liver dose of 20 Gy. PTV target coverage (V{sub 95}) was matched between conventional and functional avoidance plans. PBS pRT plans were optimized in RayStation for single field uniform dose (SFUD) and systematically perturbed to verify robustness to uncertainty in range, setup, and motion. Relative differences in FLV DVH and target dose heterogeneity (D{sub 2}-D{sub 98})/D50 were assessed. Results: For similar liver dose between functional avoidance and conventional PBS pRT plans (D{sub mean}≤5% difference, V{sub 18Gy}≤1% difference), dose to functional liver volumes were lower in avoidance plans but varied in magnitude across patients (FLV{sub 70%max} D{sub mean}≤26% difference, V{sub 18Gy}≤8% difference). Higher PTV dose heterogeneity in avoidance plans was associated with lower functional liver dose, particularly for the largest lesion [(D{sub 2}-D{sub 98})/D{sub 50}=13%, FLV{sub 90%max}=50% difference]. Conclusion: Differential avoidance of functional liver regions defined on sulfur colloid SPECT/CT is feasible with proton therapy. The magnitude of benefit appears to be patient specific and dependent on tumor location, size, and proximity to functional volumes. Further investigation in a larger cohort of patients may validate the clinical utility of functional avoidance planning of HCC radiotherapy.« less

Molecular regulation of urea cycle function by the liver glucocorticoid receptor.

PubMed

Okun, Jürgen G; Conway, Sean; Schmidt, Kathrin V; Schumacher, Jonas; Wang, Xiaoyue; de Guia, Roldan; Zota, Annika; Klement, Johanna; Seibert, Oksana; Peters, Achim; Maida, Adriano; Herzig, Stephan; Rose, Adam J

2015-10-01

One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function. Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (∼+32%) and loss (∼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.

Lovastatin decreases mortality and improves liver functions in fulminant hepatic failure from 90% partial hepatectomy in rats.

PubMed

Cai, S R; Motoyama, K; Shen, K J; Kennedy, S C; Flye, M W; Ponder, K P

2000-01-01

Liver insufficiency occurs when the liver cannot perform critical functions such as ammonia metabolism, gluconeogenesis, or production of coagulation factors The hypothesis of this study was that decreased function of existing hepatocytes may contribute to hepatic failure, and that the function of these cells might be increased pharmacologically. Lovastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that inhibits cholesterol biosynthesis and affects the activity of some signal transduction pathways and liver transcription factors. Changes in hepatic transcription factors during liver regeneration might result in decreased liver functions, and lovastatin might prevent these changes Rats received 90% partial hepatectomy (90% PH), and either lovastatin or vehicle alone daily. Survival and liver functions were assessed. Lovastatin increased survival to 58% (vs. 6% in controls that received 90% PH without drug), decreased the peak ammonia level to 427 microM (vs. 846 microM in controls), increased the nadir of glucose to 88 mg/dl (vs. 57 mg/dl in controls), decreased the peak prothrombin time to 23 s (vs 29 s in controls), and decreased the peak activated partial thromboplastin time to 29 s (vs. 39 s in controls). The full survival and metabolic benefits were observed when lovastatin was started at 30 min after 90% PH, but lovastatin was less efficacious when started at later times. Lovastatin increases the function of existing hepatocytes and might be used to improve liver function after extensive hepatic resection.

Inhibition of glycogen synthase kinase (GSK)-3-β improves liver microcirculation and hepatocellular function after hemorrhagic shock.

PubMed

Jellestad, Lena; Fink, Tobias; Pradarutti, Sascha; Kubulus, Darius; Wolf, Beate; Bauer, Inge; Thiemermann, Chris; Rensing, Hauke

2014-02-05

Ischemia and reperfusion may cause liver injury and are characterized by hepatic microperfusion failure and a decreased hepatocellular function. Inhibition of glycogen synthase kinase (GSK)-3β, a serine-threonine kinase that has recently emerged as a key regulator in the modulation of the inflammatory response after stress events, may be protective in conditions like sepsis, inflammation and shock. Therefore, aim of the study was to assess the role of GSK-3β in liver microcirculation and hepatocellular function after hemorrhagic shock and resuscitation (H/R). Anesthetized male Sprague-Dawley rats underwent pretreatment with Ringer´s solution, vehicle (DMSO) or TDZD-8 (1 mg/kg), a selective GSK-3β inhibitor, 30 min before induction of hemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 min) and were resuscitated with shed blood and Ringer´s solution (2h). 5h after resuscitation hepatic microcirculation was assessed by intravital microscopy. Propidium iodide (PI) positive cells, liver enzymes and alpha-GST were measured as indicators of hepatic injury. Liver function was estimated by assessment of indocyanine green plasma disappearance rate. H/R led to a significant decrease in sinusoidal diameters and impairment of liver function compared to sham operation. Furthermore, the number of PI positive cells in the liver as well as serum activities of liver enzymes and alpha-GST increased significantly after H/R. Pretreatment with TDZD-8 prevented the changes in liver microcirculation, hepatocellular injury and liver function after H/R. A significant rise in the plasma level of IL-10 was observed. Thus, inhibition of GSK-3β before hemorrhagic shock modulates the inflammatory response and improves hepatic microcirculation and hepatocellular function. Copyright © 2013 Elsevier B.V. All rights reserved.

[Kidney function and liver transplantation].

PubMed

Gámán, György; Gelley, Fanni; Gerlei, Zsuzsa; Dabasi, Eszter; Görög, Dénes; Fehérvári, Imre; Kóbori, László; Lengyel, Gabriella; Zádori, Gergely; Fazakas, János; Doros, Attila; Sárváry, Enikő; Nemes, Balázs

2013-06-30

In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. Retrospective data analysis was performed after primary liver transplantations (n = 319). impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). Selection of personalized immunosuppressive medication has a positive effect on renal function.

Liver Transplant

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Function of GATA Factors in the Adult Mouse Liver

PubMed Central

Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

2013-01-01

GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

Functional hepatocyte clusters on bioactive blend silk matrices towards generating bioartificial liver constructs.

PubMed

Janani, G; Nandi, Samit K; Mandal, Biman B

2018-02-01

The creation of in vitro functional hepatic tissue simulating micro-environmental niche of native liver is a keen area of research due to its demand in bioartificial liver (BAL) and cell-based tissue engineering. Here, we investigated the potential of novel blend (BA) silk scaffold fabricated by blending mulberry (Bombyx mori, BM) silk fibroin with cell adhesion motif (RGD) rich non-mulberry (Antheraea assamensis, AA) silk fibroin, in generating a functional liver construct. Three-dimensional (3D) porous silk scaffolds (BM, AA and BA) were physico-chemically characterized and functionally evaluated using human hepatocarcinoma cells (HepG2) and primary neonatal rat hepatocytes. The growth and distribution of hepatocytes within the scaffolds were tracked by FESEM, alamar blue proliferation assay and live/dead staining. Hemocompatible BA scaffolds supported the formation of high density hepatocyte clusters, facilitating cell-matrix and cell-cell interactions. Blend scaffolds evinced enhanced liver-specific functions of cultured hepatocytes in terms of albumin synthesis, urea synthesis and cytochrome P450 enzyme activity over 21 days. Subcutaneous implantation of scaffolds demonstrated minimal macrophage infiltration in blend scaffolds. These findings substantiate that the integral property of blend (BA) scaffold offers a befitting environment by influencing spheroidal growth of hepatocytes with enhanced biological activity. Collectively, the present study provides a new 3D bio-matrix niche for growing functional liver cells that would have future prospects in BAL as well as regenerative medicine. An end stage liver disease called cirrhosis perturbs the self-healing ability and physiological functions of liver. Due to the scarcity of healthy donors, a functional in vitro hepatic construct retaining the liver-specific functions is in great demand for its prospects in bioartificial liver (BAL) and cell-based tissue engineering. Physicochemical attributes of a matrix influence the behavior of cultured hepatocytes in terms of attachment, morphology and functionality. Mulberry and non-mulberry silk fibroin presents unique amino acid sequence with difference in hydrophobicity and crystallinity. Considering this, the present study focuses on the development of a suitable three-dimensional (3D) bioactive matrix incorporating both mulberry silk fibroin and cell adhesion motif (RGD) rich non-mulberry silk fibroin. Porous silk blend scaffolds facilitated the formation of hepatocyte clusters with enhanced liver-specific functions emphasizing both cell-cell and cell-matrix interactions. Hemocompatibility and integral property of blend scaffolds offers a biological niche for seeding functional liver cells that would have future prospects in biohybrid devices. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In Vivo Mitochondrial Oxygen Tension Measured by a Delayed Fluorescence Lifetime Technique

PubMed Central

Mik, Egbert G.; Johannes, Tanja; Zuurbier, Coert J.; Heinen, Andre; Houben-Weerts, Judith H. P. M.; Balestra, Gianmarco M.; Stap, Jan; Beek, Johan F.; Ince, Can

2008-01-01

Mitochondrial oxygen tension (mitoPO2) is a key parameter for cellular function, which is considered to be affected under various pathophysiological circumstances. Although many techniques for assessing in vivo oxygenation are available, no technique for measuring mitoPO2 in vivo exists. Here we report in vivo measurement of mitoPO2 and the recovery of mitoPO2 histograms in rat liver by a novel optical technique under normal and pathological circumstances. The technique is based on oxygen-dependent quenching of the delayed fluorescence lifetime of protoporphyrin IX. Application of 5-aminolevulinic acid enhanced mitochondrial protoporphyrin IX levels and induced oxygen-dependent delayed fluorescence in various tissues, without affecting mitochondrial respiration. Using fluorescence microscopy, we demonstrate in isolated hepatocytes that the signal is of mitochondrial origin. The delayed fluorescence lifetime was calibrated in isolated hepatocytes and isolated perfused livers. Ultimately, the technique was applied to measure mitoPO2 in rat liver in vivo. The results demonstrate mitoPO2 values of ∼30–40 mmHg. mitoPO2 was highly sensitive to small changes in inspired oxygen concentration around atmospheric oxygen level. Ischemia-reperfusion interventions showed altered mitoPO2 distribution, which flattened overall compared to baseline conditions. The reported technology is scalable from microscopic to macroscopic applications, and its reliance on an endogenous compound greatly enhances its potential field of applications. PMID:18641065

Risk factors for stent graft thrombosis after transjugular intrahepatic portosystemic shunt creation

PubMed Central

Jahangiri, Younes; Kerrigan, Timothy; Li, Lei; Prosser, Dominik; Brar, Anantnoor; Righetti, Johnathan; Schenning, Ryan C.; Kaufman, John A.

2017-01-01

Background To identify risk factors of stent graft thrombosis after transjugular intrahepatic portosystemic shunt (TIPS) creation. Methods Patients who underwent TIPS creation between June 2003 and January 2016 and with follow-up assessing stent graft patency were included (n=174). Baseline comorbidities, liver function, procedural details and follow-up liver function tests were analyzed in association with hazards of thrombosis on follow-up. Competing risk cox regression models were used considering liver transplant after TIPS creation as the competing risk variable. Results One-, 2- and 5-year primary patency rates were 94.1%, 91.7% and 78.2%, respectively. Patient age [sub-hazard ratio (sHR): 1.13; P=0.001], body mass index (BMI) <30 (sHR: 33.08; P=0.008) and a higher post-TIPS portosystemic pressure gradient (sHR: 1.14; P=0.023) were significantly associated with TIPS thrombosis in multivariate analysis. A higher rate of TIPS thrombosis was observed in those for whom the procedure was clinically unsuccessful (P=0.014). A significant increase in incidence of thrombosis was noted with increasing tertiles of post-TIPS portosystemic gradients (P value for trend=0.017). Conclusions Older age, lower BMI and higher post-TIPS portosystemic gradients were associated with higher hazards of shunt thrombosis after TIPS creation using stent grafts. Higher rates of shunt thrombosis were seen in patients for whom TIPS creation was clinically unsuccessful. The association between TIPS thrombosis and higher post-TIPS portosystemic gradients may indicate impaired flow through the shunt, a finding which may be technical or anatomic in nature and should be assessed before procedure completion. PMID:29399518

Benign Liver Tumors

MedlinePlus

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Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis

PubMed Central

Al-Fayoumi, Suliman; Hashiguchi, Taishi; Shirakata, Yuka; Mascarenhas, John; Singer, Jack W

2018-01-01

Background Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK–STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling. Purpose To investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease. Methods Pacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured. Results Pacritinib-treated mice had significantly (P<0.01) reduced fibrotic areas in liver compared to vehicle control and significantly (P<0.05) lower levels of CK18. The antifibrotic effect of pacritinib was comparable to that of telmisartan, but without significant effects on fat accumulation. Conclusion These results, the first to demonstrate hepatic antifibrotic effects for pacritinib in an animal model of liver disease, provide preliminary support for potential clinical applications of pacritinib in fibrotic diseases other than myelofibrosis. PMID:29785143

Ad Integrum Functional and Volumetric Recovery in Right Lobe Living Donors: Is It Really Complete 1 Year After Donor Hepatectomy?

PubMed

Duclos, J; Bhangui, P; Salloum, C; Andreani, P; Saliba, F; Ichai, P; Elmaleh, A; Castaing, D; Azoulay, D

2016-01-01

The partial liver's ability to regenerate both as a graft and remnant justifies right lobe (RL) living donor liver transplantation. We studied (using biochemical and radiological parameters) the rate, extent of, and predictors of functional and volumetric recovery of the remnant left liver (RLL) during the first year in 91 consecutive RL donors. Recovery of normal liver function (prothrombin time [PT] ≥70% of normal and total bilirubin [TB] ≤20 µmol/L), liver volumetric recovery, and percentage RLL growth were analyzed. Normal liver function was regained by postoperative day's 7, 30, and 365 in 52%, 86%, and 96% donors, respectively. Similarly, mean liver volumetric recovery was 64%, 71%, and 85%; whereas the percentage liver growth was 85%, 105%, and 146%, respectively. Preoperative PT value (p = 0.01), RLL/total liver volume (TLV) ratio (p = 0.03), middle hepatic vein harvesting (p = 0.02), and postoperative peak TB (p < 0.01) were predictors of early functional recovery, whereas donor age (p = 0.03), RLL/TLV ratio (p = 0.004), and TLV/ body weight ratio (p = 0.02) predicted early volumetric recuperation. One-year post-RL donor hepatectomy, though functional recovery occurs in almost all (96%), donors had incomplete restoration (85%) of preoperative total liver volume. Modifiable predictors of regeneration could help in better and safer donor selection, while continuing to ensure successful recipient outcomes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Primary biliary cirrhosis

MedlinePlus

... stools Itching Poor appetite and weight loss As liver function worsens, symptoms may include: Fluid buildup in the ... your liver is working properly: Albumin blood test Liver function tests (serum alkaline phosphatase is most important) Prothrombin ...

Bioengineered transplantable porcine livers with re-endothelialized vasculature.

PubMed

Ko, In Kap; Peng, Li; Peloso, Andrea; Smith, Charesa J; Dhal, Abritee; Deegan, Daniel B; Zimmerman, Cindy; Clouse, Cara; Zhao, Weixin; Shupe, Thomas D; Soker, Shay; Yoo, James J; Atala, Anthony

2015-02-01

Donor shortage remains a continued challenge in liver transplantation. Recent advances in tissue engineering have provided the possibility of creating functional liver tissues as an alternative to donor organ transplantation. Small bioengineered liver constructs have been developed, however a major challenge in achieving functional bioengineered liver in vivo is the establishment of a functional vasculature within the scaffolds. Our overall goal is to bioengineer intact livers, suitable for transplantation, using acellular porcine liver scaffolds. We developed an effective method for reestablishing the vascular network within decellularized liver scaffolds by conjugating anti-endothelial cell antibodies to maximize coverage of the vessel walls with endothelial cells. This procedure resulted in uniform endothelial attachment throughout the liver vasculature extending to the capillary bed of the liver scaffold and greatly reduced platelet adhesion upon blood perfusion in vitro. The re-endothelialized livers, when transplanted to recipient pigs, were able to withstand physiological blood flow and maintained for up to 24 h. This study demonstrates, for the first time, that vascularized bioengineered livers, of clinically relevant size, can be transplanted and maintained in vivo, and represents the first step towards generating engineered livers for transplantation to patients with end-stage liver failure. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Correlation between red blood cell count and liver function status].

PubMed

Xie, Xiaomeng; Wang, Leijie; Yao, Mingjie; Wen, Xiajie; Chen, Xiangmei; You, Hong; Jia, Jidong; Zhao, Jingmin; Lu, Fengmin

2016-02-01

To investigate the changes in red blood cell count in patients with different liver diseases and the correlation between red blood cell count and degree of liver damage. The clinical data of 1427 patients with primary liver cancer, 172 patients with liver cirrhosis, and 185 patients with hepatitis were collected, and the Child-Pugh class was determined for all patients. The differences in red blood cell count between patients with different liver diseases were retrospectively analyzed, and the correlation between red blood cell count and liver function status was investigated. The Mann-Whitney U test, Kruskal-Wallis H test, rank sum test, Spearman rank sum correlation test, and chi-square test were performed for different types of data. Red blood cell count showed significant differences between patients with chronic hepatitis, liver cancer, and liver cirrhosis and was highest in patients with chronic hepatitis and lowest in patients with liver cirrhosis (P < 0.05). In the patients with liver cirrhosis, red blood cell count tended to decrease in patients with a higher Child-Pugh class (P < 0.05). For patients with liver cirrhosis, red blood cell count can reflect the degree of liver damage, which may contribute to an improved liver function prediction model for these patients.

Postoperative Decrease in Platelet Counts Is Associated with Delayed Liver Function Recovery and Complications after Partial Hepatectomy.

PubMed

Takahashi, Kazuhiro; Kurokawa, Tomohiro; Oshiro, Yukio; Fukunaga, Kiyoshi; Sakashita, Shingo; Ohkohchi, Nobuhiro

2016-05-01

Peripheral platelet counts decrease after partial hepatectomy; however, the implications of this phenomenon are unclear. We assessed if the observed decrease in platelet counts was associated with postoperative liver function and morbidity (complications grade ≤ II according to the Clavien-Dindo classification). We enrolled 216 consecutive patients who underwent partial hepatectomy for primary liver cancers, metastatic liver cancers, benign tumors, and donor hepatectomy. We classified patients as either low or high platelet percentage (postoperative platelet count/preoperative platelet count) using the optimal cutoff value calculated by a receiver operating characteristic (ROC) curve analysis, and analyzed risk factors for delayed liver functional recovery and morbidity after hepatectomy. Delayed liver function recovery and morbidity were significantly correlated with the lowest value of platelet percentage based on ROC analysis. Using a cutoff value of 60% acquired by ROC analysis, univariate and multivariate analysis determined that postoperative lowest platelet percentage ≤ 60% was identified as an independent risk factor of delayed liver function recovery (odds ratio (OR) 6.85; P < 0.01) and morbidity (OR, 4.90; P < 0.01). Furthermore, patients with the lowest platelet percentage ≤ 60% had decreased postoperative prothrombin time ratio and serum albumin level and increased serum bilirubin level when compared with patients with platelet percentage ≥ 61%. A greater than 40% decrease in platelet count after partial hepatectomy was an independent risk factor for delayed liver function recovery and postoperative morbidity. In conclusion, the decrease in platelet counts is an early marker to predict the liver function recovery and complications after hepatectomy.

Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha

PubMed Central

Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.

2016-01-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329

Progression of Liver Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain.

PubMed

Bilbao, Itxarone; Salcedo, Magdalena; Gómez, Miguel Angel; Jimenez, Carlos; Castroagudín, Javier; Fabregat, Joan; Almohalla, Carolina; Herrero, Ignacio; Cuervas-Mons, Valentín; Otero, Alejandra; Rubín, Angel; Miras, Manuel; Rodrigo, Juan; Serrano, Trinidad; Crespo, Gonzalo; De la Mata, Manuel; Bustamante, Javier; Gonzalez-Dieguez, M Luisa; Moreno, Antonia; Narvaez, Isidoro; Guilera, Magda

2015-08-01

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2) ) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy. © 2015 American Association for the Study of Liver Diseases.

Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula.

PubMed Central

Kenler, A S; Swails, W S; Driscoll, D F; DeMichele, S J; Daley, B; Babineau, T J; Peterson, M B; Bistrian, B R

1996-01-01

OBJECTIVES: The authors compared the safety, gastrointestinal tolerance, and clinical efficacy of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) versus an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. SUMMARY BACKGROUND DATA: Previous studies suggest that feeding with n-3 fatty acids from fish oil can alter eicosanoid and cytokine production, yielding an improved immunocompetence and a reduced inflammatory response to injury. The use of n-3 fatty acids as a structured lipid can improve long-chain fatty acid absorption. METHODS: This prospective, blinded, randomized trial was conducted in 50 adult patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, plasma and erythrocyte fatty acid analysis, urinary prostaglandins, and outcome parameters were measured at baseline and on day 7. Comparisons were made in 18 and 17 evaluable patients based a priori on the ability to reach a tube feeding rate of 40 mL/hour. RESULTS: Patients receiving FOSL-HN experienced no untoward side effects, significant incorporation of eicosapentaenoic acid into plasma and erythrocyte phospholipids, and a 50% decline in the total number of gastrointestinal complications and infections compared with patients given O-HN. The data strongly suggest improved liver and renal function during the postoperative period in the FOSL-HN group. CONCLUSION: Early enteral feeding with FOSL-HN was safe and well tolerated. Results suggest that the use of such a formula during the postoperative period may reduce the number of infections and gastrointestinal complications per patient, as well as improve renal and liver function through modulation of urinary prostaglandin levels. Additional clinical trials to fully quantify clinical benefits and optimize nutritional support with FOSL-HN should be undertaken. Images Figure 1. Figure 2. Figure 3. PMID:8604913

Design of liver functional reserve monitor based on three-wavelength from IR to NIR.

PubMed

Ye, Fuli; Zhan, Huimiao; Shi, Guilian

2018-05-04

The preoperative evaluation of liver functional reserve is very important to determine the excision of liver lobe for the patients with liver cancer. There already exist many effective evaluation methods, but these ones have many disadvantages such as large trauma, complicated process and so on. Therefore, it is essential to develop a fast, accurate and simple detection method of liver functional reserve for the practical application in the clinical engineering field. According to the principle of spectrophotometry, this paper proposes a detection method of liver functional reserve based on three-wavelength from infrared light (IR) to near-infrared light (NIR), in which the artery pulse, the vein pulse and the move of tissue are taken into account. By using near-infrared photoelectric sensor technology and excreting experiment of indocyanine green, a minimally invasive, fast and simple testing equipment is designed in this paper. The testing result shows this equipment can greatly reduce the interference from human body and ambient, realize continuous and real-time detection of arterial degree of blood oxygen saturation and liver functional reserve.

Functions of autophagy in normal and diseased liver

PubMed Central

Czaja, Mark J.; Ding, Wen-Xing; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-hsiung James; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao-Ming

2013-01-01

Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases. PMID:23774882

Weight loss and severe jaundice in a patient with hyperthyroidism.

PubMed

Breidert, M; Offensperger, S; Blum, H E; Fischer, R

2011-09-01

Thyrotoxicosis may significantly alter hepatic function and is associated with autoimmune disorders of the liver. We report the case of a thyrotoxic patient with Graves' disease and histologically established cholestatic hepatitis. Medical treatment of hyperthyroidism normalized liver function tests. In patients with elevated liver function parameters and jaundice of unknown origin, thyroid function should generally be tested. Moreover, medical treatment of hyperthyroidism with thyrostatics may cause severe hepatitis whereas untreated hyperthyroid patients are at risk of developing chronic liver failure. © Georg Thieme Verlag KG Stuttgart · New York.

HEPATIC FUNCTION AFTER GENETICALLY-ENGINEERED PIG LIVER TRANSPLANTATION IN BABOONS

PubMed Central

Ekser, Burcin; Echeverri, Gabriel J.; Hassett, Andrea Cortese; Yazer, Mark H.; Long, Cassandra; Meyer, Michael; Ezzelarab, Mohamed; Lin, Chih Che; Hara, Hidetaka; van der Windt, Dirk J.; Dons, Eefje M.; Phelps, Carol; Ayares, David; Cooper, David K.C.; Gridelli, Bruno

2010-01-01

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from α1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed. PMID:20606605

Liver metal concentrations in Greater Sage-grouse (Centrocercus urophasianus).

PubMed

Dailey, Rebecca N; Raisbeck, Merl F; Siemion, Roger S; Cornish, Todd E

2008-04-01

Greater Sage-grouse (Centrocercus urophasianus) are a species of concern due to shrinking populations associated with habitat fragmentation and loss. Baseline health parameters for this species are limited or lacking, especially with regard to tissue metal concentrations. To obtain a range of tissue metal concentrations, livers were collected from 71 Greater Sage-grouse from Wyoming and Montana. Mean +/- SE metal concentrations (mg/kg wet weight) in liver were determined for vanadium (V) (0.12 +/- 0.01), chromium (Cr) (0.50 +/- 0.02), manganese (Mn) (2.68 +/- 0.11), iron (Fe) (1,019 +/- 103), nickel (Ni) (0.40 +/- 0.04), cobalt (Co) (0.08 +/- 0.02), copper (Cu) (6.43 +/- 0.40), mercury (Hg) (0.30 +/- 0.09), selenium (Se) (1.45 +/- 0.64), zinc (Zn) (59.2 +/- 4.70), molybdenum (Mo) (0.93 +/- 0.07), cadmium (Cd) (1.44 +/- 0.14), barium (Ba) (0.20 +/- 0.03), and lead (Pb) (0.17 +/- 0.03). In addition to providing baseline data, metal concentrations were compared between sex, age (juvenile/adult), and West Nile virus (WNv) groups (positive/negative). Adult birds had higher concentrations of Ni and Cd compared to juveniles. In addition, Zn and Cu concentrations were significantly elevated in WNv-positive birds.

Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting

PubMed Central

Selden, Clare; Spearman, Catherine Wendy; Kahn, Delawir; Miller, Malcolm; Figaji, Anthony; Erro, Eloy; Bundy, James; Massie, Isobel; Chalmers, Sherri-Ann; Arendse, Hiram; Gautier, Aude; Sharratt, Peter; Fuller, Barry; Hodgson, Humphrey

2013-01-01

Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4–6×1010cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale. PMID:24367515

The extent of intestinal failure-associated liver disease in patients referred for intestinal rehabilitation is associated with increased mortality: an analysis of the pediatric intestinal failure consortium database.

PubMed

Javid, Patrick J; Oron, Assaf P; Duggan, Christopher; Squires, Robert H; Horslen, Simon P

2017-09-05

The advent of regional multidisciplinary intestinal rehabilitation programs has been associated with improved survival in pediatric intestinal failure. Yet, the optimal timing of referral for intestinal rehabilitation remains unknown. We hypothesized that the degree of intestinal failure-associated liver disease (IFALD) at initiation of intestinal rehabilitation would be associated with overall outcome. The multicenter, retrospective Pediatric Intestinal Failure Consortium (PIFCon) database was used to identify all subjects with baseline bilirubin data. Conjugated bilirubin (CBili) was used as a marker for IFALD, and we stratified baseline bilirubin values as CBili<2 mg/dL, CBili 2-4 mg/dL, and CBili>4 mg/dL. The association between baseline CBili and mortality was examined using Cox proportional hazards regression. Of 272 subjects in the database, 191 (70%) children had baseline bilirubin data collected. 38% and 28% of patients had CBili >4 mg/dL and CBili <2 mg/dL, respectively, at baseline. All-cause mortality was 23%. On univariate analysis, mortality was associated with CBili 2-4 mg/dL, CBili >4 mg/dL, prematurity, race, and small bowel atresia. On regression analysis controlling for age, prematurity, and diagnosis, the risk of mortality was increased by 3-fold for baseline CBili 2-4 mg/dL (HR 3.25 [1.07-9.92], p=0.04) and 4-fold for baseline CBili >4 mg/dL (HR 4.24 [1.51-11.92], p=0.006). On secondary analysis, CBili >4 mg/dL at baseline was associated with a lower chance of attaining enteral autonomy. In children with intestinal failure treated at intestinal rehabilitation programs, more advanced IFALD at referral is associated with increased mortality and decreased prospect of attaining enteral autonomy. Early referral of children with intestinal failure to intestinal rehabilitation programs should be strongly encouraged. Treatment Study, Level III. Copyright © 2017 Elsevier Inc. All rights reserved.

Prevalence and causes of abnormal liver function in patients with coeliac disease.

PubMed

Casella, Giovanni; Antonelli, Elisabetta; Di Bella, Camillo; Villanacci, Vincenzo; Fanini, Lucia; Baldini, Vittorio; Bassotti, Gabrio

2013-08-01

Coeliac disease patients frequently display mild elevation of liver enzymes and this abnormality usually normalizes after gluten-free diet. To investigate the cause and prevalence of altered liver function tests in coeliac patients, basally and after 1 year of gluten-free diet. Data from 245 untreated CD patients (196 women and 49 men, age range 15-80 years) were retrospectively analysed and the liver function tests before and after diet, as well as associated liver pathologies, were assessed. Overall, 43/245 (17.5%) patients had elevated values of one or both aminotransferases; the elevation was mild (<5 times the upper reference limit) in 41 (95%) and marked (>10 times the upper reference limit) in the remaining 2 (5%) patients. After 1 year of gluten-free diet, aminotransferase levels normalized in all but four patients with HCV infection or primary biliary cirrhosis. In coeliac patients, hypertransaminaseaemia at diagnosis and the lack of normalization of liver enzymes after 12 months of diet suggest coexisting liver disease. In such instance, further evaluation is recommended to exclude the liver disease. Early recognition and treatment of coeliac disease in patients affected by liver disease are important to improve the liver function and prevent complications. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CYP2E1 immunoglobulin G4 subclass antibodies after desflurane anesthesia

PubMed Central

Batistaki, Chrysanthi; Michalopoulos, George; Matsota, Paraskevi; Nomikos, Tzortzis; Kalimeris, Konstantinos; Riga, Maria; Nakou, Maria; Kostopanagiotou, Georgia

2014-01-01

AIM: To investigate CYP2E1 IgG4 autoantibody levels and liver biochemical markers in adult patients after anesthesia with desflurane. METHODS: Forty patients who were > 18 years old and undergoing elective surgery under general anesthesia with desflurane were studied. Alpha-glutathione-S-transferase (αGST) and IgG4 antibodies against CYP2E1 were measured preoperatively and 96 h postoperatively, as well as complete blood count, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), g-glutamyl-transpeptidase (gGT), alkaline phosphatase, total serum proteins, albumin and bilirubin. A separate group of 8 patients who received regional anesthesia was also studied for calibration of the methodology used for CYP2E1 IgG4 and αGST measurements. Student’s t-test and the Mann-Whitney U test were used for comparison of the continuous variables, and Fisher’s exact test was used for the categorical variables. All tests were two-tailed, with statistical significance set as P < 0.05. RESULTS: None of the patients developed postoperative liver dysfunction, and all patients were successfully discharged from the hospital. No statistically significant difference was observed regarding liver function tests (SGOT, SGPT, γGT, bilirubin, INR), αGST and CYP2E1 IgG4, before and after exposure to desflurane. After dividing patients into two subgroups based on whether or not they had received general anesthesia in the past, no significant difference in the levels of CYP2E1 IgG4 was observed at baseline or 96 h after desflurane administration (P = 0.099 and P = 0.051, respectively). Alpha-GST baseline levels and levels after the intervention also did not differ significantly between these two subgroups (P > 0.1). The mean αGST differences were statistically elevated in men by 2.15 ng/mL compared to women when adjusted for BMI, duration of anesthesia, number of times anesthesia was administered previously and length of hospital stay. No significant difference was observed between patients who received desflurane and those who received regional anesthesia at any time point. CONCLUSION: There was no difference in CYP2E1 IgG4 or αGST levels after desflurane exposure; further research is required to investigate their role in desflurane-induced liver injury. PMID:24868327

Abdominal Ultrasound With Scintigraphic and Clinical Correlates in Infants With Sickle Cell Anemia: Baseline Data From the BABY HUG Trial

PubMed Central

McCarville, M. Beth; Luo, Zhaoyu; Huang, Xiangke; Rees, Renee C.; Rogers, Zora R.; Miller, Scott T.; Thompson, Bruce; Kalpatthi, Ram; Wang, Winfred C.

2015-01-01

OBJECTIVE The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data. SUBJECTS AND METHODS After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5–18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, 99mTc sulfur colloid liver-spleen scans, and 99mTc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings. RESULTS The mean (± SD) spleen volume (108 ± 47 mL) was significantly greater than published normal control values (30 ± 14 mL; p < 0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 ± 34 mL/min/1.73 m2) was elevated compared with control GFRs (92 ± 18 mL/min/1.73 m2). Renal volumes (right kidney, 29 ± 8 mL; left kidney, 31 ± 9 mL) were significantly greater than control volumes (right kidney, 27 ± 3 mL; left kidney, 27 ± 3 mL; p < 0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results. CONCLUSION In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent. PMID:21606305

Impact of nitinol stent surface processing on in-vivo nickel release and biological response.

PubMed

Nagaraja, Srinidhi; Sullivan, Stacey J L; Stafford, Philip R; Lucas, Anne D; Malkin, Elon

2018-05-01

Although nitinol is widely used in percutaneous cardiovascular interventions, a causal relationship between nickel released from implanted cardiovascular devices and adverse systemic or local biological responses has not been established. The objective of this study was to investigate the relationship between nitinol surface processing, in-vivo nickel release, and biocompatibility. Nitinol stents manufactured using select surface treatments were implanted into the iliac arteries of minipigs for 6 months. Clinical chemistry profile, complete blood count, serum and urine nickel analyses were performed periodically during the implantation period. After explant, stented arteries were either digested and analyzed for local nickel concentration or fixed and sectioned for histopathological analysis of stenosis and inflammation within the artery. The results indicated that markers for liver and kidney function were not different than baseline values throughout 180 days of implantation regardless of surface finish. In addition, white blood cell, red blood cell, and platelet counts were similar to baseline values for all surface finishes. Systemic nickel concentrations in serum and urine were not significantly different between processing groups and comparable to baseline values during 180 days of implantation. However, stents with non-optimized surface finishing had significantly greater nickel levels in the surrounding artery compared to polished stents. These stents had increased stenosis with potential for local inflammation compared to polished stents. These findings demonstrate that proper polishing of nitinol surfaces can reduce in-vivo nickel release locally, which may aid in minimizing adverse inflammatory reactions and restenosis. Nitinol is a commonly used material in cardiovascular medical devices. However, relationships between nitinol surface finishing, in-vivo metal ion release, and adverse biological responses have yet to be established. We addressed this knowledge gap by implanting single and overlapped nitinol stents with different surface finishes to assess systemic impact on minipigs (i.e. serum and urine nickel levels, liver and kidney function, immune and blood count) over the 6 month implantation period. In addition, nickel levels and histopathology in stented arteries were analyzed on explant to determine relationships between surface processing and local adverse tissue reactions. The findings presented here highlight the importance of surface processing on in-vivo nickel release and subsequent impact on local biological response for nitinol implants. Published by Elsevier Ltd.

Liver cell therapy and tissue engineering for transplantation.

PubMed

Vacanti, Joseph P; Kulig, Katherine M

2014-06-01

Liver transplantation remains the only definitive treatment for liver failure and is available to only a tiny fraction of patients with end-stage liver diseases. Major limitations for the procedure include donor organ shortage, high cost, high level of required expertise, and long-term consequences of immune suppression. Alternative cell-based liver therapies could potentially greatly expand the number of patients provided with effective treatment. Investigative research into augmenting or replacing liver function extends into three general strategies. Bioartificial livers (BALs) are extracorporeal devices that utilize cartridges of primary hepatocytes or cell lines to process patient plasma. Injection of liver cell suspensions aims to foster organ regeneration or provide a missing metabolic function arising from a genetic defect. Tissue engineering recreates the organ in vitro for subsequent implantation to augment or replace patient liver function. Translational models and clinical trials have highlighted both the immense challenges involved and some striking examples of success. Copyright © 2014. Published by Elsevier Inc.

Alcoholic liver disease.

PubMed

Penny, Steven M

2013-01-01

In the United States, approximately 100,000 deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, culminates in a dysfunctional and diffusely scarred liver. This article discusses the clinical manifestations, imaging considerations, and treatment of alcoholic liver disease and cirrhosis. Normal liver function, liver hemodynamics, the disease of alcoholism, and the deleterious effects of alcohol also are reviewed.

Prognostic value of enzymatic liver function for the estimation of short-term survival of liver transplant candidates: a prospective study with the LiMAx test.

PubMed

Jara, Maximilian; Malinowski, Maciej; Lüttgert, Katja; Schott, Eckart; Neuhaus, Peter; Stockmann, Martin

2015-01-01

LiMAx has been recently proposed as a new quantitative liver function test. Thus, we aimed to evaluate the diagnostic ability of LiMAx to assess short-term survival in liver transplant candidates and compare its performance to the model for end-stage liver disease (MELD) and indocyanine green plasma disappearance rate (ICG-PDR). Liver function of 167 chronic liver failure patients without hepatocellular carcinoma was prospectively investigated when they were evaluated for liver transplantation. Primary study endpoints were liver-related death within 6 months of follow-up. Within 6 months of follow-up, 18 patients died and 36 underwent liver transplantation. Median LiMAx results on evaluation day were significantly lower in patients who died (99 μg/kg/h vs. 55 μg/kg/h; P = 0.024), while median ICG-PDR results did not differ within both groups (4.4%/min vs. 3.5%/min; P = 0.159). LiMAx showed a higher negative predictive value (NPV: 0.93) as compared with ICG-PDR (NPV: 0.90) and the MELD (NPV: 0.91) in predicting risk of death within 6 months. In conclusion, LiMAx provides good prognostic information of liver transplant candidates. In particular, patients who are not at risk of death can be identified reliably by measuring actual enzymatic liver function capacity. © 2014 Steunstichting ESOT.

Prevalence and factors associated with the presence of abnormal function liver tests in patients with ulcerative colitis.

PubMed

Yamamoto-Furusho, Jesús K; Sánchez-Osorio, Magdalena; Uribe, Misael

2010-01-01

To investigate the prevalence of abnormal function liver tests and risk factors associated with their development in Mexican patients with UC. A total of 200 patients with confirmed diagnosis of UC were evaluated prospectively during a one year period from January 1, 2007 to December 31, 2008. A total of 94 females and 106 males patients with UC were analyzed. The age at diagnosis was 31.4 ± 13.2 years and the mean of disease duration was 6.7 ± 5.2 years. We found a high prevalence of abnormal function livers tests in 40% of UC patients. The pattern of abnormal function liver test was hepatitis in 70%, cholestatic (20%) and mixed (10%). The most common cause of abnormal function liver test was transient elevation in 50 patients (63%) followed by fatty liver disease (11.2%), primary sclerosing cholangitis (6.3%), drug-toxicity (6%) and others (13.5%) including chronic hepatitis C, total parenteral nutrition, granulomatous and ischemic hepatitis. In the multivariate logistic regression model, active disease, colectomy and abdominal sepsis were factors that persisted associated with the development of abnormal liver tests in UC patients. A high prevalence of abnormal function liver tests (40%) was found in Mexican UC patients is likely to be related to active disease, colectomy and the presence of sepsis.

[Liver diseases in the elderly].

PubMed

Bruguera, Miguel

2014-11-01

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.

Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease.

PubMed

Granér, Marit; Nyman, Kristofer; Siren, Reijo; Pentikäinen, Markku O; Lundbom, Jesper; Hakkarainen, Antti; Lauerma, Kirsi; Lundbom, Nina; Nieminen, Markku S; Taskinen, Marja-Riitta

2015-01-01

Nonalcoholic fatty liver disease has emerged as a novel cardiovascular risk factor. The aim of the study was to assess the effect of different ectopic fat depots on left ventricular (LV) function in subjects with nonalcoholic fatty liver disease. Myocardial and hepatic triglyceride contents were measured with 1.5 T magnetic resonance spectroscopy and LV function, visceral adipose tissue (VAT) and subcutaneous adipose tissue, epicardial and pericardial fat by MRI in 75 nondiabetic men. Subjects were stratified by hepatic triglyceride content into low, moderate, and high liver fat groups. Myocardial triglyceride, epicardial and pericardial fat, VAT, and subcutaneous adipose tissue increased stepwise from low to high liver fat group. Parameters of LV diastolic function showed a stepwise decrease over tertiles of liver fat and VAT, and they were inversely correlated with hepatic triglyceride, VAT, and VAT/subcutaneous adipose tissue ratio. In multivariable analyses, hepatic triglyceride and VAT were independent predictors of LV diastolic function, whereas myocardial triglyceride was not associated with measures of diastolic function. Myocardial triglyceride, epicardial and pericardial fat increased with increasing amount of liver fat and VAT. Hepatic steatosis and VAT associated with significant changes in LV structure and function. The association of LV diastolic function with hepatic triglyceride and VAT may be because of toxic systemic effects. The effects of myocardial triglyceride on LV structure and function seem to be more complex than previously thought and merit further study. © 2014 American Heart Association, Inc.

Growth hormone and drug metabolism. Acute effects on microsomal mixed-function oxidase activities in rat liver.

PubMed Central

Wilson, J T; Spelsberg, T C

1976-01-01

Adult male rats were subjected either to sham operation or to hypophysectomy and adrenalectomy and maintained for a total of 10 days before treatment with growth hormone. Results of the early effects of growth hormone on the activities of the mixed-function oxidases in rat liver over a 96h period after growth-hormone treatment are presented. 2. Hypophysectomy and adrenalectomy result in decreased body and liver weight and decreased drug metabolism (mixed-function oxidases). Concentrations of electron-transport-system components are also decreased. 3. In the hypophysectomized/adrenalectomized rats, growth hormone decreases the activities of the liver mixed-function oxidases and the cytochrome P-450 and cytochrome c reductases, as well as decreasing the concentration of cytochrome P-450 compared with that of control rats. Similar but less dramatic results are obtained with sham-operated rats. 4. It is concluded that whereas growth hormone enhances liver growth, including induction of many enzyme activities, it results in a decrease in mixed-function oxidase activity. Apparently, mixed-function oxidase activity decreases in liver when growth (mitogenesis) increases. PMID:938458

Hemochromatosis

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Galactosemia

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Intraoperative factors associated with delayed recovery of liver function after hepatectomy: analysis of 1969 living donors.

PubMed

Choi, S-S; Cho, S-S; Ha, T-Y; Hwang, S; Lee, S-G; Kim, Y-K

2016-02-01

The safety of healthy living donors who are undergoing hepatic resection is a primary concern. We aimed to identify intraoperative anaesthetic and surgical factors associated with delayed recovery of liver function after hepatectomy in living donors. We retrospectively analysed 1969 living donors who underwent hepatectomy for living donor liver transplantation. Delayed recovery of hepatic function was defined by increases in international normalised ratio of prothrombin time and concomitant hyperbilirubinaemia on or after post-operative day 5. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with delayed recovery of hepatic function after living donor hepatectomy. Delayed recovery of liver function after donor hepatectomy was observed in 213 (10.8%) donors. Univariate logistic regression analysis showed that sevoflurane anaesthesia, synthetic colloid, donor age, body mass index, fatty change and remnant liver volume were significant factors for prediction of delayed recovery of hepatic function. Multivariate logistic regression analysis showed that independent factors significantly associated with delayed recovery of liver function after donor hepatectomy were sevoflurane anaesthesia (odds ratio = 3.514, P < 0.001), synthetic colloid (odds ratio = 1.045, P = 0.033), donor age (odds ratio = 0.970, P = 0.003), female gender (odds ratio = 1.512, P = 0.014) and remnant liver volume (odds ratio = 0.963, P < 0.001). Anaesthesia with sevoflurane was an independent factor in predicting delayed recovery of hepatic function after donor hepatectomy. Although synthetic colloid may be associated with delayed recovery of hepatic function after donor hepatectomy, further study is required. These results can provide useful information on perioperative management of living liver donors. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Culture of C3A cells in alginate beads for fluidized bed bioartificial liver.

PubMed

Kinasiewicz, A; Gautier, A; Lewinska, D; Bukowski, J; Legallais, C; Weryński, A

2007-11-01

Extracorporeal bioartificial liver has been designed to sustain the detoxification and synthetic function of the failed liver in patients suffering from acute liver failure until the time of liver allotransplantation or regeneration of their own. A fluidized bed, bioartificial liver improves the mass transfer velocity between the medium and the hepatocytes. Detoxification functions of the liver could be replaced by completely artificial systems, but the synthetic functions of hepatocytes may be obtained only by metabolically active cells. The aim of our study was to investigate the influence of C3A cell culture in alginate beads on synthetic function in a fluidized bed, bioartificial liver. Cells in alginate beads were prepared using an electrostatic droplet generator of our own design using low-viscosity alginate. Beads were cultured for 24 hours then 7 days in static conditions and then 24 hours of fluidization in the bioreactor to assess albumin production. We observed significantly increased albumin production by C3A cells entrapped in alginate beads during static culture. Fluidization increased albumin production compared with static culture. Fluidization performed after 7 days of static culture resulted in a significant increase in albumin synthesis. In conclusion, static culture of alginate beads hosting hepatic cells facilitates restoration of cell function.

Effect of Liver Disease on Hepatic Transporter Expression and Function.

PubMed

Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R

2017-09-01

Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Measurement of hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath tests in chronic liver disease: Comparison with Child-Pugh score and serum bile acid levels

PubMed Central

Festi, D.; Capodicasa, S.; Sandri, L.; Colaiocco-Ferrante, L.; Staniscia, T.; Vitacolonna, E.; Vestito, A.; Simoni, P.; Mazzella, G.; Portincasa, P.; Roda, E.; Colecchia, A.

2005-01-01

AIM: To evaluate and compare the clinical usefulness of 13C-phenylalanine and 13C-methacetin breath tests in quantitating functional hepatic mass in patients with chronic liver disease and to further compare these results with those of conventional tests, Child-Pugh score and serum bile acid levels. METHODS: One hundred and forty patients (50 HCV- related chronic hepatitis, 90 liver cirrhosis patients) and 40 matched healthy controls were studied. Both breath test and routine liver test, serum levels of cholic and chenodeoxycholic acid conjugates were evaluated. RESULTS: Methacetin breath test, expressed as 60 min cumulative percent of oxidation, discriminated the hepatic functional capacity not only between controls and liver disease patients, but also between different categories of chronic liver disease patients. Methacetin breath test was correlated with liver function tests and serum bile acids. Furthermore, methacetin breath test, as well as serum bile acids, were highly predictive of Child-Pugh scores. The diagnostic power of phenylalanine breath test was always less than that of methacetin breath test. CONCLUSION: Methacetin breath test represents a safe and accurate diagnostic tool in the evaluation of hepatic functional mass in chronic liver disease patients. PMID:15609414

Neutrophil gelatinase‐associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases

PubMed Central

Yoshikawa, Kyoko; Iwasa, Motoh; Kojima, Shinichi; Yoshizawa, Naohiko; Tempaku, Mina; Sugimoto, Ryosuke; Yamamoto, Norihiko; Sugimoto, Kazushi; Kobayashi, Yoshinao; Hasegawa, Hiroshi; Takei, Yoshiyuki

2017-01-01

Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end‐stage liver disease and Child‐Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase‐associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme‐linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real‐time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll‐like receptor 4, and interleukin‐6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow‐up period of 9.9 months. The patients with blood NGAL ≤119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946–956) PMID:29404502

Hepatobiliary magnetic resonance imaging in patients with liver disease: correlation of liver enhancement with biochemical liver function tests.

PubMed

Kukuk, Guido M; Schaefer, Stephanie G; Fimmers, Rolf; Hadizadeh, Dariusch R; Ezziddin, Samer; Spengler, Ulrich; Schild, Hans H; Willinek, Winfried A

2014-10-01

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 valuable biomarker for liver function. The strongest correlation with liver enhancement was found for the MELD Score. • Relative enhancement (RLE) of Gd-EOB-DTPA is related to biochemical liver function tests. • Correlation of RLE with bilirubin, ALT, AST, GGT, INR and MELD Score is reverse. • The correlation of relative liver enhancement with prothrombin time is positive. • AST, ALT, GLDH, prothrombin time, INR and MELD Score correlate with pre-contrast liver-spleen contrast ratio. • Such biomarkers may help to evaluate liver function.

Concentrations of metallic elements in kidney, liver, and lung tissue of Indo-Pacific bottlenose dolphin Tursiops aduncus from coastal waters of Zanzibar, Tanzania.

PubMed

Mapunda, Edgar C; Othman, Othman C; Akwilapo, Leonard D; Bouwman, Hindrik; Mwevura, Haji

2017-09-15

Concentrations of metallic elements in kidney, liver and lung tissues of Indo-Pacific bottlenose dolphins Tursiops aduncus from coastal waters of Zanzibar were determined using inductively coupled plasma - optical emission spectroscopy. Cadmium, chromium, copper, and zinc were quantifiable in all tissues at concentration ranges of 0.10-150, 0.08-3.2, 1.1-88 and 14-210μg/g dry mass, respectively. Copper and zinc was significantly higher in liver, and females had significantly higher Cd in liver, and chromium in lung. Generally, T. aduncus dolphins from coastal waters around Zanzibar carry low concentrations of metals compared with dolphins from other areas. Cadmium increased significantly with age in kidney and lung. Copper decreased significantly with age in liver, probably due to foetal metallothionein. This study supplied baseline data against which future trends in marine mammals in the Indian Ocean, the world's third largest, can be assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cognitive and Adaptive Functioning after Liver Transplantation for Maple Syrup Urine Disease: A Case Series

PubMed Central

Shellmer, D. A.; Dabbs, A. DeVito; Dew, M. A.; Noll, R. B.; Feldman, H.; Strauss, K.; Morton, D. H.; Vockley, G.; Mazariegos, G. V.

2011-01-01

MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one year and/or three years post-liver transplantation. Findings show either no significant change or improvement in IQ scores pre- to post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced either no significant change or improvement in adaptive scores. In general, findings may indicate that liver transplantation curtails additional central nervous system damage and neurocognitive decline providing an opportunity for stabilization or improvement in functioning. PMID:20946191

Microbiome and Bile Acid Profiles in Duodenal Aspirates from Cirrhotics: The Microbiome, Microbial Markers and Liver Disease Study.

PubMed

Jacobs, Jonathan P; Dong, Tien S; Agopian, Vatche; Lagishetty, Venu; Sundaram, Vinay; Noureddin, Mazen; Ayoub, Walid; Durazo, Francisco; Benhammou, Jihane; Enayati, Pedram; Elashoff, David; Goodman, Marc T; Pisegna, Joseph; Hussain, Shehnaz

2018-06-20

Cirrhosis is a leading cause of death in the world, yet there are no well-established risk stratifying tools for lethal complications including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples which may be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to demonstrate feasibility of developing biomarkers for HCC risk stratification. Thirty patients with liver cirrhosis were enrolled in the Microbiome, Microbial Markers, and Liver Disease (M 3 LD) study between May 2015 and March 2017. Detailed clinical and epidemiological data were collected at baseline and at 6-monthly follow-up visits. Duodenal aspirate fluid was collected at baseline for microbial characterization using 16S ribosomal RNA sequencing and bile acid quantification using mass spectroscopy. Alcohol-related cirrhosis was associated with reductions in the Bacteroidetes phylum, particularly Prevotella (13-fold reduction), and expansion of Staphylococcus (13-fold increase), compared to HCV-related cirrhosis. Participants with hepatic encephalopathy (HE) had less microbial diversity compared to patients without HE (p<0.05), and were characterized by expansion of Mycobacterium (45-fold increase) and Gram positive cocci including Granulicatella (3.1-fold increase), unclassified Planococcaceae (3.3-fold increase), and unclassified Streptococcaceae (4.5-fold increase). Non-Hispanic Whites had reduced microbial richness (p<0.01) and diversity (p<0.05), and increased levels of conjugated ursodeoxycholic acid (glycoursodeoxycholic acid and tauroursodeoxycholic acid, p<0.05) compared to Hispanics. Microbial profiles of duodenal aspirates differed by cirrhosis etiology, HE, and Hispanic ethnicity. This article is protected by copyright. All rights reserved.

Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitation: Results From a Randomized Controlled Trial

PubMed Central

2013-01-01

Background. Androgen receptor (AR) knockout male mice display hepatic steatosis, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone replacement on hepatic fat in men are unknown. The aim of this study was to determine the effects of testosterone administration on hepatic fat in older men with mobility limitation and low testosterone levels who were participating in a randomized trial (the Testosterone in Older Men trial). Methods. Two hundred and nine men with mobility limitation and low total or free testosterone were randomized in the parent trial to either placebo or 10-g testosterone gel daily for 6 months. Hepatic fat was determined by magnetic resonance imaging in 73 men (36 in placebo and 37 in testosterone group) using the volumetric method. Insulin sensitivity (homeostatic model assessment–insulin resistance) was derived from fasting glucose and insulin. Results. Baseline characteristics were similar between the two groups, including liver volumes (1583±363 in the testosterone group vs 1522±271mL in the placebo group, p = .42). Testosterone concentrations increased from 250±72 to 632±363ng/dL in testosterone group but did not change in placebo group. Changes in liver volume during intervention did not differ significantly between groups (p = .5) and were not related to on-treatment testosterone concentrations. The change in homeostatic model assessment–insulin resistance also did not differ significantly between groups and was not related to either baseline or change in liver fat. Conclusion. Testosterone administration in older men with mobility limitation and low testosterone levels was not associated with a reduction in hepatic fat. Larger trials are needed to determine whether testosterone replacement improves liver fat in men with nonalcoholic hepatic steatosis. PMID:23292288

Assessment of liver ablation using cone beam computed tomography.

PubMed

Abdel-Rehim, Mohamed; Ronot, Maxime; Sibert, Annie; Vilgrain, Valérie

2015-01-14

To investigate the feasibility and accuracy of cone beam computed tomography (CBCT) in assessing the ablation zone after liver tumor ablation. Twenty-three patients (17 men and 6 women, range: 45-85 years old, mean age 65 years) with malignant liver tumors underwent ultrasound-guided percutaneous tumor ablation [radiofrequency (n = 14), microwave (n = 9)] followed by intravenous contrast-enhanced CBCT. Baseline multidetector computed tomography (MDCT) and peri-procedural CBCT images were compared. CBCT image quality was assessed as poor, good, or excellent. Image fusion was performed to assess tumor coverage, and quality of fusion was rated as bad, good, or excellent. Ablation zone volumes on peri-procedural CBCT and post-procedural MDCT were compared using the non-parametric paired Wilcoxon t-test. Rate of primary ablation effectiveness was 100%. There were no complications related to ablation. Local tumor recurrence and new liver tumors were found 3 mo after initial treatment in one patient (4%). The ablation zone was identified in 21/23 (91.3%) patients on CBCT. The fusion of baseline MDCT and peri-procedural CBCT images was feasible in all patients and showed satisfactory tumor coverage (at least 5-mm margin). CBCT image quality was poor, good, and excellent in 2 (9%), 8 (35%), and 13 (56%), patients respectively. Registration quality between peri-procedural CBCT and post-procedural MDCT images was good to excellent in 17/23 (74%) patients. The median ablation volume on peri-procedural CBCT and post-procedural MDCT was 30 cm(3) (range: 4-95 cm(3)) and 30 cm(3) (range: 4-124 cm(3)), respectively (P-value > 0.2). There was a good correlation (r = 0.79) between the volumes of the two techniques. Contrast-enhanced CBCT after tumor ablation of the liver allows early assessment of the ablation zone.

Statin-induced liver injury in an area endemic for hepatitis B virus infection: risk factors and outcome analysis.

PubMed

Wang, Li Yueh; Huang, Yi-Shin; Perng, Chin-Lin; Huang, Bryan; Lin, Han-Chieh

2016-09-01

Statin-induced liver injury (SILI) is quite rare, but may be severe. Little is known about the impact of chronic hepatitis B infection (CHBI) on SILI. We aimed to investigate the risk factors and outcome of SILI, with special reference to its interaction with CHBI. Patients with SILI were recruited from our hospital, and three-to-one drug-matched controls were randomly selected. The clinical data of the patients were then compared. A total of 108 patients with SILI and 324 controls were enrolled. The patients with SILI were both older and had a higher statin dose than the controls. There was no predilection of liver injury associated with the seven available statins. Among the SILI patients, there was no statistical difference between the baseline and peak liver enzyme tests, and latency and severity between hepatitis B carriers (n = 16) and non-carriers (n = 92). High dose of statin and age were the two independent risk factors of SILI (OR and 95% CI: 1.93, 1.08-3.35, P = 0.025, and 1.73, 1.07-2.80, P = 0.027, respectively). Permanent discontinuation of statin was noted in 50 (46.3%) patients with SILI due to severe SILI or recurrent hepatotoxicity after rechallenge of other statins. High dose of statin and old age may increase patient susceptibility to SILI; however, CHBI and abnormal baseline liver tests are not risk factors of SILI. Nonetheless, SILI is still worthy of notice, because nearly half of the overt cases discontinued statin treatment due to severe hepatotoxicity in this study. © 2016 The British Pharmacological Society.

Expression of Enzymes that Metabolize Medications

NASA Technical Reports Server (NTRS)

Wotring, Virginia E.; Peters, C. P.

2012-01-01

Most pharmaceuticals are metabolized by the liver. Clinically-used medication doses are given with normal liver function in mind. A drug overdose can result if the liver is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism we want to understand the effects of spaceflight on the enzymes of the liver.

Salton Sea sampling program: baseline studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tullis, R.E.; Carter, J.L.; Langlois, G.W.

1981-04-13

Baseline data are provided on three species of fish from the Salton Sea, California. The fishes considered were the orange mouth corvina (Cynoscion xanthulus), gulf croaker (Bairdiella icistius) and sargo (Anisotremus davidsonii). Morphometric and meristic data are presented as a baseline to aid in the evaluation of any physiological stress the fish may experience as a result of geothermal development. Analyses were made on muscle, liver, and bone of the fishes sampled to provide baseline data on elemental tissue burdens. The elements measured were: As, Br, Ca, Cu, Fe, Ga, K, Mn, Mi, Pb, Rb, Se, Sr, Zn, and Zr.more » These data are important if an environmentally sound progression of geothermal power production is to occur at the Salton Sea.« less

A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies.

PubMed

Jakobsen, Steen; Busk, Morten; Jensen, Jonas Brorson; Munk, Ole Lajord; Zois, Nora Elisabeth; Alstrup, Aage K O; Jessen, Niels; Frøkiær, Jørgen

2016-04-01

Organic cation transporters (OCTs) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases, and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT type 2 located in the PT. Thus, we hypothesized that (11)C-labeled metformin would be a suitable PET tracer for quantification of renal function. (11)C-metformin was prepared by (11)C-methylation of 1-methylbiguanide. In vitro cell uptake of (11)C-metformin was studied in LLC-PK1 cells in the presence of increasing doses of unlabeled metformin. In vivo small-animal PET studies in Sprague-Dawley rats were performed at baseline and after treatment with OCT inhibitors to evaluate renal uptake of (11)C-metformin. Kidney and liver pharmacokinetics of (11)C-metformin was investigated in vivo by dynamic (11)C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of (11)C-metformin was compared with renal clearance of (51)Cr-ethylenediaminetetraacetic acid (EDTA). Formation of (11)C metabolites was investigated by analysis of blood and urine samples. The radiochemical yield of (11)C-metformin was 15% ± 3% (n= 40, decay-corrected), and up to 1.5 GBq of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of (11)C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed (11)C-metformin uptake in the kidney and liver, the kinetics of which were changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney, and a high dose of metformin caused a delayed renal uptake and clearance compared with baseline consistent with transporter-mediated competition. Renal clearance of (11)C-metformin was approximately 3 times the renal clearance of (51)Cr-EDTA. We successfully synthesized an (11)C-metformin tracer, and PET studies in rats and pigs showed a rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for γ-camera renography. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Liver function assessment using 99mTc-GSA single-photon emission computed tomography (SPECT)/CT fusion imaging in hilar bile duct cancer: A retrospective study.

PubMed

Sumiyoshi, Tatsuaki; Shima, Yasuo; Okabayashi, Takehiro; Kozuki, Akihito; Hata, Yasuhiro; Noda, Yoshihiro; Kouno, Michihiko; Miyagawa, Kazuyuki; Tokorodani, Ryotaro; Saisaka, Yuichi; Tokumaru, Teppei; Nakamura, Toshio; Morita, Sojiro

2016-07-01

The objective of this study was to determine the utility of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT)/CT fusion imaging for posthepatectomy remnant liver function assessment in hilar bile duct cancer patients. Thirty hilar bile duct cancer patients who underwent major hepatectomy with extrahepatic bile duct resection were retrospectively analyzed. Indocyanine green plasma clearance rate (KICG) value and estimated KICG by (99m)Tc-GSA scintigraphy (KGSA) and volumetric and functional rates of future remnant liver by (99m)Tc-GSA SPECT/CT fusion imaging were used to evaluate preoperative whole liver function and posthepatectomy remnant liver function, respectively. Remnant (rem) KICG (= KICG × volumetric rate) and remKGSA (= KGSA × functional rate) were used to predict future remnant liver function; major hepatectomy was considered unsafe for values <0.05. The correlation of remKICG and remKGSA with posthepatectomy mortality and morbidity was determined. Although remKICG and remKGSA were not significantly different (median value: 0.071 vs 0.075), functional rates of future remnant liver were significantly higher than volumetric rates (median: 0.54 vs 0.46; P < .001). Hepatectomy was considered unsafe in 17% and 0% of patients using remKICG and remKGSA, respectively. Postoperative liver failure and mortality did not occur in the patients for whom hepatectomy was considered unsafe based on remKICG. remKGSA showed a stronger correlation with postoperative prothrombin time activity than remKICG. (99m)Tc-GSA SPECT/CT fusion imaging enables accurate assessment of future remnant liver function and suitability for hepatectomy in hilar bile duct cancer patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Alagille Syndrome

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Newborn Jaundice

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Reye Syndrome

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia.

PubMed

Shin, Mi-Kyung; Yao, Qiaoling; Jun, Jonathan C; Bevans-Fonti, Shannon; Yoo, Doo-Young; Han, Woobum; Mesarwi, Omar; Richardson, Ria; Fu, Ya-Yuan; Pasricha, Pankaj J; Schwartz, Alan R; Shirahata, Machiko; Polotsky, Vsevolod Y

2014-10-01

Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.-9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity. Copyright © 2014 the American Physiological Society.

Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects.

PubMed

Haufe, Sven; Engeli, Stefan; Kast, Petra; Böhnke, Jana; Utz, Wolfgang; Haas, Verena; Hermsdorf, Mario; Mähler, Anja; Wiesner, Susanne; Birkenfeld, Andreas L; Sell, Henrike; Otto, Christoph; Mehling, Heidrun; Luft, Friedrich C; Eckel, Juergen; Schulz-Menger, Jeanette; Boschmann, Michael; Jordan, Jens

2011-05-01

Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (-30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7-fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids. A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet. Copyright © 2011 American Association for the Study of Liver Diseases.

Liver stiffness and portal blood flow modifications induced by a liquid meal consumption: pathogenetic mechanisms and clinical relevance.

PubMed

Barone, Michele; Iannone, Andrea; Brunetti, Natale Daniele; Sebastiani, Francesco; Cecere, Onofrio; Berardi, Elsa; Antonica, Gianfranco; Di Leo, Alfredo

2015-05-01

The correlation between liver stiffness (LS) variations and portal blood flow (PBF) modifications induced by a standardized liquid meal consumption and the clinical relevance of this matter are two aspects not yet fully elucidated. Herein, we evaluated the variations of LS and PBF after a standardized liquid meal intake in patients with chronic liver disease. PBF and LS were determined after an overnight fasting period in 54 patients. They were divided in three groups according to baseline LS (absent, moderate, and severe). They consumed 200 ml of water and a standardized liquid meal (300 Kcal/200 ml) after 60 min. PBF and LS were measured at 30 min after water and liquid meal consumption. In all groups, LS and PBF values significantly increased only after meal consumption. A significant correlation between baseline LS values and post-meal increase of LS was observed. Moreover, higher basal stiffness values were associated to a larger increase of LS variation after meal consumption. The effect of the meal on LS remained statistically significant after multiple regression analysis. A significant correlation between increase of LS and PBF was found in patients with absent and moderate baseline LS. Nine patients (17%) switched from a lower to a higher level of LS after meal consumption. A low calories/low-volume meal is capable of significantly increasing LS regardless of the grade of stiffness, determining a reclassification rate of 17%. In presence of minimal or moderate stiffness, the increase of LS is significantly correlated with the augment of PBF.

Perioperative and oncologic outcomes of minimally invasive liver resection for colorectal metastases: A case-control study of 130 patients.

PubMed

Karagkounis, Georgios; Akyuz, Muhammet; Guerron, Alfredo Daniel; Yazici, Pinar; Aucejo, Federico N; Quintini, Cristiano; Miller, Charles M; Vogt, David P; Fung, John J; Berber, Eren

2016-10-01

Our aim was to compare the perioperative and oncologic outcomes of open liver resection and minimally invasive liver resection in the management of colorectal liver metastases. Patients who underwent minimally invasive liver resection for colorectal liver metastases between January 2006 and June 2015 at a single center were identified and matched by extent of resection to consecutive open liver resection patients from the same period. Clinicopathologic characteristics, perioperative data, recurrence, and survival outcomes were collected and analyzed based on intention-to-treat. Sixty-five patients underwent minimally invasive liver resection during this period and were matched to 65 consecutive open liver resection patients, with similar baseline demographic, tumor, and chemotherapy parameters. Conversion to open occurred in 5 (7.7%) minimally invasive liver resection patients. R0 resection rates and operative times were comparable, but the estimated blood loss was less in the minimally invasive liver resection group (median 200 mL vs 400 mL, P < .001), as were perioperative transfusion rates (4.6% vs 15.4%, P = .04). The duration of stay was shorter after minimally invasive liver resection (median 4 days vs 6 days, P < .001), while major and minor complication rates were similar and no perioperative mortality was recorded. At a median follow-up of 28 months, there was no difference regarding disease-free (P = .90) or overall survival (P = .37). In selected patients with colorectal liver metastases, minimally invasive liver resection resulted in similar oncologic outcomes, with decreased blood loss and shorter duration of stay compared to patients who underwent open liver resection. Copyright © 2016 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Hesheng, E-mail: hesheng@umich.edu; Feng, Mary; Jackson, Andrew

Purpose: To develop a local and global function model in the liver based on regional and organ function measurements to support individualized adaptive radiation therapy (RT). Methods and Materials: A local and global model for liver function was developed to include both functional volume and the effect of functional variation of subunits. Adopting the assumption of parallel architecture in the liver, the global function was composed of a sum of local function probabilities of subunits, varying between 0 and 1. The model was fit to 59 datasets of liver regional and organ function measures from 23 patients obtained before, during, andmore » 1 month after RT. The local function probabilities of subunits were modeled by a sigmoid function in relating to MRI-derived portal venous perfusion values. The global function was fitted to a logarithm of an indocyanine green retention rate at 15 minutes (an overall liver function measure). Cross-validation was performed by leave-m-out tests. The model was further evaluated by fitting to the data divided according to whether the patients had hepatocellular carcinoma (HCC) or not. Results: The liver function model showed that (1) a perfusion value of 68.6 mL/(100 g · min) yielded a local function probability of 0.5; (2) the probability reached 0.9 at a perfusion value of 98 mL/(100 g · min); and (3) at a probability of 0.03 [corresponding perfusion of 38 mL/(100 g · min)] or lower, the contribution to global function was lost. Cross-validations showed that the model parameters were stable. The model fitted to the data from the patients with HCC indicated that the same amount of portal venous perfusion was translated into less local function probability than in the patients with non-HCC tumors. Conclusions: The developed liver function model could provide a means to better assess individual and regional dose-responses of hepatic functions, and provide guidance for individualized treatment planning of RT.« less

Anti-angiogenic therapy with contrast-enhanced ultrasound in colorectal cancer patients with liver metastasis.

PubMed

Wu, Zhiyong; Yang, Xiaowei; Chen, Li; Wang, Zhikuan; Shi, Yan; Mao, Hui; Dai, Guanghai; Yu, Xiaoling

2017-05-01

The aim of the study was to evaluate the efficacy of anti-angiogenic therapy with dynamic contrast-enhanced ultrasound (DCE-US) in colorectal cancer (CRC) patients with liver metastasis.A total of 50 CRC patients with liver metastasis who received bevacizumab (BEV)-based chemotherapy (BEV + FOLFOX6 protocol) were recruited into the present study. Before the study (d0), and 3, 7, 14, and 42 days (d3, d7, d14, and d42) after chemotherapy, DCE-US was performed, and tumor perfusion was evaluated quantitatively by retention time (RT), peak enhancement (PE), and wash-in area under the curve (WiAUC) on the basis of a contrast-uptake curve determined with original linear data.Routine ultrasonography was used to evaluate metastatic foci in the liver at baseline. A metastatic focus was selected for dynamic monitoring with ultrasound. The metastatic foci were 1.5 to 8 cm (median: 2.5 cm). The results of hemodynamics monitored at different time points, including RT, PE, and WiAUC, showed that RT at baseline was significantly different between groups (P < .001; Responder group: 10.54 seconds; nonresponder group: 15.33 seconds). The2 groups had opposite changes in RT (continuous increase in the responder group and transient reduction in the nonresponder). The RT of metastatic foci was normalized to that of adjacent normal liver as standard RT-quotient, a similar trend was observed, and no marked difference was noted in the standard RT-quotient between the 2 groups. The median progression-free survival was significantly higher in the increased-RT group (10.8 months) than the decreased-RT group (2.5 months) (P = .002). There were no significant differences in peak intensity and WiAUC between the 2 groups.DCE-US can be used to quantitatively evaluate the hemodynamics of liver metastasis in CRC patients who received bevacizumab-based chemotherapy.

Noninvasive markers of liver fibrosis: on-treatment changes of serum markers predict the outcome of antifibrotic therapy.

PubMed

Tanwar, Sudeep; Trembling, Paul M; Hogan, Brian J; Srivastava, Ankur; Parkes, Julie; Harris, Scott; Grant, Paul; Nastouli, Eleni; Ocker, Mathias; Wehr, Klaus; Herold, Christoph; Neureiter, Daniel; Schuppan, Detlef; Rosenberg, William M

2017-03-01

The utility of noninvasive serum markers to longitudinally monitor liver fibrosis is not established. A total of 70 patients with chronic hepatitis C who had previously failed antiviral therapy were randomized to receive pegylated interferon with or without silymarin for 24 months. Enhanced Liver Fibrosis (ELF) tests (hyularonic acid, terminal peptide of procollagen III, tissue inhibitor of matrix metaloproteinase-1) were performed on patient sera obtained before, during and at the end of the study (0, 12, 24 months) and liver histology obtained before and at the end of the study. At 24 months, absolute changes in Ishak fibrosis stage and ELF ranged from -4 to +4 and from -2.41 to +2.68, respectively. Absolute changes in ELF at 12 months were significantly associated with changes in both ELF and histology at 24 months. A model combining both baseline ELF and change of ELF at 12 months could predict the 24-month ELF (R=0.609, P<1×10), a decrease in ELF at 24 months [area under the curve (AUC): 0.80-0.85] and an increase in ELF at 24 months (AUC: 0.81-0.85). Furthermore, a model combining both baseline histologic stage and ELF together with the change of ELF at 12 months could predict 24-month histology (R=0.601, P<1×10, AUC: 0.88-0.92), histologic fibrosis regression (AUC: 0.81-0.84) and progression (AUC: 0.86-0.91). Our observations suggest that a change in the serum marker ELF predicts changes in liver fibrosis over a longer period. These data support the use of ELF as a surrogate marker of liver fibrosis evolution in monitoring antifibrotic treatments, thus permitting 'response-guided' therapy by the early identification of patients who will benefit from prolonged treatment.

Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel.

PubMed

Lee, Ho-Joon; Son, Myung Jin; Ahn, Jiwon; Oh, Soo Jin; Lee, Mihee; Kim, Ansoon; Jeung, Yun-Ji; Kim, Han-Gyeul; Won, Misun; Lim, Jung Hwa; Kim, Nam-Soon; Jung, Cho-Rock; Chung, Kyung-Sook

2017-12-01

Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells.

PubMed

Werner, Melanie; Driftmann, Sabrina; Kleinehr, Kathrin; Kaiser, Gernot M; Mathé, Zotlan; Treckmann, Juergen-Walter; Paul, Andreas; Skibbe, Kathrin; Timm, Joerg; Canbay, Ali; Gerken, Guido; Schlaak, Joerg F; Broering, Ruth

2015-01-01

Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Cell preparation yielded the following cell counts per gram of liver tissue: 2.0 ± 0.4 × 10(7) hepatocytes, 1.8 ± 0.5 × 10(6 )Kupffer cells, 4.3 ± 1.9 × 10(5) liver sinusoidal endothelial cells, and 3.2 ± 0.5 × 10(5) stellate cells. Hepatocytes were identified by albumin (95.5 ± 1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5 ± 1.2%) and exhibited phagocytic activity, as determined with 1 μm latex beads. Endothelial cells were CD146(+) (97.8 ± 1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1 ± 1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.

Morphometric and chronological behavior of 2.45 GHz microwave ablation zones for colorectal cancer metastases and hepatocellular carcinoma in the liver: preliminary report.

PubMed

Hickson, Guy; Patel, Nirav; King, Alexander; Breen, David

2016-08-01

Percutaneous microwave ablation (MWA) is increasingly utilized in the treatment of primary and secondary hepatic malignancy. As an in-situ treatment appreciation of any signs of recurrence is critical for improving long-term oncological outcomes. Volumetry has been recognized as having advantages over orthogonal measurements in the response assessment of malignant lesions. Our study set out to look at the normal involution of an ablation zone (AZ) both volumetrically and morphologically to see if this information might aid the detection of local tumor progression. Cases were identified retrospectively from our database of liver MWA. We identified 34 AZs in total, 18 AZs in 16 hepatocellular carcinoma (HCC) patients with cirrhosis on imaging grounds and 13 AZs in patients with metastatic colorectal cancer. How these AZs developed over time was analyzed both morphologically and quantitatively using Siemens Syngo Via post-processing software. We used the software to produce volume measurements and short axis orthogonal measurements. A baseline measurement was taken on the first <30 day post-ablation scan and the chronological changes were then plotted. We saw differences between the cirrhotic and non-cirrhotic patients both in terms of morphological and volumetric changes. 12/13 non-cirrhotic AZs had a volume of <50% of the baseline scan within the first year. The cirrhotic patients were less predictable, but 14/18 still shrunk to less than 50% of baseline volume in the first year. Orthogonal measurements were less useful in both groups. Qualitatively, there was initially a slightly less well-defined border to the AZ in the first 3 months, which became better defined over time and certainly over the first year of AZ involution. Volumetric analysis is a useful adjunct to conventional measurements and qualitative analysis of AZs. This can be reassuring when orthogonal measurements are static or difficult to interpret. Our preliminary data suggest that the normal pattern in a non-cirrhotic liver is that the AZ volume should drop below 50% of baseline at 1 year. Volumes in cirrhotic livers are less predictable, but the majority will still follow a similar pattern. Future studies could evaluate if failure to follow these patterns correlates with local tumor progression.

Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells

PubMed Central

Tokita, Daisuke; Sumpter, Tina L.; Raimondi, Giorgio; Zahorchak, Alan F.; Wang, Zhiliang; Nakao, Atsunori; Mazariegos, George V.; Abe, Masanori; Thomson, Angus W.

2008-01-01

Background/Aims The liver is comparatively rich in plasmacytoid (p) dendritic cells (DC),- innate immune effector cells that are also thought to play key roles in the induction and regulation of adaptive immunity. Methods Liver and spleen pDC were purified from fms-like tyrosine kinase ligand-reated control or lipopolysaccharide-injected C57BL/10 mice. Flow cytometric and molecular biologic assays were used to characterize their function and interaction with naturally-occurring regulatory T cells (Treg). Results While IL-10 production was greater for freshly-isolated liver compared with splenic pDC, the former produced less bioactive IL-12p70. Moreover, liver pDC expressed a low Delta4/Jagged1 Notch ligand ratio, skewed towards T helper 2 cell differentiation/cytokine production, and promoted allogeneic CD4+ T cell apoptosis. T cell proliferation in response to liver pDC was, however, enhanced by blocking IL-10 function at the initiation of cultures. In the absence of naturally occurring CD4+CD25+ regulatory T cells, similar levels of T cell proliferation were induced by liver and spleen pDC and the pro-apoptotic activity of liver pDC was reversed. Conclusion The inferior T cell allostimulatory activity of in vivo-stimulated liver pDC may depend on the presence and function of Treg, a property that may contribute to inherent liver tolerogenicity. PMID:18926588

Correlation of four potential biomarkers of liver fibrosis with liver function and grade of hepatic fibrosis in a neonatal cholestatic rat model.

PubMed

Tang, Ning; Zhang, Yaping; Liu, Zeyu; Ai, Xuemei; Liang, Qinghong

2017-07-01

The present study investigated the correlation between four serum biomarkers of liver fibrosis, liver function and pathological hepatic fibrosis grade in neonatal cholestatic rats. A total of 38 Sprague‑Dawley rats, aged 3 weeks, were randomly assigned to the experimental group (EG), control group (CG) and the blank control group (BCG). EG received intragastric administration of 1% α‑naphthylisothiocyanate, 75 mg/kg, to induce acute cholestasis liver injury, CG and BCG were set as control groups. Blood samples from all groups were collected 48 h following the procedure. The levels of liver function markers, and four biomarkers of liver fibrosis in serum, were measured and sections of liver tissue were stained for pathological analysis. The results of the present study demonstrated that the degree of hepatic fibrosis in EG, in the serum levels or by pathological analysis, was markedly more evident compared with the CG. Several indices of four biomarkers for liver fibrosis in serum were identified and correlated with the levels of liver function markers. The pathological hepatic fibrosis grade was correlated with γ‑glutamyl transferase (γ‑GT) and Hyaluronic acid (HA). Therefore, HA and γ‑GT were positively correlated with the grade of hepatic fibrosis, indicating their efficacy as biomarkers of infantile cholestatic hepatic fibrosis.

Evaluation of liver function using gadoxetate disodium (Gd-EOB-DTPA) enhanced MR imaging

NASA Astrophysics Data System (ADS)

Yamada, Akira; Hara, Takeshi; Li, Feng; Doi, Kunio

2010-03-01

Indocyanine green (ICG) is widely used for its clearance test in the evaluation of liver function. Gadoxetate disodium (Gd-EOB-DTPA) is a targeted MR contrast agent partially taken up by hepatocytes. The objective of this study was to evaluate the feasibility of an estimation of the liver function corresponding to plasma disappearance rate of indocyanine green (ICG-PDR) by use of the signal intensity of the liver alone in Gd-EOB-DTPA enhanced MR imaging (EOB-MRI). We evaluated fourteen patients who had EOB-MRI and ICG clearance test within 1 month. 2D-GRE T1 weighted images were obtained at pre contrast, 3 min (equilibrium phase) and 20 min (hepatobiliary phase) after the intravenous administration of Gd-EOB-DTPA, and the mean signal intensity of the liver was measured. The correlation between ICG-PDR and many parameters derived from the signal intensity of the liver in EOB-MRI was evaluated. The correlation coefficient between ICG-PDR and many parameters derived from the signal intensity of the liver in EOBMRI was low and not significant. The estimation of the liver function corresponding to ICG-PDR by use of the signal intensity of the liver alone in EOB-MRI would not be reliable.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

PubMed

LaMattina, John C; Mezrich, Joshua D; Fernandez, Luis A; D'Alessandro, Anthony M; Djamali, Arjang; Musat, Alexandru I; Pirsch, John D; Foley, David P

2013-01-01

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen. © 2013 John Wiley & Sons A/S.

Generation, characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells.

PubMed

Zhang, Zhenzhen; Liu, Jianfang; Liu, Yang; Li, Zheng; Gao, Wei-Qiang; He, Zuping

2013-02-01

Liver cancer is the sixth most common tumor in the world and the majority of patients with this disease usually die within 1 year. The effective treatment for end-stage liver disease (also known as liver failure), including liver cancer or cirrhosis, is liver transplantation. However, there is a severe shortage of liver donors worldwide, which is the major handicap for the treatment of patients with liver failure. Scarcity of liver donors underscores the urgent need of using stem cell therapy to the end-stage liver disease. Notably, hepatocytes have recently been generated from hepatic and extra-hepatic stem cells. We have obtained mature and functional hepatocytes from rat hepatic stem cells. Here, we review the advancements on hepatic differentiation from various stem cells, including hepatic stem cells, embryonic stem cells, the induced pluripotent stem cells, hematopoietic stem cells, mesenchymal stem cells, and probably spermatogonial stem cells. The advantages, disadvantages, and concerns on differentiation of these stem cells into hepatic cells are highlighted. We further address the methodologies, phenotypes, and functional characterization on the differentiation of numerous stem cells into hepatic cells. Differentiation of stem cells into mature and functional hepatocytes, especially from an extra-hepatic stem cell source, would circumvent the scarcity of liver donors and human hepatocytes, and most importantly it would offer an ideal and promising source of hepatocytes for cell therapy and tissue engineering in treating liver disease. Copyright © 2012 Wiley Periodicals, Inc.

Primary Sclerosing Cholangitis (PSC)

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Type I Glycogen Storage Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

The effect of Polygonum minus extract on cognitive and psychosocial parameters according to mood status among middle-aged women: a randomized, double-blind, placebo-controlled study

PubMed Central

Shahar, Suzana; Aziz, Ainor Farahin; Ismail, Siti Nur Arina; Yahya, Hanis Mastura; Din, Normah Che; Manaf, Zahara Abdul; Badrasawi, Manal M

2015-01-01

Background Polygonum minus (PM) or locally known in Malaysia, as “kesum” is rich in micronutrients and natural antioxidants. However, its beneficial effect on outcome associates with oxidative stress including cognitive function is yet to be discovered. We assessed the efficacy of PM extract (LineMinus™) on cognitive function and psychosocial status among middle-aged women in Klang Valley of Malaysia. Methods A randomized, double-blind, placebo-controlled trial among 35 healthy middle-aged women was performed, and subjects were randomized to receive either 250 mg PM or placebo of 100 mg maltodextrin each were taken twice daily for 6 weeks. Subjects were assessed for neuropsychological test, psychosocial status, and anthropometric at baseline, week 3, and week 6. Biomarkers were also determined at baseline and week 6. Results The supplementation of PM showed significant intervention effect on Digit Span test (P<0.05) social functioning domain of 36-Item Short Form Health Survey (P<0.05) among subjects with mood disturbance. While, among subjects with good mood, PM supplementation improved Wechsler Abbreviated Scale of Intelligence (WASI) for IQ verbal (P=0.016) and Full Scale IQ of WASI (P=0.004). There were no adverse effects reported for the supplementation as indicated using biomarkers, including liver function and clinical symptoms. Conclusion Supplementation of PM is safe to be consumed for 6 weeks, with potential benefits to attention, short-term memory, improved quality of life, and mood, as well as IQ. PMID:26445532

Direct peritoneal resuscitation improves obesity-induced hepatic dysfunction after trauma.

PubMed

Matheson, Paul J; Franklin, Glen A; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, Richard N

2012-04-01

The metabolic syndrome and associated fatty liver disease are thought to contribute to poor outcomes in trauma patients. Experimentally, obesity compromises liver blood flow. We sought to correlate the effect of obesity, injury severity, and liver dysfunction with trauma outcomes. We hypothesized that obesity-related liver dysfunction could be mitigated with the novel technique of adjunctive direct peritoneal resuscitation (DPR). This study has clinical and experimental arms. The clinical study was a case-controlled retrospective analysis of ICU trauma patients (n = 72 obese, n = 187 nonobese). The experimental study was a hemorrhagic shock model in obese rats to assess the effect of DPR on liver blood flow, liver function, and inflammatory mediators. In trauma patients, univariate and multivariate analyses demonstrated increasing mortality (p < 0.05), septic complications (p < 0.05), liver dysfunction (p < 0.001), and renal impairment (p < 0.05) with increasing body mass index and injury severity score. Obesity in rats impairs liver blood flow, liver function, renal function, and inflammation (interleukin [IL]-1β, IL-6, high mobility group protein B1[HMGB-1]). The addition of DPR to shock resuscitation restores liver blood flow, improves organ function, and reverses the systemic proinflammatory response. Our clinical review substantiates that obesity worsens trauma outcomes regardless of injury severity. Obesity-related liver and renal dysfunction is aggravated by injury severity. In an obese rat model of resuscitated hemorrhagic shock, the addition of DPR abrogates trauma-induced liver, renal, and inflammatory responses. We conclude that the addition of DPR to the clinical resuscitation regimen will benefit the obese trauma patient. Published by Elsevier Inc.

Does adjuvant radiotherapy suppress liver regeneration after partial hepatectomy?

PubMed

Choi, Jin-Hwa; Kim, Kyubo; Chie, Eui Kyu; Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Ha, Sung W

2009-05-01

To analyze the influence of the adjuvant radiotherapy (RT) on the liver regeneration and liver function after partial hepatectomy (PH). Thirty-four patients who underwent PH for biliary tract cancer between October 2003 and July 2005 were reviewed. Hemihepatectomy was performed in 14 patients and less extensive surgery in 20. Of the patients, 19 patients had no adjuvant therapy (non-RT group) and 15 underwent adjuvant RT by a three-dimensional conformal technique (RT group). Radiation dose range was 40 to 50 Gy (median, 40 Gy). Liver volume on computed tomography and the results of liver function tests at 1, 4, 12, 24, and 52 weeks after PH were compared between the RT and non-RT groups. The preoperative characteristics were identical for both groups. During the interval between Weeks 4 and 12 when adjuvant RT was delivered in the RT group, the increase in liver volume was significantly smaller in the RT group than non-RT group (22.9 +/- 38.3cm(3) and 81.5 +/- 75.6cm(3), respectively, p = 0.007). However, the final liver volume measured at 1 year after PH did not differ between the two groups (p = 0.878). Liver function tests were comparable for both groups. The resection extent and original liver volume was independent factors for final liver volume measured at 1 year after PH. In this study, adjuvant RT delayed the liver regeneration process after PH, but the volume difference between the two study groups became nonsignificant after 1 year. Adjuvant RT had no additional adverse effect on liver function after PH.

13C Methacetin Breath Test for Assessment of Microsomal Liver Function: Methodology and Clinical Application.

PubMed

Gorowska-Kowolik, Katarzyna; Chobot, Agata; Kwiecien, Jaroslaw

2017-01-01

Assessment of the liver function, and the need of constant monitoring of the organ's capacity, concerns not only patients with primary liver diseases, but also those at risk of hepatopathies secondary to other chronic diseases. Most commonly, the diagnostics is based on measurements of static biochemical parameters, which allow us to draw conclusions only indirectly about the function and the degree of damage of the organ. On the other hand, liver biopsy is an invasive procedure and therefore it is associated with a considerable risk of complications. Dynamic tests enable us to assess quantitatively the organ's functional reserve by analyzing the kinetics of the metabolization of the substrate by the liver. In practice applied are breath tests using substances such as aminopyrine, caffeine, methacetin, erythromycin (for assessment of the microsomal function); phenylalanine, galactose (for assessment of the cytosolic function); methionine, octanoate, ketoisocaproic acid (for assessment of the mitochondrial function). The test with 13 C methacetin belongs to the best described and most widely applied methods in noninvasive liver function assessment. Due to the rising availability of this method, knowledge concerning its limitations and controversies regarding the methodology, as well as its usefulness in chosen groups of patients, seems to be vital.

Regional metabolic liver function measured in patients with cirrhosis by 2-[¹⁸F]fluoro-2-deoxy-D-galactose PET/CT.

PubMed

Sørensen, Michael; Mikkelsen, Kasper S; Frisch, Kim; Villadsen, Gerda E; Keiding, Susanne

2013-06-01

There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[(18)F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet. Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (p<0.001), in accordance with decreased metabolic function in cirrhotic livers. Mean CoV for Kmet in liver tissue was 24.4% in patients and 14.4% in healthy subjects (p<0.0001). The degree of intrahepatic metabolic heterogeneity correlated positively with HVPG (p<0.05). A 20-min dynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Study of Abnormal Liver Function Test during Pregnancy in a Tertiary Care Hospital in Chhattisgarh.

PubMed

Mishra, Nalini; Mishra, V N; Thakur, Parineeta

2016-10-01

Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. Eighty pregnant women with abnormal liver dysfunction were studied prospectively. Women with chronic liver disease and drug-induced abnormal liver function test were excluded. All available LFTs including LDH were studied along with some more definitive tests to aid identification of underlying cause. Foetomaternal outcome was noted in all. The incidence of abnormal LFT was 0.9 %. 13/80 (16.75 %) women had liver disorder not specific to pregnancy, whereas 67/80 (83.25 %) women had pregnancy-specific liver dysfunction. Of these, 65(81.25 %) women with liver dysfunction had pre-eclampsia including 11 (13.75 %) with HELLP and six women with eclampsia. 48/65 (60 %) women had pre-eclampsia in the absence of HELLP syndrome or eclampsia. The mean value for bilirubin (mg %) in hypertensive disorders of pregnancy ranged from 1.64 to 3.8, between 5 and 10 for ICP and AFLP and >10 in infective hepatitis. Transaminases were highest in infective hepatitis, whereas alkaline phosphate was highest in ICP. Total 27 (33.75 %) women suffered from adverse outcome with four (5 %) maternal deaths and 23 (28.75 %) major maternal morbidities. 33/80 (41.25 %) women had intrauterine death. 26.25 % babies were small for date. Pregnancy-specific disorders are the leading cause of abnormal liver function test during pregnant state particularly in the third trimester. Pre-eclampsia-related disorder is the commonest. Gestational age of pregnancy and relative values of various liver function tests in different pregnancy-specific and pregnancy nonspecific disorders appear to be the best guide to clinch the diagnosis.

Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure?

PubMed

Burra, Patrizia; Germani, Giacomo; Masier, Annalisa; De Martin, Eleonora; Gambato, Martina; Salonia, Andrea; Bo, Patrizio; Vitale, Alessandro; Cillo, Umberto; Russo, Francesco Paolo; Senzolo, Marco

2010-06-27

The goal of liver transplantation is not only to ensure patient long-term survival but also to offer the opportunity to achieve psychologic and physical integrity. Quality of life after liver transplantation may be affected by unsatisfactory sexual function. Before liver transplantation, sexual dysfunction and sex hormone disturbances are reported in men and women mainly due to abnormality of physiology of the hypothalamic-pituitary-gonadal axis and, in some cases, origin of liver disease. Successful liver transplantation should theoretically restore hormonal balance and improve sexual function both in men and women, thus improving the reproductive performance. However, after transplantation, up to 25% of patients report persistent sexual dysfunction, and approximately one third of patients describe the appearance of de novo sexual dysfunction. Despite the described high prevalence of this condition, epidemiologic data are relatively scant. Further studies on pathophysiology and risk factors in the field of sexual function after liver transplantation along with new strategies to support and inform patients on the waiting list and after surgery are needed.

[Pilot study of levosimendan : Effect on liver blood flow and liver function in acute decompensated heart failure].

PubMed

Lenz, K; Gegenhuber, A; Firlinger, F; Lohr, G; Piringer, P

2014-05-01

In a pilot study, 9 patients (39-48 years) with acute decompensated heart failure and a cardiac index (CI) of 1.9 ± 0.3 l/min/m(2) were included after exclusion of an underlying hepatic disease. The effect of levosimendan on liver blood flow and liver function was measured with the LiMON(®) system using the indocyane green plasma disappearance rate (ICG PDR). Levosimendan (Simdax(®)) infusion resulted in a significant increase of the CI, thus, achieving normal ranges of 2.9 ± 0.9 l/min/m(2) after 4 h and 3.3 ± 1 l/min/m(2) (p = 0.003) after 24 h. ICG PDR increased from 8.2 ± 0.8 % to 10.2 + 1.8 % after 4 h and to 11.9 ± 2.9 % after 24 h (p = 0.04). The reason for the early increase in systemic blood flow with no concomitant change in ICG PDR is not clear. A primary increase in liver blood flow with sustained low liver function might be one explanation; a low flow-mediated increased release of cytokines from liver cells with consequent deterioration of liver function is another possible explanation.

Measurement of serum, liver, and brain cytokine induction, thiamine levels, and hepatopathology in rats exposed to a 4-day alcohol binge protocol.

PubMed

Zahr, Natalie M; Luong, Richard; Sullivan, Edith V; Pfefferbaum, Adolf

2010-11-01

 In rodent and human studies, ethanol (EtOH) exposure is associated with elevated brain levels of the magnetic resonance spectroscopy (MRS) signal representing choline-containing compounds (Cho). One interpretation of elevated brain Cho is that it is a marker of neuroinflammation, and some evidence suggests that EtOH exposure promotes neuroinflammation. This study aimed to determine whether binge EtOH exposure (intragastric 3 g/kg 25% EtOH every 8 hours for 4 days) would induce the expression of certain cytokines in blood, liver, or brain, thereby supporting the neuroinflammation hypothesis of elevated Cho. Ten of 18 wild-type male Wistar rats (~322 g at baseline) were exposed to EtOH and attained average blood alcohol levels of ~315 mg/dl across 4 days. Blood for cytokine immunoassays was collected at baseline, after 5 doses of EtOH (binge), and immediately preceding euthanasia either 4 or 24 hours after the last dose of EtOH. Blood was additionally assayed for the levels of thiamine and liver enzymes; liver histopathology was performed postmortem; and tissue from liver and 6 brain regions was assayed for the potential induction of 7 cytokines. There were no group effects on the levels of thiamine or its phosphate derivatives, thiamine monophosphate or thiamine diphosphate. ANOVAs of liver enzyme levels indicated that only alkaline phosphatase (ALP) levels were higher in the EtOH group than in control group at binge; ALP elevations, however, are difficult to explain in the absence of changes in the levels of additional liver enzymes. Postmortem liver pathology provided evidence for minimal microvesicular lipidosis and portocentric fibrosis in the EtOH group. Group effects on the levels of the measured cytokines in the blood (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-13, and GRO/CXCL1) were not significant. Similarly, postmortem evaluation of liver cytokines did not reveal group effects. Postmortem evaluation of the 7 cytokines in 6 brain regions (anterior cerebellar vermis, cingulate cortex, frontal cortex, hippocampus, hypothalamus, striatum) also failed to identify group effects. A single 4-day bout of binge EtOH exposure alone was insufficient to induce the expression of 7 cytokines in blood, liver, or 6 brain regions of wild-type Wistar rats. Alternative interpretations for elevations in brain Cho in response to a 4-day binge EtOH treatment are therefore necessary and may include induction of cytokines not measured herein or other noninflammatory mechanisms. Copyright © 2010 by the Research Society on Alcoholism.

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

PubMed

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

2006-12-28

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

The Hepatic Response to Thermal Injury: Is the Liver Important for Postburn Outcomes?

PubMed Central

Jeschke, Marc G

2009-01-01

Thermal injury produces a profound hypermetabolic and hypercatabolic stress response characterized by increased endogenous glucose production via gluconeogenesis and glycogenolysis, lipolysis, and proteolysis. The liver is the central body organ involved in these metabolic responses. It is suggested that the liver, with its metabolic, inflammatory, immune, and acute phase functions, plays a pivotal role in patient survival and recovery by modulating multiple pathways following thermal injury. Studies have evaluated the role and function of the liver during the postburn response and showed that liver integrity and function are essential for survival, and that hepatic acute phase proteins are strong predictors for postburn survival. This review discusses these studies and delineates the pivotal role of the liver in patients following severe thermal injury. PMID:19603107

Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population.

PubMed

Jung, C H; Lee, W J; Hwang, J Y; Yu, J H; Shin, M S; Lee, M J; Jang, J E; Leem, J; Park, J-Y; Kim, H-K

2013-04-01

Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance. We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI. During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index < 20 (fatty liver index-negative) after adjusting for various confounding variables including homeostasis model assessment of insulin resistance. Odds ratios were significant regardless of the insulin resistance status at baseline. Our results suggest that fatty liver index as a simple surrogate indicator of hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis.

PubMed

Dutkowski, Philipp; Polak, Wojciech G; Muiesan, Paolo; Schlegel, Andrea; Verhoeven, Cornelia J; Scalera, Irene; DeOliveira, Michelle L; Kron, Philipp; Clavien, Pierre-Alain

2015-11-01

Exposure of donor liver grafts to prolonged periods of warm ischemia before procurement causes injuries including intrahepatic cholangiopathy, which may lead to graft loss. Due to unavoidable prolonged ischemic time before procurement in donation after cardiac death (DCD) donation in 1 participating center, each liver graft of this center was pretreated with the new machine perfusion "Hypothermic Oxygenated PErfusion" (HOPE) in an attempt to improve graft quality before implantation. HOPE-treated DCD livers (n = 25) were matched and compared with normally preserved (static cold preservation) DCD liver grafts (n = 50) from 2 well-established European programs. Criteria for matching included duration of warm ischemia and key confounders summarized in the balance of risk score. In a second step, perfused and unperfused DCD livers were compared with liver grafts from standard brain dead donors (n = 50), also matched to the balance of risk score, serving as baseline controls. HOPE treatment of DCD livers significantly decreased graft injury compared with matched cold-stored DCD livers regarding peak alanine-aminotransferase (1239 vs 2065 U/L, P = 0.02), intrahepatic cholangiopathy (0% vs 22%, P = 0.015), biliary complications (20% vs 46%, P = 0.042), and 1-year graft survival (90% vs 69%, P = 0.035). No graft failure due to intrahepatic cholangiopathy or nonfunction occurred in HOPE-treated livers, whereas 18% of unperfused DCD livers needed retransplantation. In addition, HOPE-perfused DCD livers achieved similar results as control donation after brain death livers in all investigated endpoints. HOPE seems to offer important benefits in preserving higher-risk DCD liver grafts.

Impact of Liver Indicators on Clinical Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation.

PubMed

Wendt, Daniel; Kahlert, Philipp; Canbay, Ali; Knipp, Stephan; Thoenes, Martin; Cremer, Gordina; Al-Rashid, Fadi; Jánosi, Rolf-Alexander; El-Chilali, Karim; Kamler, Markus; El Gabry, Mohamed; Marx, Philipp; Dohle, Daniel Sebastian; Tsagakis, Konstantinos; Benedik, Jaroslav; Gerken, Guido; Rassaf, Tienush; Jakob, Heinz; Thielmann, Matthias

2017-10-01

Liver dysfunction increases death and morbidity after cardiac operations. There are currently no data evaluating liver function in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed therefore to evaluate our TAVR results in regard to liver function. A total of 640 consecutive TAVR patients were evaluated. Of those, 11 patients presented with chronic liver disease before TAVR. The Model for End-Stage Liver Disease score was used to measure liver function in these patients. The primary study end point was 30-day mortality in patients presenting with liver dysfunction. Secondary study end point was liver enzymes after TAVR. The mean Model for End-Stage Liver Disease score in patients with chronic liver disease was 16.8 ± 6.2 (median, 18; range, 7 to 26). The 30-day mortality was 9.1% (57 of 629) in patients presenting without liver disease and 9.1% (1 of 11) in patients with liver disease (p = 1.00). Patients with chronic liver disease showed significantly higher preoperative levels of γ-glutamyl transpeptidase (p < 0.001). After TAVR, we observed a significant increase in alanine aminotransferase on postoperative day 3 compared with preoperative values (p < 0.001), accompanied by a decrease in albumin (p < 0.001). Liver cirrhosis per se is not considered as a contraindication for cardiac operations. In the present study, we did not observe a higher 30-day mortality rate in liver cirrhotic patients undergoing TAVR, suggesting TAVR as a feasible alternative with acceptable outcomes in patients with chronic liver disease. Moreover, the present study is the first to evaluate liver variables in patients undergoing TAVR. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Therapeutic effect comparison of hepatocyte-like cells and bone marrow mesenchymal stem cells in acute liver failure of rats.

PubMed

Li, Dongliang; Fan, Jingjing; He, Xiuhua; Zhang, Xia; Zhang, Zhiqiang; Zeng, Zhiyu; Ruan, Mei; Cai, Lirong

2015-01-01

To evaluate the therapeutic efficacy of rat bone marrow mesenchymal stem cells (BMSCs) induced into hepatocyte-like cells and of un-induced BMSCs in acute liver failure rats. BMSCs in highly homogenous passage 3 were cultured using the whole bone marrow adherent culture method. Hepatic-related characters were confirmed with morphology, RT-PCR analysis, glycogen staining and albumin (ALB) immunofluorescence assay. Carbon tetrachloride (CCl4) was injected intraperitoneally to establish an acute rat liver failure model. Hepatocyte-like cells or un-induced BMSCs were respectively injected into the models to examine rats' appearance, liver function assay and liver tissue pathology. Hepatocyte-like morphology, higher expression of cytokeratin 18 (CK18) mRNA and ALB protein, and glycogen accumulation were confirmed in the induced BMSCs. The transplanted DAPI-labeled BMSCs were localized in the liver tissue 3-14 days after transplantation. The levels of liver function indicators (AST, ALT, ALP, and TBIL) from transplanted rats were significant decreased and pathology was improved, indicating the recovery of liver function. However, the differences were statistically insignificant. Both hepatocyte-like cells and un-induced BMSCs had a similarly positively therapeutic efficacy on liver regeneration in rat liver failure model.

Plasma and Tissue Concentrations of α-Tocopherol and δ-Tocopherol Following High Dose Dietary Supplementation in Mice

PubMed Central

Baxter, Laura L.; Marugan, Juan J.; Xiao, Jingbo; Incao, Art; McKew, John C.; Zheng, Wei; Pavan, William J.

2012-01-01

Vitamin E isoforms are essential nutrients that are widely used as dietary supplements and therapeutic agents for a variety of diseases. However, their pharmacokinetic (PK) properties remain poorly characterized, and high dosage animal studies may provide further information on their in vivo functions and pharmacological effects. In this study, alpha-tocopherol (α-toc) and delta-tocopherol (δ-toc) levels were measured in mouse plasma and tissues following their high dosage dietary supplementation. Average α-toc levels at 5, 10 and 20 g α-toc/kg diet increased over baseline levels 6-fold in plasma, 1.6-fold in brain, and 4.9-fold in liver. These elevated α-toc concentrations remained constant from 5 to 20 g α-toc/kg diet, rather than showing further increases across these dosages. No α-toc-related toxicity occurred at these high dosages, and strain-specific differences in liver and brain α-toc levels between Balb/cJ and C57Bl/6J mice were observed. Relatively high-dosage administration of dietary δ-toc for 1 or 4 weeks resulted in 6–30-fold increases in plasma and liver levels between dosages of 0.33 and 1.67 g δ-toc/kg diet. Co-administration of sesamin with δ-toc further increased δ-toc levels between 1.3- and 14-fold in plasma, liver, and brain. These results provide valuable PK information on high dosage α-toc and δ-toc in mouse and show that supplementation of sesamin with δ-toc further increases δ-toc levels over those seen with δ-toc supplementation alone. PMID:22822447

Breast milk is better than formula milk in preventing parenteral nutrition-associated liver disease in infants receiving prolonged parenteral nutrition.

PubMed

Kulkarni, Sakil; Mercado, Velma; Rios, Mirta; Arboleda, Richard; Gomara, Roberto; Muinos, William; Reeves-Garcia, Jesse; Hernandez, Erick

2013-09-01

Breast milk has been shown to be associated with greater success with regard to weaning children with intestinal failure off parenteral nutrition (PN). There are only a few studies investigating the role of breast milk in decreasing PN-associated liver disease (PNALD). The aim of our study was to determine whether breast milk is better than formula milk in preventing PNALD in infants receiving PN for >4 weeks. We conducted a retrospective analysis of newborns requiring prolonged parenteral nutrition. We divided the sample into 3 different groups (exclusive breast-feeding, exclusive formula-feeding, and mixed feeding. We compared baseline characteristics, feeding profiles and liver function tests, and liver enzymes among the 3 groups. Among infants receiving PN for >4 weeks, we found that infants who were fed only breast milk were significantly less likely to develop PNALD (34.6%) compared with those who were fed only formula milk (72.7%; P = 0.008). The mean maximum conjugated bilirubin (P = 0.03) and the mean maximum aspartate aminotransferase were significantly lower in the breast-fed group (P = 0.04) compared with the formula-fed group. Among the mixed-feeding group, infants who received a higher percentage of breast milk showed a significant negative correlation with the mean maximum conjugated bilirubin. (Pearson correlation -0.517, P = 0.027). The mean number of days receiving PN and the average daily lipid intake in the 2 groups was not significantly different. As a modality for early enteral nutrition, breast milk is protective against the development of PNALD in infants receiving PN for >4 weeks.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

PubMed Central

Valayannopoulos, Vassili; Malinova, Vera; Honzík, Tomas; Balwani, Manisha; Breen, Catherine; Deegan, Patrick B.; Enns, Gregory M.; Jones, Simon A.; Kane, John P.; Stock, Eveline O.; Tripuraneni, Radhika; Eckert, Stephen; Schneider, Eugene; Hamilton, Gavin; Middleton, Michael S.; Sirlin, Claude; Kessler, Bruce; Bourdon, Christopher; Boyadjiev, Simeon A.; Sharma, Reena; Twelves, Chris; Whitley, Chester B.; Quinn, Anthony G.

2014-01-01

Background and aims Lysosomal Acid Lipase Deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Methods Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. Results 216 infusions were administered to eight adult subjects through Week 52 during LAL-CL04. At Week 52, mean alanine aminotransferase and aspartate aminotransferase were normal with mean change from baseline of −58% and −40%. Mean change for low density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were −60%, −39%, −36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Conclusions Long-term dosing with sebelipase alfa in Lysosomal Acid Lipase-Deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184). PMID:24993530

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-stage Liver Disease Scores Compared With Placebo.

PubMed

Frenette, Catherine T; Morelli, Giuseppe; Shiffman, Mitchell L; Frederick, R Todd; Rubin, Raymond A; Fallon, Michael B; Cheng, Jason T; Cave, Matt; Khaderi, Saira A; Massoud, Omar; Pyrsopoulos, Nikolaos; Park, James S; Robinson, James M; Yamashita, Mason; Spada, Alfred P; Chan, Jean L; Hagerty, David T

2018-06-15

Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT002209456. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanuki, Naoko; Takeda, Atsuya; Oku, Yohei

Purpose: Focal liver reaction (FLR) appears on radiographic images after stereotactic ablative body radiation therapy (SABR) in patients with hepatocellular carcinoma (HCC) and chronic liver disease. We investigated the threshold dose (TD) of FLR and possible factors affecting the TD on gadoxetate acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). Methods and Materials: In 50 patients who were treated with SABR for small HCC and followed up by MRI for >6 months, FLR, seen as a hypointense area, was evaluated on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. The follow-up MRI with the largest extent of FLR was fused to the planning computedmore » tomography (CT) image, and patients with good image fusion concordance were eligible. After delineating the border of the FLR manually, a dose–volume histogram was used to identify the TD for the FLR. Clinical and volumetric factors were analyzed for correlation with the TD. Results: A total of 45 patients were eligible for analysis with a median image fusion concordance of 84.9% (range, 71.6-95.4%). The median duration between SABR and subsequent hepatobiliary phase MRI with the largest extent of FLR was 3 months (range, 1-6 months). The median TD for FLR was 28.0 Gy (range, 22.3-36.4 Gy). On univariate analysis, pre-treatment Child-Pugh (CP) score and platelet count were significantly correlated with the TD. On multiple linear regression analysis, CP score was the only parameter that predicted TD. Median TDs were 30.5 Gy (range, 26.2.3-36.4 Gy) and 25.2 Gy (range, 22.3-27.5 Gy) for patients with CP-A and CP-B disease, respectively. Conclusion: The TD was significantly correlated with baseline liver function. We propose 30 Gy for CP-A disease and 25 Gy for CP-B disease in 5 fractions as TDs for FLR after SABR for patients with HCC and chronic liver disease. Use of these TDs will help to predict potential loss of liver tissue after SABR.« less

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

PubMed Central

Russell, Jacquelyn O.; Monga, Satdarshan P.

2018-01-01

The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type–specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology. PMID:29125798

Functional image-guided stereotactic body radiation therapy planning for patients with hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsegmed, Uranchimeg; Kimura, Tomoki, E-mail: tkkimura@hiroshima-u.ac.jp; Nakashima, Takeo

The aim of the current planning study is to evaluate the ability of gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI)–guided stereotactic body radiation therapy (SBRT) planning by using intensity-modulated radiation therapy (IMRT) techniques in sparing the functional liver tissues during SBRT for hepatocellular carcinoma. In this study, 20 patients with hepatocellular carcinoma were enrolled. Functional liver tissues were defined according to quantitative liver-spleen contrast ratios ≥ 1.5 on a hepatobiliary phase scan. Functional images were fused with the planning computed tomography (CT) images; the following 2 SBRT plans were designed using a “step-and-shoot” static IMRT technique for each patient: (1) an anatomicalmore » SBRT plan optimization based on the total liver; and (2) a functional SBRT plan based on the functional liver. The total prescribed dose was 48 gray (Gy) in 4 fractions. Dosimetric parameters, including dose to 95% of the planning target volume (PTV D{sub 95%}), percentages of total and functional liver volumes, which received doses from 5 to 30 Gy (V5 to V30 and fV5 to fV30), and mean doses to total and functional liver (MLD and fMLD, respectively) of the 2 plans were compared. Compared with anatomical plans, functional image-guided SBRT plans reduced MLD (mean: plan A, 5.5 Gy; and plan F, 5.1 Gy; p < 0.0001) and fMLD (mean: plan A, 5.4 Gy; and plan F, 4.9 Gy; p < 0.0001), as well as V5 to V30 and fV5 to fV30. No differences were noted in PTV coverage and nonhepatic organs at risk (OARs) doses. In conclusion, EOB-MRI–guided SBRT planning using the IMRT technique may preserve functional liver tissues in patients with hepatocellular carcinoma (HCC).« less

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers.

PubMed

Munsterman, I D; Groefsema, M M; Weijers, G; Klein, W M; Swinkels, D W; Drenth, J P H; Schellekens, A F A; Tjwa, E T T L

2018-05-03

In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption.

Association between liver function and metabolic syndrome in Chinese men and women

PubMed Central

Wang, Sen; Zhang, Jie; Zhu, Li; Song, Linlin; Meng, Zhaowei; Jia, Qiang; Li, Xue; Liu, Na; Hu, Tianpeng; Zhou, Pingping; Zhang, Qing; Liu, Li; Song, Kun; Jia, Qiyu

2017-01-01

Metabolic syndrome (MS) could be associated with liver function. Our study aimed to investigate the association between liver function and MS in a large cohort of Chinese men and women. We enrolled 32,768 ostensibly healthy participants. The associations between liver function and MS of both genders were analyzed separately after dividing total bilirubin (TBIL), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) into quartiles. Young males had significantly higher MS prevalence than females, yet after menopause, females had higher MS prevalence. We used TBIL, GGT and ALT quartiles as categorical variables in binary logistic regression models. Significantly decreased MS risks were demonstrated in TBIL quartiles 2 to 4 for males, and quartiles 3 to 4 for females. As to GGT and ALT, significantly increased MS risks were shown in high quartiles for both genders. Aging also resulted in significantly higher MS risks in both genders except for young females. This study displayed close associations between liver function and MS, which were influenced by gender and age. A high TBIL level had protective effect against MS, while high GGT and ALT levels were risk factors for MS. It is meaningful that liver function is used as clinical risk predictors for MS. PMID:28317840

Risk factors for deterioration of long-term liver function after radiofrequency ablation therapy

PubMed Central

Honda, Koichi; Seike, Masataka; Oribe, Junya; Endo, Mizuki; Arakawa, Mie; Syo, Hiroki; Iwao, Masao; Tokoro, Masanori; Nishimura, Junko; Mori, Tetsu; Yamashita, Tsutomu; Fukuchi, Satoshi; Muro, Toyokichi; Murakami, Kazunari

2016-01-01

AIM: To identify factors that influence long-term liver function following radiofrequency ablation (RFA) in patients with viral hepatitis-related hepatocellular carcinoma. METHODS: A total of 123 patients with hepatitis B virus- or hepatitis C virus-related hepatocellular car-cinoma (HCC) (n = 12 and n = 111, respectively) were enrolled. Cumulative rates of worsening Child-Pugh (CP) scores (defined as a 2-point increase) were examined. RESULTS: CP score worsening was confirmed in 22 patients over a mean follow-up period of 43.8 ± 26.3 mo. Multivariate analysis identified CP class, platelet count, and aspartate aminotransferase levels as signi-ficant predictors of a worsening CP score (P = 0.000, P = 0.011 and P = 0.024, respectively). In contrast, repeated RFA was not identified as a risk factor for liver function deterioration. CONCLUSION: Long-term liver function following RFA was dependent on liver functional reserve, the degree of fibrosis present, and the activity of the hepatitis condition for this cohort. Therefore, in order to maintain liver function for an extended period following RFA, suppression of viral hepatitis activity is important even after the treatment of HCC. PMID:27168872

Reversal of type 2 diabetes in youth who adhere to a very-low-energy diet: a pilot study.

PubMed

Gow, Megan L; Baur, Louise A; Johnson, Nathan A; Cowell, Chris T; Garnett, Sarah P

2017-03-01

The aim of the study was to investigate whether a very-low-energy diet (VLED) is a feasible and acceptable treatment option for type 2 diabetes in children and adolescents, and whether adherence can lead to rapid weight loss, reversal of type 2 diabetes and reduced liver fat as seen in adult studies. Eight participants with type 2 diabetes and obesity, aged 7-16 years, non-medicated (n = 1) or treated with metformin (n = 7) and in some cases insulin (n = 3), followed a VLED (<3360 kJ/day) for 8 weeks, then transitioned to a hypocaloric diet (∼6300 kJ/day) that they followed to 34 weeks. HbA 1c , fasting glucose and 2 h post-glucose load plasma glucose (2hG) were determined from fasting blood and an OGTT. Liver fat concentration was quantified using proton magnetic resonance spectroscopy. Adherence was defined as ≥5% weight loss during the 8 week VLED. Adherers (n = 5) and non-adherers (n = 3) had median weight loss of 7.5% and 0.5%, respectively, at 8 weeks. Overall, HbA 1c (mean [SE] 8.1% [0.7%] to 6.6% [0.5%]; p = 0.004) and 2hG (15.6 [1.6] mmol/l to 11.3 [1.0] mmol/l; p = 0.009) were significantly reduced at 8 weeks compared with baseline. Liver fat was also significantly reduced from baseline (14.7% [2.2%]) to 8 weeks (5.8% [1.7%]; p = 0.001). Only three out of eight participants met non-alcoholic fatty liver disease (NAFLD) criteria (≥5.5%) at 8 weeks, compared with eight out of eight at baseline. The three participants on insulin therapy at baseline were able to cease therapy during the 8 week VLED. At 34 weeks, adherers (n = 5) achieved 12.3% weight loss, none met NAFLD criteria and four did not meet American Diabetes Association criteria for type 2 diabetes. A VLED appears to be a feasible treatment option for some youth with type 2 diabetes on metformin therapy. Youth who agree to participate and adhere to a VLED achieve rapid weight loss, dramatic reductions in liver fat and reversal of type 2 diabetes. This highlights the capacity of a VLED to be used as a first-line treatment option in newly diagnosed youth. A larger trial with a control group and longer follow-up will be required to encourage a change in standard treatment. Australian New Zealand Clinical Trial Registration Number (ACTRN) ACTRN12616000375459 ( www.ANZCTR.org.au/ACTRN12616000375459.aspx ).

Assessment of Liver Function in Patients With Hepatocellular Carcinoma: A New Evidence-Based Approach—The ALBI Grade

PubMed Central

Johnson, Philip J.; Berhane, Sarah; Kagebayashi, Chiaki; Satomura, Shinji; Teng, Mabel; Reeves, Helen L.; O'Beirne, James; Fox, Richard; Skowronska, Anna; Palmer, Daniel; Yeo, Winnie; Mo, Frankie; Lai, Paul; Iñarrairaegui, Mercedes; Chan, Stephen L.; Sangro, Bruno; Miksad, Rebecca; Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori

2015-01-01

Purpose Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. Patients and Methods We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). Results The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. Conclusion The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade. PMID:25512453

Functional gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC).

PubMed

Hinrichs, Heiko; Hinrichs, Jan B; Gutberlet, Marcel; Lenzen, Henrike; Raatschen, Hans-Juergen; Wacker, Frank; Ringe, Kristina I

2016-04-01

To assess the value of variable flip angle-based T1 liver mapping on gadoxetate disodium-enhanced MRI in patients with primary sclerosing cholangitis (PSC) for evaluation of global and segmental liver function, and determine a possible correlation with disease severity. Sixty-one patients (19 female, 42 male; mean age 41 years) with PSC were included in this prospective study. T1 mapping was performed using a 3D-spoiled GRE sequence (flip angles 5°, 15°, 20°, 30°) before, 16 (HP1) and 132 min (HP2) after contrast injection. T1 values were measured and compared (Wilcoxon-Test) by placing ROIs in each liver segment. The mean reduction of T1 relaxation time at HP1 and HP2 was calculated and correlated with liver function tests (LFTs), MELD, Mayo Risk and Amsterdam Scores (Spearman correlation). Significant changes of T1 relaxation times between non-enhanced and gadoxetate disodium-enhanced MRI at HP1 and HP2 could be observed in all liver segments (p < 0.0001). A significant correlation of T1 reduction could be observed with LFTs, MELD and Mayo Risk Score (p < 0.05). T1 mapping of the liver using a variable flip angle-based sequence is a feasible technique to evaluate liver function on a global level, and may be extrapolated on a segmental level in patients with PSC. • T1 mapping enables evaluation of global liver function in PSC. • T1 relaxation time reduction correlates with the MELD and MayoRisk Score. • Extrapolated, T1 mapping may allow for segmental evaluation of liver function.

Orchestrating liver development.

PubMed

Gordillo, Miriam; Evans, Todd; Gouon-Evans, Valerie

2015-06-15

The liver is a central regulator of metabolism, and liver failure thus constitutes a major health burden. Understanding how this complex organ develops during embryogenesis will yield insights into how liver regeneration can be promoted and how functional liver replacement tissue can be engineered. Recent studies of animal models have identified key signaling pathways and complex tissue interactions that progressively generate liver progenitor cells, differentiated lineages and functional tissues. In addition, progress in understanding how these cells interact, and how transcriptional and signaling programs precisely coordinate liver development, has begun to elucidate the molecular mechanisms underlying this complexity. Here, we review the lineage relationships, signaling pathways and transcriptional programs that orchestrate hepatogenesis. © 2015. Published by The Company of Biologists Ltd.

Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance

PubMed Central

Dietrich, Christoph G; Götze, Oliver; Geier, Andreas

2016-01-01

Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID:26755861

Efficient and Controlled Generation of 2D and 3D Bile Duct Tissue from Human Pluripotent Stem Cell-Derived Spheroids.

PubMed

Tian, Lipeng; Deshmukh, Abhijeet; Ye, Zhaohui; Jang, Yoon-Young

2016-08-01

While in vitro liver tissue engineering has been increasingly studied during the last several years, presently engineered liver tissues lack the bile duct system. The lack of bile drainage not only hinders essential digestive functions of the liver, but also leads to accumulation of bile that is toxic to hepatocytes and known to cause liver cirrhosis. Clearly, generation of bile duct tissue is essential for engineering functional and healthy liver. Differentiation of human induced pluripotent stem cells (iPSCs) to bile duct tissue requires long and/or complex culture conditions, and has been inefficient so far. Towards generating a fully functional liver containing biliary system, we have developed defined and controlled conditions for efficient 2D and 3D bile duct epithelial tissue generation. A marker for multipotent liver progenitor in both adult human liver and ductal plate in human fetal liver, EpCAM, is highly expressed in hepatic spheroids generated from human iPSCs. The EpCAM high hepatic spheroids can, not only efficiently generate a monolayer of biliary epithelial cells (cholangiocytes), in a 2D differentiation condition, but also form functional ductal structures in a 3D condition. Importantly, this EpCAM high spheroid based biliary tissue generation is significantly faster than other existing methods and does not require cell sorting. In addition, we show that a knock-in CK7 reporter human iPSC line generated by CRISPR/Cas9 genome editing technology greatly facilitates the analysis of biliary differentiation. This new ductal differentiation method will provide a more efficient method of obtaining bile duct cells and tissues, which may facilitate engineering of complete and functional liver tissue in the future.

Non-Invasive Assessment of Liver Function

PubMed Central

Helmke, Steve; Colmenero, Jordi; Everson, Gregory T.

2015-01-01

Purpose of review It is our opinion that there is an unmet need in Hepatology for a minimally- or noninvasive test of liver function and physiology. Quantitative liver function tests (QLFTs) define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high affinity hepatic transporters exhibit high “first-pass” hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways. Recent Findings We highlight one QLFT, the dual cholate test, and introduce the concept of a disease severity index (DSI) linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting. Summary It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy. PMID:25714706

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

PubMed

Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

2016-09-01

Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Adipokines in Liver Cirrhosis.

PubMed

Buechler, Christa; Haberl, Elisabeth M; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

2017-06-29

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

Adipokines in Liver Cirrhosis

PubMed Central

Haberl, Elisabeth M.; Rein-Fischboeck, Lisa; Aslanidis, Charalampos

2017-01-01

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively. PMID:28661458

Quantitative PET of liver functions

PubMed Central

Keiding, Susanne; Sørensen, Michael; Frisch, Kim; Gormsen, Lars C; Munk, Ole Lajord

2018-01-01

Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[18F]fluoro-D-galactose (18F-FDGal) provides quantitative images of the hepatic metabolic clearance K met (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard-uptake-value (SUV) from a static liver 18F-FDGal PET/CT scan can replace K met and is currently used clinically. 2) Dynamic liver PET/CT in humans with 11C-palmitate and with the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood (K 1; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. In conclusion, SUV of non-invasive static PET with 18F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET. PMID:29755841

Quantitative PET of liver functions.

PubMed

Keiding, Susanne; Sørensen, Michael; Frisch, Kim; Gormsen, Lars C; Munk, Ole Lajord

2018-01-01

Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[ 18 F]fluoro- D -galactose ( 18 F-FDGal) provides quantitative images of the hepatic metabolic clearance K met (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard-uptake-value ( SUV ) from a static liver 18 F-FDGal PET/CT scan can replace K met and is currently used clinically. 2) Dynamic liver PET/CT in humans with 11 C-palmitate and with the conjugated bile acid tracer [ N -methyl- 11 C]cholylsarcosine ( 11 C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood ( K 1 ; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. In conclusion , SUV of non-invasive static PET with 18 F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET.

Entrapment of hepatocyte spheroids in a hollow fiber bioreactor as a potential bioartificial liver.

PubMed

Wu, F J; Peshwa, M V; Cerra, F B; Hu, W S

1995-01-01

A bioartificial liver (BAL) employing xenogeneic hepatocytes has been developed as a potential interim support for patients in hepatic failure. For application in human therapy, the BAL requires a substantial increase in liver-specific functions. Cultivation of hepatocytes as spheroids leads to enhanced liver specific functions. We explored the possibility of entrapping spheroids into the BAL in order to improve device performance. Rat hepatocyte spheroids were entrapped in collagen gel within the lumen fibers of the BAL. The morphology and ultrastructure of collagen-entrapped spheroids resembled those of suspended spheroids formed on petri dishes. Albumin synthesis and P-450 enzyme activity were measured as markers of liver specific functions of spheroids entrapped in the BAL. At least a 4-fold improvement in these functions was observed compared to BAL devices entrapped with dispersed hepatocytes in collagen gels.

Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors.

PubMed

Yamamoto, Hideaki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

2018-01-01

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease.

PubMed

Bell, Catherine C; Hendriks, Delilah F G; Moro, Sabrina M L; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C A; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L; Jenkins, Rosalind E; Nordling, Åsa; Mkrtchian, Souren; Park, B Kevin; Kitteringham, Neil R; Goldring, Christopher E P; Lauschke, Volker M; Ingelman-Sundberg, Magnus

2016-05-04

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

PubMed Central

Bell, Catherine C.; Hendriks, Delilah F. G.; Moro, Sabrina M. L.; Ellis, Ewa; Walsh, Joanne; Renblom, Anna; Fredriksson Puigvert, Lisa; Dankers, Anita C. A.; Jacobs, Frank; Snoeys, Jan; Sison-Young, Rowena L.; Jenkins, Rosalind E.; Nordling, Åsa; Mkrtchian, Souren; Park, B. Kevin; Kitteringham, Neil R.; Goldring, Christopher E. P.; Lauschke, Volker M.; Ingelman-Sundberg, Magnus

2016-01-01

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI. PMID:27143246

Modeling liver physiology: combining fractals, imaging and animation.

PubMed

Lin, Debbie W; Johnson, Scott; Hunt, C Anthony

2004-01-01

Physiological modeling of vascular and microvascular networks in several key human organ systems is critical for a deeper understanding of pharmacology and the effect of pharmacotherapies on disease. Like the lung and the kidney, the morphology of its vascular and microvascular system plays a major role in its functional capability. To understand liver function in absorption and metabolism of food and drugs, one must examine the morphology and physiology at both higher and lower level liver function. We have developed validated virtualized dynamic three dimensional (3D) models of liver secondary units and primary units by combining a number of different methods: three-dimensional rendering, fractals, and animation. We have simulated particle dynamics in the liver secondary unit. The resulting models are suitable for use in helping researchers easily visualize and gain intuition on results of in silico liver experiments.

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

PubMed Central

Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

2011-01-01

BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

PubMed

Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

2011-04-01

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Moderate doses of commercial preparations of Ginkgo biloba do not alter markers of liver function but moderate alcohol intake does: A new approach to identify and quantify biomarkers of 'adverse effects' of dietary supplements.

PubMed

Lieberman, Harris R; Kellogg, Mark D; Fulgoni, Victor L; Agarwal, Sanjiv

2017-03-01

It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001-2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed. Alcohol and ginkgo extract intake of adult consumers and clinical markers of liver function (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin) were examined. Moderate consumers of alcohol (0.80 ± 0.02 drinks/day) had higher levels of aspartate aminotransferase and gamma glutamyl transferase than non-consumers (P < 0.001). There was no difference (P > 0.01) in levels of markers of liver function in 616 ginkgo consumers (65.1 ± 4.4 mg/day intake) compared to non-consumers. While moderate alcohol consumption was associated with changes in markers of liver function, ginkgo intake as typically consumed by U.S. adults was not associated with these markers. Biomarkers measured by NHANES may be useful to examine potential adverse effects of dietary supplements for which insufficient human adverse event and toxicity data are available. Not applicable, as this is secondary analysis of publicly released observational data (NHANES 2001-2012). Published by Elsevier Inc.

The functional interrelationship between gap junctions and fenestrae in endothelial cells of the liver organoid.

PubMed

Saito, Masaya; Matsuura, Tomokazu; Nagatsuma, Keisuke; Tanaka, Ken; Maehashi, Haruka; Shimizu, Keiko; Hataba, Yoshiaki; Kato, Fumitaka; Kashimori, Isao; Tajiri, Hisao; Braet, Filip

2007-06-01

Functional intact liver organoid can be reconstructed in a radial-flow bioreactor when human hepatocellular carcinoma (FLC-5), mouse immortalized sinusoidal endothelial M1 (SEC) and A7 (HSC) hepatic stellate cell lines are cocultured. The structural and functional characteristics of the reconstructed organoid closely resemble the in vivo liver situation. Previous liver organoid studies indicated that cell-to-cell communications might be an important factor for the functional and structural integrity of the reconstructed organoid, including the expression of fenestrae. Therefore, we examined the possible relationship between functional intact gap junctional intercellular communication (GJIC) and fenestrae dynamics in M1-SEC cells. The fine morphology of liver organoid was studied in the presence of (1) irsogladine maleate (IM), (2) oleamide and (3) oleamide followed by IM treatment. Fine ultrastructural changes were studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and compared with control liver organoid data. TEM revealed that oleamide affected the integrity of cell-to-cell contacts predominantly in FLC-5 hepatocytes. SEM observation showed the presence of fenestrae on M1-SEC cells; however, oleamide inhibited fenestrae expression on the surface of endothelial cells. Interestingly, fenestrae reappeared when IM was added after initial oleamide exposure. GJIC mediates the number of fenestrae in endothelial cells of the liver organoid.

Long-term culture of human liver tissue with advanced hepatic functions.

PubMed

Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

2017-06-02

A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

FXR and liver carcinogenesis

PubMed Central

Huang, Xiong-fei; Zhao, Wei-yu; Huang, Wen-dong

2015-01-01

Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer. PMID:25500874

Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery

NASA Astrophysics Data System (ADS)

Rudolph, Karl Lenhard; Chang, Sandy; Millard, Melissa; Schreiber-Agus, Nicole; DePinho, Ronald A.

2000-02-01

Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR-/- mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of ``telomerase therapy'' for such diseases.

Robustness of external/internal correlation models for real-time tumor tracking to breathing motion variations

NASA Astrophysics Data System (ADS)

Seregni, M.; Cerveri, P.; Riboldi, M.; Pella, A.; Baroni, G.

2012-11-01

In radiotherapy, organ motion mitigation by means of dynamic tumor tracking requires continuous information about the internal tumor position, which can be estimated relying on external/internal correlation models as a function of external surface surrogates. In this work, we propose a validation of a time-independent artificial neural networks-based tumor tracking method in the presence of changes in the breathing pattern, evaluating the performance on two datasets. First, simulated breathing motion traces were specifically generated to include gradually increasing respiratory irregularities. Then, seven publically available human liver motion traces were analyzed for the assessment of tracking accuracy, whose sensitivity with respect to the structural parameters of the model was also investigated. Results on simulated data showed that the proposed method was not affected by hysteretic target trajectories and it was able to cope with different respiratory irregularities, such as baseline drift and internal/external phase shift. The analysis of the liver motion traces reported an average RMS error equal to 1.10 mm, with five out of seven cases below 1 mm. In conclusion, this validation study proved that the proposed method is able to deal with respiratory irregularities both in controlled and real conditions.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study.

PubMed

Carr, Brian I; Pancoska, Petr; Branch, Robert A

2009-12-24

967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point. We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival. The data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.

Factors associated with tumor size of hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Buulolo, B. A.

2018-03-01

Determining the association of age and laboratory parameters with tumor size of hepatocellular carcinoma (HCC). The study was at Adam Malik Hospital Medan from June- December 2016. 100 HCC patients were enrolled; those with excluding liver metastatic. Baseline characteristics of gender, age, obtaining etiology of HCC. Liver function tests, viral marker, and INR were done. Based on tumor size from abdomen CT, patients were three groups: tumor size below 3 cm, 3-5 cm, and above 5 cm size. Patients were also divided based on Child-Pugh class. Correlation of age and laboratory results with tumor size of HCC patients were analyzed. Age have negative correlation with tumor size in HCC patients (r=-0.297, p=0.032) while AFP have positive correlation with tumor size (r0.446, p=<0.001). Total bilirubin, AST, and ALT have negative correlation but non-significant (r=-0.045, -0.078, - 0.126 respectively). Albumin and INR have positive correlation but non-significant (r=0.021, 0.112 respectively). Our study suggests that older age correlates with smaller tumor size, while AFP level has a significant correlation with tumor size in HCC patients. AFP level may be a useful marker for determining the prognosis of HCC patients.

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

PubMed Central

Li, Yan; Farooq, Muhammad; Sheng, Donglai; Chandramouli, Chanchal; Lan, Tian; Mahajan, Nilesh K.; Kini, R. Manjunatha; Hong, Yunhan; Lisowsky, Thomas; Ge, Ruowen

2012-01-01

Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive AlrC131S mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alr C131S is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis. PMID:22292055

Well Preserved Renal Function in Children With Untreated Chronic Liver Disease.

PubMed

Berg, Ulla B; Németh, Antal

2018-04-01

On the basis of studies with hepatorenal syndrome, it is widely regarded that renal function is impacted in chronic liver disease (CLD). Therefore, we investigated renal function in children with CLD. In a retrospective study of 277 children with CLD, renal function was investigated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), measured as clearance of inulin and para-amino hippuric acid or clearance of iohexol. The data were analyzed with regard to different subgroups of liver disease and to the grade of damage. Hyperfiltration (>+2 SD of controls) was found in the subgroups of progressive familial intrahepatic cholestasis (44%), glycogenosis (75%), and acute fulminant liver failure (60%). Patients with biliary atresia, most other patients with metabolic disease and intrahepatic cholestasis, and those with vascular anomalies and cryptogenic cirrhosis had normal renal function. Decreased renal function was found in patients with Alagille's syndrome (64% < -2 SD). Increased GFR and ERPF was found in patients with elevated transaminases, low prothrombin level, high bile acid concentration, and high aspartate-aminotransferase-to-platelet ratio. Most children with CLD had surprisingly well preserved renal function and certain groups had even hyperfiltration. The finding that children with decompensated liver disease and ongoing liver failure had stable kidney function suggests that no prognostic markers of threatening hepatorenal syndrome were at hand. Moreover, estimation of GFR based on serum creatinine fails to reveal hyperfiltration.

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.

PubMed

Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Schnellmann, Rick G; Lemasters, John J; Zhong, Zhi

2015-07-01

Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Marino, Bruno; Starkey, Graeme; Fink, Michael; Wang, Bao Zhong; Eastwood, Glenn M; Peck, Leah; Young, Helen; Houston, Shane; Skene, Alison; Opdam, Helen; Jones, Robert

2014-09-01

Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

Circulating lipocalin 2 is neither related to liver steatosis in patients with non-alcoholic fatty liver disease nor to residual liver function in cirrhosis.

PubMed

Meier, Elisabeth M; Pohl, Rebekka; Rein-Fischboeck, Lisa; Schacherer, Doris; Eisinger, Kristina; Wiest, Reiner; Krautbauer, Sabrina; Buechler, Christa

2016-09-01

Lipocalin 2 (LCN2) is induced in the injured liver and associated with inflammation. Aim of the present study was to evaluate whether serum LCN2 is a non-invasive marker to assess hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) or residual liver function in patients with liver cirrhosis. Therefore, LCN2 was measured by ELISA in serum of 32 randomly selected patients without fatty liver (controls), 24 patients with ultrasound diagnosed NAFLD and 42 patients with liver cirrhosis mainly due to alcohol. Systemic LCN2 was comparable in patients with liver steatosis, those with liver cirrhosis and controls. LCN2 negatively correlated with bilirubin in both cohorts. In cirrhosis, LCN2 was not associated with more advanced liver injury defined by the CHILD-PUGH score and model for end-stage liver disease score. Resistin but not C-reactive protein or chemerin positively correlated with LCN2. LCN2 levels were not increased in patients with ascites or patients with esophageal varices. Consequently, reduction of portal pressure by transjugular intrahepatic portosystemic shunt did not affect LCN2 levels. Hepatic venous blood (HVS), portal venous blood and systemic venous blood levels of LCN2 were similar. HVS LCN2 was unchanged in patients with end-stage liver cirrhosis compared to those with well-compensated disease arguing against increased hepatic release. Current data exclude that serum LCN2 is of any value as steatosis marker in patients with NAFLD and indicator of liver function in patients with alcoholic liver cirrhosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of dietary interventions on liver volume in humans.

PubMed

Bian, Hua; Hakkarainen, Antti; Lundbom, Nina; Yki-Järvinen, Hannele

2014-04-01

To compare effects of similar weight loss induced either by a short-term low-carbohydrate or by a long-term hypocaloric diet, and to determine effects of high carbohydrate overfeeding on liver total, lean, and fat volumes. Liver total, lean, and fat volumes were measured before and after (i) a 6-day low-carbohydrate diet (n = 17), (ii) a 7-month standard hypocaloric diet (n = 26), and (iii) a 3-week high-carbohydrate diet (n = 17), by combining magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1) H-MRS) techniques. At baseline, three groups were comparable with respect to age, body mass index, liver volumes and the liver fat content. Body weight decreased similarly by the short-term and long-term hypocaloric diets. Liver total volume decreased significantly more during the short-term low-carbohydrate (-22 ± 2%) than the long-term (-7 ± 2%) hypocaloric diet (P < 0.001). This was due to a greater decrease in liver lean volume in the short-term (-20 ± 2%) than the long-term (-4 ± 2%) weight loss group (P < 0.001). Decreases in liver fat were comparable. Liver volume increased by 9 ± 3% due to overfeeding (P< 0.02 for before vs. after). These data support the use of a short-term low-carbohydrate diet whenever a reduction in liver volume is desirable. Overeating carbohydrate is harmful because it increases liver volume. Copyright © 2013 The Obesity Society.

Impact of hepatitis C virus genotype-4 eradication following direct acting antivirals on liver stiffness measurement.

PubMed

Tag-Adeen, Mohammed; Sabra, Ahlam Mohamed; Akazawa, Yuko; Ohnita, Ken; Nakao, Kazuhiko

2017-01-01

Liver fibrosis is the most important prognostic factor in chronic hepatitis C virus (HCV) patients, and Egypt shows the highest worldwide HCV prevalence with genotype-4 pre-dominance. The aim of this study was to investigate the degree of liver stiffness measurement (LSM) improvement after successful HCV eradication. The study included 84 chronic HCV Egyptian patients, and was conducted at Qena University Hospital from November 1, 2015 till October 31, 2016. LSM was obtained by FibroScan® before starting direct acting antiviral (DAA) treatment and after achieving sustained virologic response-24 (SVR-24). Based on baseline LSM, patients were stratified into F0-F1, F2, F3 and F4 groups (METAVIR). LSM and laboratory data after achieving SVR-24 was compared with that before starting therapy in each fibrosis group (F0-F4), p -value <0.05 was statistically significant. Following DAA treatment, 80 patients achieved SVR-24; of these, 50 were males (62.5%), mean age: 54.2±7.6 years, and mean body mass index: 28.6±2.2 kg/m 2 . Mean baseline LSM dropped from 15.6±10.8 to 12.1±8.7 kPa post-SVR; the maximum change of -5.8 occurred in F4 versus -2.79, -1.28 and +0.08 in F3, F2 and F0-F1 respectively ( p <0.0001). At baseline, 41 patients were in the F4 group; only 16 (39%) regressed to non-cirrhotic range (<12.5 kPa), while 25 (61%) were still cirrhotic despite achieving SVR-24 ( p <0.0001). Patients who achieved LSM improvement (n=64) have had significantly higher baseline aspartate transferase (AST) and alanine transaminase (ALT). Also, those patients showed significant improvement in AST, AST/platelets ratio index (APRI) and fibrosis-4 index (Fib-4) after achieving SVR; 91% showed AST improvement ( p =0.01) and APRI improvement ( p =0.01) and 81% showed Fib-4 improvement ( p =0.04). Females, diabetics, patients with S3 steatosis and patients older than 50 years showed less LSM improvements than their counterparts. Baseline LSM ≥9 kPa, bilirubin ≥1 mg/dl, ALT ≥36 U/L and AST ≥31 U/L were significant predictors for LSM improvement. Successful HCV genotype-4 eradication results in significant LSM improvement; the best improvement occurs in F4 patients. But as the majority of cirrhotics are still at risk for liver decompensation and hepatocellular carcinoma development despite achieving SVR-24, early detection and treatment are highly recommended.

Molecular and functional characterization of CD133+ stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells.

PubMed

Catani, Lucia; Sollazzo, Daria; Bianchi, Elisa; Ciciarello, Marilena; Antoniani, Chiara; Foscoli, Licia; Caraceni, Paolo; Giannone, Ferdinando Antonino; Baldassarre, Maurizio; Giordano, Rosaria; Montemurro, Tiziana; Montelatici, Elisa; D'Errico, Antonia; Andreone, Pietro; Giudice, Valeria; Curti, Antonio; Manfredini, Rossella; Lemoli, Roberto Massimo

2017-12-01

Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133 + stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133 + cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133 + and LX-2 hepatic stellate cells. We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133 + SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133 + SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. We demonstrated that the interaction between CD133 + SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Sources of Variance in Baseline Gene Expression in the Rodent Liver

EPA Science Inventory

The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the contro...

Predictive factors of short term outcome after liver transplantation: A review

PubMed Central

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-01-01

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1th and the 5th day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function. PMID:27468188

Predictive factors of short term outcome after liver transplantation: A review.

PubMed

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-07-14

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.

Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao Yue, E-mail: yuecao@umich.edu; Department of Radiology, University of Michigan, Ann Arbor, Michigan; Wang Hesheng

2013-01-01

Purpose: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. Methods and Materials: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation betweenmore » mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. Results: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. Conclusions: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.« less

Evaluation of Liver Biomarkers as Prognostic Factors for Outcomes to Yttrium-90 Radioembolization of Primary and Secondary Liver Malignancies.

PubMed

Henrie, Adam M; Wittstrom, Kristina; Delu, Adam; Deming, Paulina

2015-09-01

The objective of this study was to examine indicators of liver function and inflammation for prognostic value in predicting outcomes to yttrium-90 radioembolization (RE). In a retrospective analysis, markers of liver function and inflammation, biomarkers required to stage liver function and inflammation, and data regarding survival, tumor response, and progression after RE were recorded. Univariate regression models were used to investigate the prognostic value of liver biomarkers in predicting outcome to RE as measured by survival, tumor progression, and radiographic and biochemical tumor response. Markers from all malignancy types were analyzed together. A subgroup analysis was performed on markers from patients with metastatic colorectal cancer. A total of 31 patients received RE from 2004 to 2014. Median survival after RE for all malignancies combined was 13.6 months (95% CI: 6.7-17.6 months). Results from an exploratory analysis of patient data suggest that liver biomarkers, including albumin concentrations, international normalized ratio, bilirubin concentrations, and the model for end-stage liver disease score, possess prognostic value in predicting outcomes to RE.

The impact of longitudinal intestinal lengthening and tailoring on liver function in short bowel syndrome.

PubMed

Reinshagen, K; Zahn, K; Buch, C von; Zoeller, M; Hagl, C I; Ali, M; Waag, K-L

2008-08-01

Short bowel syndrome is a functional or anatomic loss of major parts of the small bowel leading to severe malnutrition. The limiting factor for the survival of these patients remains parenteral nutrition-related liver damage leading to end-stage liver failure. Longitudinal intestinal lengthening and tailoring (LILT) has been proven to enhance peristalsis, to decrease bacterial overgrowth and to extend the mucosal contact time for the absorption of nutrients. The aim of this study was to show the impact of LILT on the development of parenteral nutrition-related liver damage. A cohort of 55 patients with short bowel syndrome managed with LILT in our institution between 1987 and 2007 was retrospectively reviewed. LILT was performed at a mean age of 24 months (range 4 - 150 months). Mean follow-up time was 83.76 months (range 5 - 240 months). We obtained reliable data from 31 patients with regard to liver enzymes and function parameters in blood samples before LILT and at the present time. Liver biopsy was performed in 14 patients prior to LILT. Liver enzymes ALAT (mean 121 U/l), ASAT (mean 166 U/l) and bilirubin (mean 2.49 mg/dl) were elevated preoperatively in 27/31 children. After the lengthening procedure, ALAT (mean 50 U/l), ASAT (mean 63 U/l) and bilirubin (mean 1.059 mg/dl) normalized except in 5 of 8 patients who could not be weaned from parenteral nutrition after LILT. Liver function parameters such as the international normal ratio (INR) were slightly elevated in 5/31 patients. Albumin was generally low, probably due to parenteral nutrition. Liver biopsy was performed in 14 patients preoperatively, showing 4 patients with low-grade, 6 patients with intermediate and 4 patients with high-grade fibrosis. End-stage liver disease with cirrhosis was an exclusion criterion for LILT. All patients with liver fibrosis showed a normalization of liver enzymes when they were weaned from parenteral nutrition. But patients with higher grade liver fibrosis tend to develop more complications perioperatively. After LILT, all patients with liver fibrosis who could be weaned from parenteral nutrition showed a normalization of liver enzymes. Preoperative liver biopsy is mandatory in order to differentiate reversible liver fibrosis from end-stage liver disease. A higher grade of liver fibrosis and elevated INR has been shown to be a sensitive parameter for peri- and postoperative complications.

Transport Advances in Disposable Bioreactors for Liver Tissue Engineering

NASA Astrophysics Data System (ADS)

Catapano, Gerardo; Patzer, John F.; Gerlach, Jörg Christian

Acute liver failure (ALF) is a devastating diagnosis with an overall survival of approximately 60%. Liver transplantation is the therapy of choice for ALF patients but is limited by the scarce availability of donor organs. The prognosis of ALF patients may improve if essential liver functions are restored during liver failure by means of auxiliary methods because liver tissue has the capability to regenerate and heal. Bioartificial liver (BAL) approaches use liver tissue or cells to provide ALF patients with liver-specific metabolism and synthesis products necessary to relieve some of the symptoms and to promote liver tissue regeneration. The most promising BAL treatments are based on the culture of tissue engineered (TE) liver constructs, with mature liver cells or cells that may differentiate into hepatocytes to perform liver-specific functions, in disposable continuous-flow bioreactors. In fact, adult hepatocytes perform all essential liver functions. Clinical evaluations of the proposed BALs show that they are safe but have not clearly proven the efficacy of treatment as compared to standard supportive treatments. Ambiguous clinical results, the time loss of cellular activity during treatment, and the presence of a necrotic core in the cell compartment of many bioreactors suggest that improvement of transport of nutrients, and metabolic wastes and products to or from the cells in the bioreactor is critical for the development of therapeutically effective BALs. In this chapter, advanced strategies that have been proposed over to improve mass transport in the bioreactors at the core of a BAL for the treatment of ALF patients are reviewed.

Liver histopathology in Baltic eelpout (Zoarces viviparus) - A baseline study for use in marine environmental monitoring.

PubMed

Fricke, Nicolai F; Stentiford, Grant D; Feist, Stephen W; Lang, Thomas

2012-12-01

The use of liver histopathology in various fish species as a biomarker in marine monitoring programmes to assess the biological effect of exposure to anthropogenic contaminants is well established. However, although the eelpout (Zoarces viviparus) has repeatedly been recommended as an appropriate bioindicator for monitoring purposes in the Baltic Sea, information on histopathological liver alterations of this species is scarce. In order to obtain an overview, a total of 1070 eelpout, collected in the period between spring 2001 and winter 2010 from 34 sampling sites distributed over large parts of the Baltic Sea, were histologically analyzed. Liver lesions were recorded and classified according to established liver lesion categories. A high prevalence of non-specific and early toxicopathic non-neoplastic hepatic lesions was recorded. In contrast, pre-neoplastic lesions were observed only in rare cases and neoplastic changes were absent. A comparison with published data on other fish species revealed that the observed alterations may indicate effects of environmental stressors including contaminants. The results of the present study, thus, support the application of eelpout liver histopathology in environmental monitoring. Copyright © 2012 Elsevier Ltd. All rights reserved.

Preservation of Cell Structure, Metabolism, and Biotransformation Activity of Liver-On-Chip Organ Models by Hypothermic Storage.

PubMed

Gröger, Marko; Dinger, Julia; Kiehntopf, Michael; Peters, Frank T; Rauen, Ursula; Mosig, Alexander S

2018-01-01

The liver is a central organ in the metabolization of nutrition, endogenous and exogenous substances, and xenobiotic drugs. The emerging organ-on-chip technology has paved the way to model essential liver functions as well as certain aspects of liver disease in vitro in liver-on-chip models. However, a broader use of this technology in biomedical research is limited by a lack of protocols that enable the short-term preservation of preassembled liver-on-chip models for stocking or delivery to researchers outside the bioengineering community. For the first time, this study tested the ability of hypothermic storage of liver-on-chip models to preserve cell viability, tissue morphology, metabolism and biotransformation activity. In a systematic study with different preservation solutions, liver-on-chip function can be preserved for up to 2 d using a derivative of the tissue preservation solution TiProtec, containing high chloride ion concentrations and the iron chelators LK614 and deferoxamine, supplemented with polyethylene glycol (PEG). Hypothermic storage in this solution represents a promising method to preserve liver-on-chip function for at least 2 d and allows an easier access to liver-on-chip technology and its versatile and flexible use in biomedical research. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide.

PubMed

Amirtharaj, G Jayakumar; Natarajan, Sathish Kumar; Pulimood, Anna; Balasubramanian, K A; Venkatraman, Aparna; Ramachandran, Anup

2017-04-01

Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.

CD11c identifies a subset of murine liver natural killer cells that responds to adenoviral hepatitis

PubMed Central

Burt, Bryan M.; Plitas, George; Stableford, Jennifer A.; Nguyen, Hoang M.; Bamboat, Zubin M.; Pillarisetty, Venu G.; DeMatteo, Ronald P.

2008-01-01

The liver contains a unique repertoire of immune cells and a particular abundance of NK cells. We have found that CD11c defines a distinct subset of NK cells (NK1.1+CD3−) in the murine liver whose function was currently unknown. In naïve animals, CD11c+ liver NK cells displayed an activated phenotype and possessed enhanced effector functions when compared with CD11c− liver NK cells. During the innate response to adenovirus infection, CD11c+ NK cells were the more common IFN-γ-producing NK cells in the liver, demonstrated enhanced lytic capability, and gained a modest degree of APC function. The mechanism of IFN-γ production in vivo depended on TLR9 ligation as well as IL-12 and -18. Taken together, our findings demonstrate that CD11c+ NK cells are a unique subset of NK cells in the murine liver that contribute to the defense against adenoviral hepatitis. PMID:18664530

Sexual dysfunction after liver transplantation.

PubMed

Burra, Patrizia

2009-11-01

1. The goal of liver transplantation is not only to ensure the survival of patients but also to offer patients the opportunity to achieve a good balance between the functional efficacy of the graft and their psychological and physical integrity. The quality of life after transplantation may be affected by unsatisfactory sexual activity and reproductive performance. 2. Sexual dysfunction and sex hormone disturbances are widely reported in men and women with chronic liver disease before liver transplantation. 3. Successful liver transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, therefore improving reproductive performance, but immunosuppressive drugs may interfere with hormone metabolism. 4. Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy, but fetal and maternal outcomes should be regularly assessed. 5. More detailed and comprehensive data are needed in the field of sexual function after transplantation, and new strategies are needed to support and inform patients on the waiting list and after liver transplantation. (c) 2009 AASLD.

Starring role of toll-like receptor-4 activation in the gut-liver axis

PubMed Central

Carotti, Simone; Guarino, Michele Pier Luca; Vespasiani-Gentilucci, Umberto; Morini, Sergio

2015-01-01

Since the introduction of the term “gut-liver axis”, many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types. PMID:26600967

Plants Consumption and Liver Health

PubMed Central

He, Qing

2015-01-01

The liver is a very important organ with a lot of functions for the host to survive. Dietary components are essential for and can be beneficial or detrimental to the healthy or diseased liver. Plants food is an essential part of the human diet and comprises various compounds which are closely related to liver health. Selected food plants can provide nutritional and medicinal support for liver disease. At the present, the knowledge of the effects of plants on the liver is still incomplete. The most urgent task at the present time is to find the best dietary and medicinal plants for liver health in an endless list of candidates. This review article updates the knowledge about the effects of plants consumption on the health of the liver, putting particular emphasis on the potential beneficial and harmful impact of dietary and medicinal plants on liver function. PMID:26221179

Platelets: No longer bystanders in liver disease

PubMed Central

Adams, David H.; Watson, Steve P.; Lalor, Patricia F.

2016-01-01

Growing lines of evidence recognize that platelets play a central role in liver homeostasis and pathobiology. Platelets have important roles at every stage during the continuum of liver injury and healing. These cells contribute to the initiation of liver inflammation by promoting leukocyte recruitment through sinusoidal endothelium. They can activate effector cells, thus amplifying liver damage, and by modifying the hepatic cellular and cytokine milieu drive both hepatoprotective and hepatotoxic processes. Conclusion: In this review we summarize how platelets drive such pleiotropic actions and attempt to reconcile the paradox of platelets being both deleterious and beneficial to liver function; with increasingly novel methods of manipulating platelet function at our disposal, we highlight avenues for future therapeutic intervention in liver disease. (Hepatology 2016;64:1774‐1784) PMID:26934463

Optimization of hybrid iterative reconstruction level in pediatric body CT.

PubMed

Karmazyn, Boaz; Liang, Yun; Ai, Huisi; Eckert, George J; Cohen, Mervyn D; Wanner, Matthew R; Jennings, S Gregory

2014-02-01

The objective of our study was to attempt to optimize the level of hybrid iterative reconstruction (HIR) in pediatric body CT. One hundred consecutive chest or abdominal CT examinations were selected. For each examination, six series were obtained: one filtered back projection (FBP) and five HIR series (iDose(4)) levels 2-6. Two pediatric radiologists, blinded to noise measurements, independently chose the optimal HIR level and then rated series quality. We measured CT number (mean in Hounsfield units) and noise (SD in Hounsfield units) changes by placing regions of interest in the liver, muscles, subcutaneous fat, and aorta. A mixed-model analysis-of-variance test was used to analyze correlation of noise reduction with the optimal HIR level compared with baseline FBP noise. One hundred CT examinations were performed of 88 patients (52 females and 36 males) with a mean age of 8.5 years (range, 19 days-18 years); 12 patients had both chest and abdominal CT studies. Radiologists agreed to within one level of HIR in 92 of 100 studies. The mean quality rating was significantly higher for HIR than FBP (3.6 vs 3.3, respectively; p < 0.01). HIR caused minimal (0-0.2%) change in CT numbers. Noise reduction varied among structures and patients. Liver noise reduction positively correlated with baseline noise when the optimal HIR level was used (p < 0.01). HIR levels were significantly correlated with body weight and effective diameter of the upper abdomen (p < 0.01). HIR, such as iDose(4), improves the quality of body CT scans of pediatric patients by decreasing noise; HIR level 3 or 4 is optimal for most studies. The optimal HIR level was less effective in reducing liver noise in children with lower baseline noise.

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

PubMed

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

2015-06-01

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

Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.

PubMed

Reuben, Adrian; Koch, David G; Lee, William M

2010-12-01

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival. Copyright © 2010 American Association for the Study of Liver Diseases.

Patent foramen ovale does not have a negative impact on early outcomes in patients undergoing liver transplantation.

PubMed

Alba, Ana Carolina; Verocai Flaman, F; Granton, J; Delgado, D H

2011-01-01

To identify the impact of the presence of patent foramen ovale (PFO) in patients undergoing liver transplantation. Twenty-seven pre-liver transplant patients who had a PFO (PFO group) were identified and compared with 61 patients without PFO (NoPFO group). Patients were matched according to age, gender and cause of liver disease. The diagnosis of PFO was made by transthoracic echocardiography prior to liver transplantation. Patient baseline characteristics and complications during the early post-transplant period were analyzed. The mean age in the PFO group was 47 ± 14 (range 18-68) yr and 50 ± 11 (range 12-65) yr in the NoPFO group. The PFO group had a mean model for end-stage liver disease (MELD) score of 15 ± 10 whereas in the NoPFO group the MELD score was 19 ± 10 (p = 0.08). There were non-significant differences in echocardiographic parameters between groups. Duration of mechanical ventilation and the incidence of neurological complications were similar. Thirty-day mortality rate was similar in both groups; only one patient in the NoPFO group died within the first 30 days post-transplantation. The presence of PFO in patients with end-stage liver disease undergoing liver transplantation does not appear to affect patient outcomes during the peri-operative period. © 2010 John Wiley & Sons A/S.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis.

PubMed

Xu, Wen Ping; Wang, Ze Rui; Zou, Xia; Zhao, Chen; Wang, Rui; Shi, Pei Mei; Yuan, Zong Li; Yang, Fang; Zeng, Xin; Wang, Pei Qin; Sultan, Sakhawat; Zhang, Yan; Xie, Wei Fen

2018-04-01

Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA + -M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA + -M2BP in evaluating liver function and predicting prognosis of cirrhotic patients. We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA + -M2BP and various biochemical parameters were measured in all patients. With a median follow-up of 23 months, liver-related complications and deaths of 160 patients were recorded. The accuracy of WFA + -M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively. WFA + -M2BP levels increased with elevated Child-Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA + -M2BP for the assessment of liver function using Child-Pugh classification. WFA + -M2BP was also significantly positively correlated with the model for end-stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA + -M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876-76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA + -M2BP as an independent risk factor for liver-related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356-82.820, P = 0.024). Serum WFA + -M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection. © 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells

PubMed Central

Werner, Melanie; Driftmann, Sabrina; Kleinehr, Kathrin; Kaiser, Gernot M.; Mathé, Zotlan; Treckmann, Juergen-Walter; Paul, Andreas; Skibbe, Kathrin; Timm, Joerg; Canbay, Ali; Gerken, Guido; Schlaak, Joerg F.; Broering, Ruth

2015-01-01

Background & Aims Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Methods Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Results Cell preparation yielded the following cell counts per gram of liver tissue: 2.0±0.4×107 hepatocytes, 1.8±0.5×106 Kupffer cells, 4.3±1.9×105 liver sinusoidal endothelial cells, and 3.2±0.5×105 stellate cells. Hepatocytes were identified by albumin (95.5±1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5±1.2%) and exhibited phagocytic activity, as determined with 1μm latex beads. Endothelial cells were CD146+ (97.8±1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1±1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Conclusions Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease. PMID:26407160

Proliferative human cell sources applied as biocomponent in bioartificial livers: a review.

PubMed

Nibourg, Geert A A; Chamuleau, Robert A F M; van Gulik, Thomas M; Hoekstra, Ruurdtje

2012-07-01

Bioartificial livers (BALs) are urgently needed to bridge severe liver failure patients to liver transplantation or liver regeneration. When based on primary hepatocytes, their efficacy has been shown in animal experiments and their safety was confirmed in clinical trials. However, a proliferative human cell source with therapeutic functionality is needed to secure availability and move BAL application forward. This review compares the performance of BALs based on proliferative human biocomponents and primary hepatocytes. This review evaluates relevant studies identified by searching the MEDLINE database until July 2011 and some of our own unpublished data. All the discussed hepatocyte-like biocomponents show deficiencies in their hepatic functionality compared with primary hepatocytes, particularly functions occurring late in liver development. Nonetheless, the HepaRG, HepG2-GS-CYP3A4, and mesenchymal stem cells show efficacy in a statistically well-powered animal model of acute liver failure, when applied in a BAL device. Various methods to gain higher functionality of BALs, including genetic modification, the usage of combinatory cell sources, and improvement of culture methods, have scarcely been applied, but may further pave the path for BAL application. Clinical implementation of a BAL based on a human proliferative biocomponent is still several years away.

Effect of a short-term physical activity intervention on liver fat content in obese children.

PubMed

Kang, Dong-Woo; Park, Ji-Hye; Lee, Mi Kyung; Kim, YoonMyung; Kong, In Deok; Chung, Choon Hee; Lee, Young Hee; Jeon, Justin Y

2018-06-01

Nonalcoholic fatty liver disease is the most common chronic liver disease and can present with advanced fibrosis or nonalcoholic steatohepatitis. The purpose of this study was to investigate the effect of a 7-day intense physical activity intervention on liver fat content in children with obesity. Fifty-seven obese children (mean body mass index: 26.5 ± 3.2 kg/m 2 ; mean age: 12.0 ± 0.8 years) participated in a 7-day physical activity program. All participants were housed together, and their food intake and energy expenditure were strictly controlled. Anthropometric measurements, abdominal computerized tomography scans, and blood analyses were conducted at baseline and post-intervention. Participants lost weight by 2.53 ± 0.85 kg on average (61.0 ± 9.8 vs. 58.5 ± 9.5 kg, p < 0.05), fat mass (16.7 ± 5.1 vs. 15.7 ± 4.9 kg, p < 0.05), and serum insulin (13.7 ± 6.7 vs. 3.5 ± 2.0 μU/mL, p < 0.05). However, liver fat content was increased, presented as liver-to-spleen ratio (LSR) where lower LSR represents higher liver fat content. The intervention increased aspartate transaminase level (29.42 ± 6.78 IU/L vs. 33.50 ± 9.60 IU/L, p < 0.001). The change in liver fat content was not associated with the change in fasting insulin and liver enzymes. Short-term intense physical activity increased liver fat content independent of change in fasting insulin level and liver enzymes. This is the first human study to report increased liver fat content after physical activity-induced rapid weight loss.

Carbamazepine-hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine.

PubMed Central

Pirmohamed, M; Graham, A; Roberts, P; Smith, D; Chadwick, D; Breckenridge, A M; Park, B K

1991-01-01

1. Seven patients clinically diagnosed as being hypersensitive to carbamazepine and one patient hypersensitive to both carbamazepine and oxcarbazepine have been identified. They have been compared with a control group (hereafter referred to as 'control subjects') comprising five patients on chronic carbamazepine therapy without adverse effects and 12 healthy volunteers who have never been exposed to anticonvulsants. 2. An in vitro cytotoxicity assay employing mononuclear leucocytes as target cells has been used first, to determine the ability of 10 different human livers to bioactivate carbamazepine to a cytotoxic metabolite, and secondly, to compare the cell defences of carbamazepine-hypersensitive patients and control subjects to oxidative drug metabolites generated by a murine microsomal system, using a blinded protocol. 3. With human liver microsomes, the metabolism-dependent cytotoxicity of carbamazepine increased with increasing microsomal protein concentration. At a protein concentration of 2 mg per incubation, the cytotoxicity of carbamazepine with human liver microsomes (n = 10 livers) increased from 7.2 +/- 0.8% (baseline) to 16.4 +/- 2.1% (with NADPH; P = 0.002). 4. In the presence of phenobarbitone-induced mouse microsomes and NADPH, the mean increase in cytotoxicity above the baseline with carbamazepine was significantly greater (P less than 0.001) for the cells from the carbamazepine-hypersensitive patients (7.9 +/- 0.8%) than from control subjects (2.6 +/- 0.3%). 5. In the presence of phenobarbitone-induced mouse microsomes and NADPH, there was no significant difference in cytotoxicity between the cells from carbamazepine hypersensitive patients and from control subjects in the presence of either phenytoin or oxcarbazepine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1768568

Enhanced resolution of eosinophilic liver abscess associated with toxocariasis by albendazole treatment.

PubMed

Jang, Eun Young; Choi, Moon Seok; Gwak, Geum Youn; Koh, Kwang Cheol; Paik, Seung Woon; Lee, Joon Hyeok; Paik, Yong Han; Yoo, Byung Chul

2015-04-01

Visceral larva migrans, caused by Toxocara canis and Toxocara cati, has emerged as a significant cause of eosinophilic liver abscess (ELA). Differentiation of ELA associated with toxocariasis (ELA-T) from metastasis or primary liver malignancy is sometimes difficult. However, the role of albendazole treatment remains uncertain in this condition. The aim of this study was to evaluate whether albendazole can enhance the radiologic resolution of ELA-T. We retrospectively reviewed the medical records of the patients diagnosed with ELA-T at our institution between January 2008 and December 2011. ELA-T was diagnosed based on the imaging findings on computed tomography or magnetic resonance imaging and the presence of positive serum IgG antibody for Toxocara canis. Among a total of 163 patients, 32 patients received albendazole (albendazole group) and 131 did not (control group). Baseline characteristics and fate of liver nodules were compared between the two groups. Baseline characteristics (age, sex, number and maximal size of lesions, eosinophil count) were similar between the two groups. Median duration for achieving radiologic resolution in the albendazole group was significantly shorter than in the control group (207 days [range 186-228] vs. 302 days [range 224-380], p=0.023). In Cox regression analysis of the cumulative rates of radiologic resolution, the hazard ratio for albendazole treatment was 1.99 (95% confidence interval, 1.22-3.23). Radiologic resolution of ELA-T can be accelerated with albendazole treatment. Hence, inconvenience associated with long-term follow-up and unnecessary worries among patients can be eliminated with albendazole treatment.

Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population.

PubMed

Hsieh, S; Leaderer, B P; Feldstein, A E; Santoro, N; McKay, L A; Caprio, S; McConnell, R

2018-06-01

Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO 2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO 2 increased from 8 to 10 ppb. Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry. © 2017 World Obesity Federation.

Albumin in chronic liver disease: structure, functions and therapeutic implications.

PubMed

Spinella, Rosaria; Sawhney, Rohit; Jalan, Rajiv

2016-01-01

Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.

Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study.

PubMed

Hirschfield, Gideon M; Gershwin, M Eric; Strauss, Richard; Mayo, Marlyn J; Levy, Cynthia; Zou, Bin; Johanns, Jewel; Nnane, Ivo P; Dasgupta, Bidisha; Li, Katherine; Selmi, Carlo; Marschall, Hanns-Ulrich; Jones, David; Lindor, Keith

2016-07-01

The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67× upper limit of normal [ULN] after ≥6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.67×-2.8× ULN) or <1.67× ULN (if baseline ALP >2.8× ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 μmol/L); 13 of 20 (65%) patients had baseline ALP >3× ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 μmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (Hepatology 2016;64:189-199). © 2015 by the American Association for the Study of Liver Diseases.

The liver in regulation of iron homeostasis.

PubMed

Rishi, Gautam; Subramaniam, V Nathan

2017-09-01

The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. Copyright © 2017 the American Physiological Society.

Differential Location and Distribution of Hepatic Immune Cells

PubMed Central

Freitas-Lopes, Maria Alice; Mafra, Kassiana; David, Bruna A.; Carvalho-Gontijo, Raquel; Menezes, Gustavo B.

2017-01-01

The liver is one of the main organs in the body, performing several metabolic and immunological functions that are indispensable to the organism. The liver is strategically positioned in the abdominal cavity between the intestine and the systemic circulation. Due to its location, the liver is continually exposed to nutritional insults, microbiota products from the intestinal tract, and to toxic substances. Hepatocytes are the major functional constituents of the hepatic lobes, and perform most of the liver’s secretory and synthesizing functions, although another important cell population sustains the vitality of the organ: the hepatic immune cells. Liver immune cells play a fundamental role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. Here we discuss the location of these pivotal cells within the different liver compartments, and how their frequency and tissular location can dictate the fate of liver immune responses. PMID:29215603

[The current state of the surgery of portal hypertension].

PubMed

Mercado, M A; Orozco, H

1992-01-01

Surgery for bleeding portal hypertension has evolved widely in the last decades. The surgical procedures that preserve portal blood flow are the first operative choice for well selected patients. Operative procedures that deprive the portal blood flow to the liver, are most likely to promote deterioration of liver function in the late postoperative period. The operation most frequently performed are the selective shunts (Warren) and the thoraco abdominal devascularization (Sugiura). The best results are obtained in patients with a good liver function that are operated in an elective fashion. Non-selective shunts have a restricted indication and low diameter porto systemic shunts are still under evaluation. The combination of drug therapy and/or sclerotherapy with surgery appears to improve survival. Liver transplants are indicated for those patients with associated liver failure. For patients with good liver function, surgery is the therapy of choice.

Manganese chloride tetrahydrate (CMC-001) enhanced liver MRI: evaluation of efficacy and safety in healthy volunteers.

PubMed

Albiin, Nils; Kartalis, Nikolaos; Bergquist, Annika; Sadigh, Bita; Brismar, Torkel B

2012-10-01

To evaluate the efficacy of three dose levels of the oral hepatobiliary manganese-based magnetic resonance imaging (MRI) contrast agent CMC-001, and assess its safety profile and patient acceptability. After ethics committee approval, 32 healthy volunteers (males/females: 18/14) were included. Liver MRI was performed before and 3 h after ingestion of 0.8, 0.4, and 0.2 g of CMC-001 on separate occasions. Liver-to-muscle signal intensity (SI) ratio from baseline to post-contrast and image quality was assessed. Adverse drug reactions/adverse events (ADRs/AEs) and clinico-laboratory tests were monitored. The increase in liver-to-muscle SI ratio was significantly higher after 0.8 g (0.696) compared to 0.4 g (0.458) and 0.2 g (0.223) (in all pair-wise comparisons, P < 0.0001). The overall image quality was superior after 0.8 g. ADRs/AEs were dose-related and predominantly of mild intensity. Liver MRI using 0.8 g CMC-001 has the highest efficacy and still acceptable ADRs and should therefore be preferred.

Changes in Liver Metabolic Gene Expression after Radiation Exposure

NASA Technical Reports Server (NTRS)

Peters, C. P.; Wotring, Virginia E.

2012-01-01

The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments.

Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.

PubMed

Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

2016-07-01

Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD. © 2016 American Association for the Study of Liver Diseases.

Gut microbial balance and liver transplantation: alteration, management, and prediction.

PubMed

Tian, Xinyao; Yang, Zhe; Luo, Fangzhou; Zheng, Shusen

2018-04-01

Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia-reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

Muscular exercise can cause highly pathological liver function tests in healthy men

PubMed Central

Pettersson, Jonas; Hindorf, Ulf; Persson, Paula; Bengtsson, Thomas; Malmqvist, Ulf; Werkström, Viktoria; Ekelund, Mats

2008-01-01

Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice. What is already known about this subject The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals.Physical exercise can result in transient elevations of liver function tests.There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting.Liver function tests are significantly increased for at least 7 days after weightlifting.It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. PMID:17764474

Muscular exercise can cause highly pathological liver function tests in healthy men.

PubMed

Pettersson, Jonas; Hindorf, Ulf; Persson, Paula; Bengtsson, Thomas; Malmqvist, Ulf; Werkström, Viktoria; Ekelund, Mats

2008-02-01

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. Physical exercise can result in transient elevations of liver function tests. There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. Liver function tests are significantly increased for at least 7 days after weightlifting. It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (gamma GT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10-12 days postexercise. Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, gamma GT and ALP remained within the normal range. The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.

Do older patients utilize excess health care resources after liver transplantation?

PubMed

Shankar, Neil; AlBasheer, Mamoun; Marotta, Paul; Wall, William; McAlister, Vivian; Chandok, Natasha

2011-01-01

Liver transplantation is a highly effective treatment for end-stage liver disease. However, there is debate over the practice of liver transplantation in older recipients (age ≥ 60 years) given the relative shortage of donor grafts, worse post-transplantation survival, and concern that that older patients may utilize excess resources postoperatively, thus threatening the economic feasibility of the procedure. To determine if patients ≥ 60 years of age utilize more health resources following liver transplantation compared with younger patients. Consecutive adult patients who underwent primary liver transplantation (n = 208) at a single center were studied over a 2.5-year period. Data were collected on clinico-demographic characteristics and resource utilization. Descriptive statistics, including means, standard deviations, or frequencies were obtained for baseline variables. Patients were stratified into 2 groups: age ≥ 60 years (n = 51) and < 60 years (n = 157). The Chi-Square Test, Mantel-Haenszel Test, 2-sample test and odds ratios were calculated to ascertain associations between age and resource utilization parameters. Regression analyses were adjusted for model for end-stage liver disease score, location before surgery, diabetes mellitus, donor age, cold ischemia time, albumin, and diagnosis of hepatitis C. Recipients ≥ 60 years of age have similar lengths of hospitalization, re-operative rates, need for consultative services and readmission rates following liver transplantation, but have longer lengths of stay in the intensive care (hazard ratio 1.97, p = 0.03). Overall, liver transplant recipients ≥ 60 years of age utilize comparable resources following LT vs. younger recipients. Our findings have implications on cost-containment policies for liver transplantation.

Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration | Center for Cancer Research

Cancer.gov

The liver has an exceptional capacity to proliferate. This ability allows the liver to regenerate its mass after partial surgical removal or injury and is the key to successful partial liver transplants. Liver cells, called hepatocytes, are packed with mitochondria, and regulating mitochondrial DNA (mtDNA) copy number is crucial to mitochondrial function, including energy production, during proliferation. Yves Pommier, M.D., Ph.D., of CCR’s Developmental Therapeutics Branch, and his colleagues recently showed that the vertebrate mitochondrial topoisomerase, Top1mt, was critical in maintaining mitochondrial function in the heart after doxorubicin-induced damage. The group wondered whether Top1mt might play a similar role in liver regeneration.

Drug Metabolism, Drug Interactions, and Drug-Induced Liver Injury in Living Donor Liver Transplant Patients.

PubMed

Ganesh, Swaytha; Almazroo, Omar Abdulhameed; Tevar, Amit; Humar, Abhinav; Venkataramanan, Raman

2017-02-01

Living donor liver transplant (LDLT) fills a critically needed gap in the number of livers available for transplant. However, little is known about the functional recovery of the liver in the donor and in the recipient after surgery. Given that both donor and recipients are treated with several drugs, it is important to characterize the time course of recovery of hepatic synthetic, metabolic, and excretory function in these patients. In the absence of data from LDLT, information on the effect of liver disease on the pharmacokinetics of medications can be used as guidance for drug dosing in LDLT patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of L-Carnitine in Patients With Liver Cirrhosis on Energy Metabolism Using Indirect Calorimetry: A Pilot Study.

PubMed

Sakai, Yoshiyuki; Nishikawa, Hiroki; Enomoto, Hirayuki; Yoh, Kazunori; Iwata, Yoshinori; Hasegawa, Kunihiro; Nakano, Chikage; Kishino, Kyohei; Shimono, Yoshihiro; Takata, Ryo; Nishimura, Takashi; Aizawa, Nobuhiro; Ikeda, Naoto; Takashima, Tomoyuki; Ishii, Akio; Iijima, Hiroko; Nishiguchi, Shuhei

2016-12-01

L-carnitine supplementation has been suggested to show several favorable effects on patients with liver cirrhosis (LC). However, there have been no reports regarding the effect of L-carnitine on energy metabolism in patients with LC using indirect calorimetry which is a well-established method for assessing the degree of liver malnutrition. We examined the effect of L-carnitine in patients with LC on energy metabolism using indirect calorimetry. A total of 13 LC patients who are scheduled to be treated with L-carnitine (1,800 mg/day) were analyzed in this study. None of the patients previously received L-carnitine. An evaluation of the nutritional status was performed at the initiation of L-carnitine therapy and after 4 weeks of L-carnitine therapy. We evaluated the effect of L-carnitine on the nutritional status and energy metabolism by comparing various clinical variables at these two time points. In addition, the changes in the nutritional status of the patients were also evaluated using indirect calorimetry. After 4 weeks of L-carnitine treatment, for all cases, the mean substrate oxidation rates of carbohydrate (%C) increased from 37.6% to 48.2%, the mean substrate oxidation rates of fat (%F) decreased from 40.2% to 31.9% and the mean substrate oxidation rates of protein (%P) decreased from 22.2% to 19.9%. In a subgroup analysis of patients with baseline non-protein respiratory quotient (npRQ) < 0.85, the mean %C increased from 15.3% to 34.2%, the mean %F decreased from 59.9% to 45.1%, and the mean %P decreased from 24.8% to 20.6%. After 4 weeks of L-carnitine treatment, for all cases (n = 13), the mean value of npRQ increased in comparison with the baseline levels, although the difference was not significant (0.868 ± 0.060 vs. 0.838 ± 0.097, P = 0.19). Conversely, in patients with baseline npRQ < 0.85, the npRQ value significantly increased after 4 weeks treatment of L-carnitine compared with the baseline levels (0.827 ± 0.030 vs. 0.760 ± 0.043, P = 0.016). L-carnitine supplementation can be useful for improving energy metabolism, especially in patients who have an advanced LC status and lower baseline npRQ values.

Protein C activity and postoperative metabolic liver function after liver transplantation.

PubMed

Wagener, G; Diaz, G; Guarrera, J V; Minhaz, M; Renz, J F; Sladen, R N

2012-06-01

Protein C is a natural thrombin antagonist produced by hepatocytes. Its levels are low in liver failure and predispose patients to increased risk for thrombosis. Little is known about the relationship between protein C activity and hepatic function after orthotopic liver transplantation (OLT). We measured protein C activity of 41 patients undergoing liver transplantation by the Staclot method (normal range, 70%-130%) preoperatively and then daily on postoperative days (POD) 0-5. The mean protein C activity was low before OLT (34.3 ± 4.3%) and inversely correlated with the preoperative Model for End-Stage Liver Disease score (Spearman's r = -0.643; P < .0001). Mean activity increased significantly on POD 1 (58.9 ± 4.5%), and remained above preoperative levels through POD 5. Ten patients developed metabolic liver dysfunction defined by a serum total bilirubin >5 mg/dL on POD 7. These patients had significantly lower protein C activity from POD 3 (47.2 ± 9.6% vs 75.9 ± 5.8%; P = .01) to POD 5. Preoperative protein C activity correlated inversely with the severity of liver failure as indicated by preoperative MELD score. Protein C activity recovered rapidly in patients with good allograft function but remained significantly lower in patients who had limited metabolic function as evidenced by increased total bilirubin levels. Copyright © 2012 Elsevier Inc. All rights reserved.

Effect of evacuation on liver function after the Fukushima Daiichi Nuclear Power Plant accident: The Fukushima Health Management Survey.

PubMed

Takahashi, Atsushi; Ohira, Tetsuya; Hosoya, Mitsuaki; Yasumura, Seiji; Nagai, Masato; Ohira, Hiromasa; Hashimoto, Shigeatsu; Satoh, Hiroaki; Sakai, Akira; Ohtsuru, Akira; Kawasaki, Yukihiko; Suzuki, Hitoshi; Kobashi, Gen; Ozasa, Kotaro; Yamashita, Shunichi; Kamiya, Kenji; Abe, Masafumi

2017-04-01

The Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident caused residents to switch from their normal lives to lives focused on evacuation. We evaluated liver function before and after this disaster to elucidate the effects of evacuation on liver function. This study was a longitudinal survey of 26,006 Japanese men and women living near the Fukushima Daiichi Nuclear Power Plant. This study was undertaken using data from annual health checkups conducted for persons aged 40-90 years between 2008 and 2010. Follow-up examinations were conducted from June 2011 to the end of March 2013, with a mean follow up of 1.6 years. Changes in liver function before and after the disaster were compared among evacuees and non-evacuees. We also assessed groups according to alcohol drinking status. The prevalence of liver dysfunction significantly increased in all participants from 16.4% before to 19.2% after the disaster. The incidence of liver dysfunction was significantly higher in evacuees than in non-evacuees. Multivariate logistic regression analysis showed that evacuation was significantly associated with liver dysfunction among residents. This is the first study to show that evacuation due to the Fukushima Daiichi nuclear power plant disaster was associated with an increase in liver dysfunction. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Valproic acid induced hyperammonaemic encephalopathy.

PubMed

Amanat, Saima; Shahbaz, Naila; Hassan, Yasmin

2013-01-01

To observe clinical and laboratory features of valproic acid-induced hyperammonaemic encephalopathy in patients taking valproic acid. Observational study was conducted at the Neurology Department, Dow University of Health Sciences, Civil Hospital, Karachi, from February 26, 2010 to March 20, 2011. Ten patients on valproic acid therapy of any age group with idiopathic or secondary epilepsy, who presented with encephalopathic symptoms, were registered and followed up during the study. Serum ammonia level, serum valproic acid level, liver function test, cerebrospinal fluid examination, electroencephalogram and brain imaging of all the patients were done. Other causes of encephalopathy were excluded after clinical and appropriate laboratory investigations. Microsoft Excell 2007 was used for statistical analysis. Hyperammonaemia was found in all patients with encephalopathic symptoms. Rise in serum ammonia was independent of dose and serum level of valproic acid. Liver function was also found to be normal in 80% (n = 8) of the patients. Valproic acid was withdrawn in all patients. Three (30%) patients improved only after the withdrawal of valproic acid. Six (60%) patients improved after L-Carnitine replacement, one (10%) after sodium benzoate. On followup, serum ammonia had reduced to normal in five (50%) patients and to more than half of the baseline level in two (20%) patients. Three (30%) patients were lost to followup after complete clinical improvement. Within therapeutic dose and serum levels, valproic acid can cause symptomatic hyperammonaemia resulting in encephalopathy. All patients taking valproic acid presenting with encephalopathic symptoms must be monitored for the condition.

Checking physical care of people on risperidone long term injectable depot.

PubMed

Najim, Hellme; Islam, Nazrul

2013-09-01

To assess the existing physical care of patients with severe mental illness and whether it has complied with national protocols and guidelines. Medical notes of patients who has been on risperidone long acting injectable depot for a year were reviewed and a form was filled with the information of each patient including weight, physical examination, fasting blood sugar (FBS), Serum lipid (S.L.), pulse, blood pressure and ECG liver function tests (LFT). 50% had comorbidity with other physical illness, at the start of treatment, at three months and six months intervals. 65 notes were reviewed. 70% males. 70% between 18-50 years. 80% had the illness more than 5 years and 50% more than 10 years. The following was done baseline: 50% had physical examination. 25% had pulse, blood pressure and ECG. Body weight 10%. Triglycerides 20%. Urea and electrolytes (U&E) 15%. 40% had their liver function tests (LFT). 50% had comorbidity with other physical illness. The following were done on six monthly maintenance measures: Only 5% had maintenance ECG. LFT 10%. U&E 30%. Triglycerides 5%. Physical illnesses are neglected areas in the care of the severely mentally ill patients. It is an important area in the management of severe mental illness. Proper physical assessment and regular follow up should be adopted. Promotion of healthy living and eating, exercise and monitoring weight should be recommended. All these measures may improve the physical health of severely mentally ill patients and improve the total outcome of these illnesses.

Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study

PubMed Central

2012-01-01

Background Mistletoe (Viscum album L.) extracts are widely used in complementary cancer therapy. Aim of this study was to evaluate safety and efficacy of a standardized mistletoe extract (abnobaVISCUM® Quercus, aVQ) in patients with gastric cancer. Patients and Methods 32 operated gastric cancer patients (stage Ib or II) who were waiting for oral chemotherapy with the 5-FU prodrug doxifluridine were randomized 1:1 to receive additional therapy with aVQ or no additional therapy. aVQ was injected subcutaneously three times per week from postoperative day 7 to week 24 in increasing doses. EORTC QLQ-C30 and -STO22 Quality of Life questionnaire, differential blood count, liver function tests, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-2), CD 16+/CD56+ and CD 19+ lymphocytes were analyzed at baseline and 8, 16 and 24 weeks later. Results Global health status (p <0.01), leukocyte- and eosinophil counts (p ≤0.01) increased significantly in the treatment group compared to the control group. Diarrhea was less frequently reported (7% vs. 50%, p=0.014) in the intervention group. There was no significant treatment effect on levels of TNF-alpha, IL-2, CD16+/CD56+ and CD 19+ lymphocytes and liver function tests measured by ANOVA. Conclusion Additional treatment with aVQ is safe and was associated with improved QoL of gastric cancer patients. ClinicalTrials.Gov Registration number NCT01401075. PMID:23033982

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

PubMed

Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

2016-12-14

To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves.

PubMed

Marinò, M; Morabito, E; Altea, M A; Ambrogini, E; Oliveri, F; Brunetto, M R; Pollina, L E; Campani, D; Vitti, P; Bartalena, L; Pincheral, A; Marcocci, C

2005-03-01

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves' ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation.

PubMed

Mergental, H; Perera, M T P R; Laing, R W; Muiesan, P; Isaac, J R; Smith, A; Stephenson, B T F; Cilliers, H; Neil, D A H; Hübscher, S G; Afford, S C; Mirza, D F

2016-11-01

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT. © Copyright 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Liver function in cats with hyperthyroidism before and after 131I therapy.

PubMed

Berent, Allyson C; Drobatz, Kenneth J; Ziemer, Lisa; Johnson, Victoria S; Ward, Cynthia R

2007-01-01

The clinical significance of high serum concentration or activity of markers of liver damage in cats with hyperthyroidism is unknown. To evaluate serum markers of liver function and damage, and ultrasonographic changes in cats with hyperthyroidism and with high liver enzymes, and to determine if abnormalities resolve after treatment with 131I. Nineteen cats with hyperthyroidism (15 with high serum activities of liver enzymes) and 4 age-matched healthy control cats. Serum bile acids, albumin, ammonia, cholesterol, and blood urea nitrogen concentrations, and activities of liver-derived enzymes, and blood glucose concentrations were measured before and after 131I therapy. These values were compared with those of cats that were euthyroid. In addition, gross liver parenchymal changes detected by abdominal ultrasonographic examination, before and after 131I therapy were evaluated. High serum liver enzyme activities were not associated with abnormalities in hepatic parenchyma and liver functional variables, regardless of the degree of increase. Serum liver enzyme activities return to normal after control of hyperthyroidism with 131I therapy. Cats with hyperthyroidism have a significantly higher serum fasting ammonia concentration than cats who were euthyroid (P = .019). Cats with hyperthyroidism also have significantly lower serum cholesterol (P = .005) and glucose (P = .002) concentrations before compared with after 131I therapy. Nine of 19 cats with hyperthyroidism had trace ketonuria. These results demonstrate that extensive examination for hepatobiliary disease in most cats with hyperthyroidism is unnecessary.

Normothermic extracorporeal perfusion of isolated porcine liver after warm ischaemia: a preliminary report.

PubMed

Bellomo, Rinaldo; Suzuki, Satoshi; Marino, Bruno; Starkey, Graeme K; Chambers, Brenton; Fink, Michael A; Wang, Bao Zhong; Houston, Shane; Eastwood, Glenn; Calzavacca, Paolo; Glassford, Neil; Skene, Alison; Jones, Daryl A; Jones, Robert

2012-09-01

Liver transplantation is a major life-saving procedure, and donation after cardiac death (DCD) has increased the pool of potential liver donors. However, DCD livers are at increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to protect, evaluate and, in future, transplant DCD livers. We conducted proof-of-concept experiments using a DCD model in the pig to assess the short-term (4 hours) feasibility and functional efficacy of NELP. Using extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion, and physiological perfusion pressures, we achieved NELP and evidence of function (bile production, paracetamol removal, maintenance of normal ammonia and lactate levels) for 4 hours in pig livers subjected to 15 and 30 minutes of cardiac arrest before explantation. Our experiments justify further investigations of the feasibility and efficacy of human DCD liver preservation by ex-vivo perfusion.

Delayed gastric emptying of both the liquid and solid components of a meal in chronic liver disease.

PubMed

Galati, J S; Holdeman, K P; Dalrymple, G V; Harrison, K A; Quigley, E M

1994-05-01

To evaluate gastric emptying in patients with chronic liver disease and portal hypertension. We measured gastric emptying of both the liquid and solid components of a meal in 10 consecutive patients with chronic liver disease and portal hypertension, but free of ascites, and 14 age- and sex-matched healthy controls. In the patients with liver disease, relationships between emptying and liver function were examined. To measure gastric emptying, subjects consumed a test meal that consisted of scrambled eggs labeled with 99mTc-sulfur colloid and 4 oz of water labeled with 111In-diethylene triamine pentacetic acid (DTPA). Patients with liver disease and portal hypertension demonstrated delayed emptying of both the liquid (t1/2, min, mean +/- SE, patients vs. 69.4 +/- 19.4 vs. 31.4 +/- 1.8, p < 0.01) and solid (post-lag phase solid emptying: 141 +/- 32.9 vs. 69.8 +/- 4.6, p < 0.006) components of the meal. We could not identify any correlation between gastric emptying and tests of liver function. Gastric emptying is delayed in patients with liver disease and portal hypertension; this abnormal gastric motor function may contribute to the pathophysiology of foregut complaints in this patient population.

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

PubMed Central

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

2011-01-01

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

Body mass index, waist circumference, type 2 diabetes mellitus and risk of liver cancer for U.S. adults

PubMed Central

Campbell, Peter T.; Newton, Christina C.; Freedman, Neal D.; Koshiol, Jill; Alavanja, Michael C.; Beane Freeman, Laura E.; Buring, Julie E.; Chan, Andrew T.; Chong, Dawn Q.; Datta, Mridul; Gaudet, Mia M.; Gaziano, J. Michael; Giovannucci, Edward; Graubard, Barry; Hollenbeck, Albert R.; King, Lindsey; Lee, I-Min; Linet, Martha; Palmer, Julie; Petrick, Jessica L.; Poynter, Jenny N.; Purdue, Mark; Robien, Kim; Rosenberg, Lynn; Sahasrabuddhe, Vikrant; Schairer, Catherine; Sesso, Howard D.; Sigurdson, Alice; Stevens, Victoria L.; Wactowski-Wende, Jean; Zeleniuch-Jacquotte, Anne; Renehan, Andrew G.; McGlynn, Katherine A.

2016-01-01

Incidence rates for liver cancer have increased threefold since the mid-1970s in the United States in parallel with increasing trends for obesity and type 2 diabetes mellitus (T2DM). We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and T2DM with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and T2DM). Stratified analyses assessed whether the BMI-liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n=220) and controls (n=547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR: 1.38; 95% CI: 1.30 to 1.46) than women (HR: 1.25; 95% CI: 1.17 to 1.35; p-interaction: 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR: 1.08; 95% CI: 1.04 to 1.13). T2DM was associated with higher risk of liver cancer (HR: 2.61; 95% CI: 2.34 to 2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and T2DM are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. PMID:27742674

Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice.

PubMed

Ming, Ya-Nan; Zhang, Jing-Yi; Wang, Xiao-Lin; Li, Chun-Min; Ma, Si-Cong; Wang, Zheng-Yang; Liu, Xiao-Lin; Li, Xiao-Bo; Mao, Yi-Min

2017-08-14

Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice. A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high-throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot. Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt). Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver.

Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.

PubMed

Kitson, Matthew T; Sarrazin, Christoph; Toniutto, Pierluigi; Eslick, Guy D; Roberts, Stuart K

2014-12-01

The baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. Two reviewers searched four electronic databases (Medline, Embase, PubMed, and Cochrane trials register) and relevant international conference proceedings up to March 2014 for studies treating chronic HCV infection with PEG-IFN plus RBV where baseline 25(OH)D level was tested. Studies involving patients with HIV co-infection, previous liver transplantation or those receiving vitamin D supplementation were excluded. The mean baseline 25(OH)D level was compared between those who achieved and those who failed to achieve SVR. Pooled standard difference in mean 25(OH)D level, odds ratios (OR) and 95% confidence intervals (CI) were calculated with the Comprehensive Meta-Analysis software (version 2.0) using a random effects model. 11 studies comprising 2605 patients were included in the meta-analysis. There was no significant association between the baseline mean 25(OH)D level and SVR (OR 1.44, 95% CI 0.92-2.26; p=0.11), either in patients infected with genotypes 1/4/5 (OR 1.48, 95% CI 0.94-2.34; p=0.09) or genotypes 2/3 (OR 1.51, 95% CI 0.26-8.87; p=0.65). The baseline 25(OH)D level is not associated with SVR to PEG-IFN plus RBV therapy in chronic HCV infection, regardless of genotype. Any effect of vitamin D supplementation on SVR is yet to be definitively determined. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

SOURCES OF VARIABILITY IN BASELINE GENE EXPRESSION IN RAT LIVER AND KIDNEY

EPA Science Inventory

Toxicogenomic studies are typically variable in design, but the impact of variations in study design and conduct on control animal gene expression has not been well characterized. A working group of the Health and Environmental Sciences Institute (HESI) Technical Committee on the...

Use of OKT3 with Ciclosporin and Steroids for Reversal of Acute Kidney and Liver Allograft Rejection 1

PubMed Central

Fung, John J.; Demetris, A. Jake; Porter, Kendrick A.; Iwatsuki, Shunzaburo; Gordon, Robert D.; Esquivel, Carlos O.; Jaffe, Ronald; Tzakis, Andreas; Shaw, Byers W.; Starzl, Thomas E.

2010-01-01

OKT3 monoclonal antibody therapy was added to preexisting baseline immunosuppressive treatment with ciclosporin and steroids to treat rejection in 52 recipients of cadaveric livers and 10 recipients of cadaveric kidneys. Rejection was controlled in 75% of patients treated, often after high-dose steroid therapy had failed. Rejection recurred during the 17-month follow-up period, after completion of OKT3, in only 25% of the patients who had responded. The safety and effectiveness of this monoclonal therapy, added to ciclosporin and steroids, has been established in this study. PMID:3306422

Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis.

PubMed

Petta, Salvatore; Adinolfi, Luigi Elio; Fracanzani, Anna Ludovica; Rini, Francesca; Caldarella, Rosalia; Calvaruso, Vincenza; Cammà, Calogero; Ciaccio, Marcello; Di Marco, Vito; Grimaudo, Stefania; Licata, Anna; Marrone, Aldo; Nevola, Riccardo; Pipitone, Rosaria Maria; Pinto, Antonio; Rinaldi, Luca; Torres, Daniele; Tuttolomondo, Antonino; Valenti, Luca; Fargion, Silvia; Craxì, Antonio

2018-07-01

Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT ≥1 mm) and carotid plaques, defined as focal thickening of ≥1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 ± 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 ± 0.29 mm, 42.8% had IMT ≥1 mm, and 42.8% had carotid plaques. All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 ± 0.29 mm vs. 0.81 ± 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity. HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Thymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats.

PubMed

Asgharzadeh, Fereshteh; Bargi, Rahimeh; Beheshti, Farimah; Hosseini, Mahmoud; Farzadnia, Mehdi; Khazaei, Majid

2017-01-01

Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats. Fifty male Wistar rats were randomly divided into five groups (n=10 in each group) as follow: (1) control; (2) LPS (1 mg/kg/day; i.p); (3) LPS+TQ 2 mg/kg/day (i.p) (LPs+TQ2); (4) LPS+TQ 5 mg/kg/day (LPS+TQ5); (5) LPS+ TQ 10 mg/kg/day (LPS+ TQ10). After three weeks, blood samples were taken for evaluation of liver function tests. Then, the livers were harvested for histological evaluation of fibrosis and collagen content and measurement of oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase activity in tissue homogenates. LPS group showed higher levels of fibrosis and collagen content stained by Masson's trichrome in liver tissue with impaired liver function test and increased oxidative stress markers (p<0.05). Treatment by TQ restored liver fibrosis, improved liver function tests and increased the levels of anti-oxidative enzymes (SOD and catalase), while reduced MDA concentration (p<0.05). Treatment by TQ restores inflammation-induced liver fibrosis possibly through affecting oxidative stress status. It seems that administration of TQ can be considered as a part of liver fibrosis management.

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

PubMed Central

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

2006-01-01

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

Approach to the patient with abnormal liver tests.

PubMed

Mahl, T C

1998-01-01

Patients with abnormal liver blood tests are frequently encountered by primary care practitioners. An understanding of the cellular implications of these abnormalities is helpful in determining the etiology of liver injury. Elevated serum aminotransferases suggest injury of hepatocytes. Elevations in alkaline phosphatase suggest injury to any part of the biliary tree. Neither of these enzymes measures liver function. Serum bilirubin and albumin levels, as well as prothrombin time, do measure function and can be used in conjunction with the physical examination and the specific etiology of the patient's disorder to determine a patient's prognosis. Many diverse disorders result in similar biochemical patterns of liver injury. The history, physical examination, and use of specific disease markers (hepatitis serology, autoimmune markers, and so forth) help to narrow the differential diagnosis. The definitive diagnosis of all liver diseases usually rests on histology: the liver biopsy is the gold standard. With the advent of treatments for liver disease, identifying and accurately diagnosing patients with liver disorders will result in improved quality of life and survival.

Stopping Liver Cancer's Rogue COP | Center for Cancer Research

Cancer.gov

Liver cancer is the fourth most common cancer type and the third leading cause of cancer death worldwide. Many liver tumors are actually metastases, tumors seeded in the liver by cancer cells from another organ, but hepatocellular carcinomas (HCCs), the most common liver tumors, are a heterogeneous family of cancers that arise in hepatocytes, the functional cells of the liver.

Liver Function Indicators Performed Better to Eliminate Cardioembolic Stroke than to Identify It from Stroke Subtypes.

PubMed

Tan, Ge; Yuan, Ruozhen; Hao, Zilong; Lei, Chunyan; Xiong, Yao; Xu, Mangmang; Liu, Ming

2017-01-01

Identifying the etiology of ischemic stroke is essential to acute management and secondary prevention. The value of liver function indicators in differentiating stroke subtypes remains to be evaluated. A total of 1333 acute ischemic stroke patients were included. Liver function indicators collected within 24 hours from stroke onset, including alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin (BILI), were collapsed into quartiles (Q) and also dichotomized by Q1. Multivariate regression analysis was conducted to identify the independent association between liver function indicators and cardioembolic stroke (SCE). Area under the curve (AUC) of receiver operating characteristic analysis was conducted, and sensitivity (Sen), specificity (Spe), positive prospective value (PPV), and negative prospective value (NPV) were determined to evaluate the predictive value of liver function indicators for SCE. AST, GGT, and BILI were associated with SCE. After adjustment, only AST was related to SCE independently. The incidence of SCE in the Q1 of AST, GGT, and BILI, particularly in the Q1 of AST, was quite low. The ability of AST, GGT, and BILI to identify SCE was poor, with low AUC, Sen, and PPV. The value of AST, GGT, and BILI in eliminating SCE from stroke subtypes was good, with high Spe and moderate NPV, and was enhanced after combining each liver function indicator. Results of present study demonstrated that AST, GGT, and BILI, particularly AST, had a potential to eliminate SCE from stroke subtypes, and the ability of eliminating SCE would be strengthened after combining each liver function indicator together. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE).

PubMed

Donnan, Peter T; McLernon, David; Steinke, Douglas; Ryder, Stephen; Roderick, Paul; Sullivan, Frank M; Rosenberg, William; Dillon, John F

2007-04-16

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs. A population-based retrospective cohort study will follow up all those who have had an incident liver function test (LFT) in primary care to subsequent liver disease or mortality over a period of 15 years (approx. 2.3 million tests in 99,000 people). The study is set in Primary Care in the region of Tayside, Scotland (pop approx. 429,000) between 1989 and 2003. The target population consists of patients with no recorded clinical signs or symptoms of liver disease and registered with a GP. The health technologies being assessed are LFTs, viral and auto-antibody tests, ultrasound, CT, MRI and liver biopsy. The study will utilise the Epidemiology of Liver Disease In Tayside (ELDIT) database to determine the outcomes of liver disease. These are based on hospital admission data (Scottish Morbidity Record 1), dispensed medication records, death certificates, and examination of medical records from Tayside hospitals. A sample of patients (n = 150) with recent initial ALF tests or invitation to biopsy will complete questionnaires to obtain quality of life data and anxiety measures. Cost-effectiveness and cost utility Markov model analyses will be performed from health service and patient perspectives using standard NHS costs. The findings will also be used to develop a computerised clinical decision support tool. The results of this study will be widely disseminated to primary care, as well as G.I. hospital specialists through publications and presentations at local and national meetings and the project website. This will facilitate optimal decision-making both for the benefit of the patient and the National Health Service.

Impact of 'Mad Cow Disease' publicity on trends in meat and total vitamin A consumption in Geneva between 1993 and 2000.

PubMed

Sorenson, A W; Delhumeau, C; Bernstein, M S; Costanza, M C; Morabia, A

2003-01-01

In March 1996, revelations about the possible risk for humans of the 'mad cow disease' epidemic had a sudden impact on the diets of European populations. To assess changes in meat and nutrient intakes in adults living in Geneva, Switzerland from 1993 to 2000. Independent annual cross-sectional surveys (4047 women and 4092 men total). Dietary habits assessed and compared to baseline (January 1993-April 1996) via validated semi-quantitative food-frequency questionnaire. Women beef abstainers increased from 8.9 to 14.9% in late 1996 (P<0.001) and 13.3% in 1997 (P<0.05); among meat consumers, in late 1996 meat/beef intakes declined -10/-12% (both P<0.05). From 1997 to 2000 most intake levels drifted back toward those at baseline, but chicken intakes were significantly (all P<0.05) greater each year (+19% in 2000 (P<0.001). Consistent but less dramatic changes were observed among men. From late 1996 until 2000, liver abstention was significantly (all P<0.05) greater (women from 60 to 78%; men from 61 to 73% in 2000; (both P<0.001). The only nutrient intakes that decreased significantly (all P<0.05) each year from 1997 through 2000 were retinol and total vitamin A women: -22% (P<0.001); -11% (P<0.05) respectively; men: -16% (P<0.001); -10% (P<0.05) respectively, in 2000). Total vitamin A intakes exceeded the dietary reference intake (DRI) for liver eaters (women 185%, men 153%), but were below the DRI for liver abstainers (women 83%; men 66%) in 2000. The decreases in beef and liver consumption since late 1996 led to the discovery of a long-term disparity in the retinol and total vitamin A intakes of liver eaters vs abstainers.

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.

PubMed

Ryan, Marno C; Itsiopoulos, Catherine; Thodis, Tania; Ward, Glenn; Trost, Nicholas; Hofferberth, Sophie; O'Dea, Kerin; Desmond, Paul V; Johnson, Nathan A; Wilson, Andrew M

2013-07-01

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, cross-over 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ((1)H-MRS). At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M=2.7 ± 1.0 mg/kg/min(-1)). Mean weight loss was not different between the two diets (p=0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD: 39 ± 4% versus 7 ± 3%, as measured by (1)H-MRS (p=0.012). Insulin sensitivity improved with the MD, whereas after the LF/HCD there was no change (p=0.03 between diets). Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study.

PubMed

Smits, Loek P; Coolen, Bram F; Panno, Maria D; Runge, Jurgen H; Nijhof, Wouter H; Verheij, Joanne; Nieuwdorp, Max; Stoker, Jaap; Beuers, Ulrich H; Nederveen, Aart J; Stroes, Erik S

2016-03-01

To (a) study the optimal timing and dosing for ultrasmall superparamagnetic iron oxide particle (USPIO)-enhanced magnetic resonance (MR) imaging of the liver in nonalcoholic fatty liver disease, (b) evaluate whether hepatic USPIO uptake is decreased in nonalcoholic steatohepatitis (NASH), and (c) study the diagnostic accuracy of USPIO-enhanced MR imaging to distinguish between NASH and simple steatosis. This prospective study was approved by the local institutional review board, and informed consent was obtained from all patients. Quantitative R2* MR imaging of the liver was performed at baseline and 72 hours after USPIO administration in patients with biopsy-proven NASH (n = 13), hepatic steatosis without NASH (n = 11), and healthy control subjects (n = 9). The hepatic USPIO uptake in the liver was quantified by the difference in R2* (ΔR2*) between the contrast material-enhanced images and baseline images. Between-group differences in mean ΔR2* were tested with the Student t test, and diagnostic accuracy was tested by calculating the area under the receiver operating characteristic curve. Patients with NASH had a significantly lower ΔR2* 72 hours after USPIO administration when compared with patients who had simple steatosis and healthy control subjects (mean ± standard deviation for patients with NASH, 37.0 sec(-1) ± 16.1; patients with simple steatosis, 61.0 sec(-1) ± 17.3; and healthy control subjects, 72.2 sec(-1) ± 22.0; P = .006 for NASH vs simple steatosis; P < .001 for NASH vs healthy control subjects). The area under the receiver operating characteristic curve to distinguish NASH from simple steatosis was 0.87 (95% confidence interval: 0.72, 1.00). This proof-of-concept study provides clues that hepatic USPIO uptake in patients with NASH is decreased and that USPIO MR imaging can be used to differentiate NASH from simple steatosis.

Responder Interferon λ Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV-Hepatitis C Virus Coinfection.

PubMed

Moqueet, Nasheed; Cooper, Curtis; Gill, John; Hull, Mark; Platt, Robert W; Klein, Marina B

2016-07-01

Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection. From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA-positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4(+) T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58-9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94-2.02) for rs12979860CC, 1.34 (95% CI, .91-1.97) for rs8103142TT, and 1.79 (95% CI, 1.24-2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73-1.77]). IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Prospective study of bacteremia rate after elective band ligation and sclerotherapy with cyanoacrylate for esophageal varices in patients with advanced liver disease.

PubMed

Bonilha, Danielle Queiroz; Correia, Lucianna Motta; Monaghan, Marie; Lenz, Luciano; Santos, Marcus; Libera, Ermelindo Della

2011-01-01

Band ligation (BL) is the most appropriate endoscopic treatment for acute bleeding or prophylaxis of esophageal variceal bleeding. Sclerotherapy with N-butyl-2-cyanoacrylate (CY) can be an alternative for patients with advanced liver disease. Bacteremia is an infrequent complication after BL while the bacteremia rate following treatment with CY for esophageal varices remains unknown. To evaluate and compare the incidence of transient bacteremia between cirrhotic patients submitted to diagnostic endoscopy, CY and BL for treatment of esophageal varices. A prospective study comprising the period from 2004 to 2007 was conducted at Hospital of Universidade Federal de São Paulo, UNIFESP, SP, Brazil. Cirrhotic patients with advanced liver disease (Child-Pugh B or C) were enrolled. The patients were divided into two groups according treatment: BL Group (patients undergoing band ligation, n = 20) and CY Group (patients receiving cyanoacrylate injection for esophageal variceal, n = 18). Cirrhotic patients with no esophageal varices or without indication for endoscopic treatment were recruited as control (diagnostic group n = 20). Bacteremia was evaluated by blood culture at baseline and 30 minutes after the procedure. After 137 scheduled endoscopic procedures, none of the 58 patients had fever or any sign suggestive of infection. All baseline cultures were negative. No positive cultures were observed after CY or in the control group - diagnostic endoscopy. Three (4.6 %) positive cultures were found out of the 65 sessions of band ligation (P = 0.187). Two of these samples were positive for coagulase-negative staphylococcus, which could be regarded as a contaminant. The isolated microorganism in the other case was Klebsiella oxytoca. The patient in this case presented no evidence of immunodeficiency except liver disease. There was no significant difference in bacteremia rate between these three groups. BL or CY injection for non-bleeding esophageal varices may be considered as low-risk procedures regarding bacteremia even when performed on patients with advanced liver disease.

LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.

PubMed

Huang, Guanqun; Jiang, Hui; He, Yueming; Lin, Ye; Xia, Wuzheng; Luo, Yuanwei; Liang, Min; Shi, Boyun; Zhou, Xinke; Jian, Zhixiang

2018-05-15

Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

Effect of heme oxygenase-1 on the protection of ischemia reperfusion injury of bile duct in rats after liver transplantation.

PubMed

Zhan, Xi; Zhang, Zhiqing; Huang, Hanfei; Zhang, Yujun; Zeng, Zhong

2018-06-01

To investigate the effect of heme oxygenase-1 (HO-1) on the ischemic reperfusion injury (IRI) of bile duct in rat models after liver transplantation. 320 SD rats were equally and randomly divided into 5 groups, which were group A receiving injection of 3×10 8 /pfu/ml adenovirus (adv), group B with donor receiving Adv-HO-1 and recipient receiving Adv-HO-1-siRNA, group C with donor and recipient both receiving Adv-HO-1, group D with donor receiving Adv-HO-1-siRNA and recipient receiving Adv-HO-1, and group E with donor and recipient both receiving Adv-HO-1-siRNA at 24h before liver transplantation. Donor liver was stored in UW liquid at 4°C followed by measuring HO-1 level by western blot before transplantation. On d1, d3, d7 and d14, serum and liver was isolated for analysis of liver function, inflammatory cell infiltration by H&E staining, ultrastructure of liver by transmission electron microscopy as well as the expression of HO-1, Bsep, Mrp2 and Ntcp by western blot. Compared with group D and E, group B and C displayed improved liver function as demonstrated by lower level of ALT, AST, LDH, TBIL, ALP and GGT, increased secretion of TBA and PL as well as expression of transporter proteins (Bsep, Mrp2 and Ntcp), reduced inflammatory cells infiltration and liver injury. Our study demonstrated that overexpression of HO-1 in donor liver can ameliorate the damage to bile duct and liver, and improved liver function, suggesting HO-1 might be a new therapeutic target in the treatment of IRI after liver transplantation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cognition Predicts Quality of Life Among Patients With End-Stage Liver Disease.

PubMed

Paulson, Daniel; Shah, Mona; Miller-Matero, Lisa Renee; Eshelman, Anne; Abouljoud, Marwan

2016-01-01

Impaired cognitive functioning and poor quality of life (QoL) are both common among patients with end-stage liver disease; however, it is unclear how these are related. This study examines how specific cognitive domains predict QoL among liver transplant candidates by replicating Stewart and colleagues' (2010) 3-factor model of cognitive functioning, and determining how variability in these cognitive domains predicts mental health and physical QoL. The sample included 246 patients with end-stage liver disease who were candidates for liver transplant at a large, Midwestern health care center. Measures, including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Shipley Institute of Living Scale, Short-Form Health Survey-36 Version 2, and Hospital Anxiety and Depression Scale, comprised latent variables representing global intellectual functioning, psychomotor speed, and learning and memory functioning. Confirmatory factor analysis results indicate that the 3-factor solution model comprised of global intellectual functioning, psychomotor speed, and learning and memory functioning fit the data well. Addition of physical and mental health QoL latent factors resulted in a structural model also with good fit. Results related physical QoL to global intellectual functioning, and mental health QoL to global intellectual functioning and psychomotor functioning. Findings elucidate a relationship between cognition and QoL and support the use of routine neuropsychological screening with end-stage liver disease patients, specifically examining the cognitive domains of global intellectual, psychomotor, and learning and memory functioning. Subsequently, screening results may inform implementation of targeted interventions to improve QoL. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial.

PubMed

Scorletti, Eleonora; West, Annette L; Bhatia, Lokpal; Hoile, Samuel P; McCormick, Keith G; Burdge, Graham C; Lillycrop, Karen A; Clough, Geraldine F; Calder, Philip C; Byrne, Christopher D

2015-12-01

Genetic variation in both patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) influences severity of liver disease, and serum triglyceride concentrations in non-alcoholic fatty liver disease (NAFLD), but whether either genotype influences the responses to treatments is uncertain. One hundred three patients with NAFLD were randomised to omega-3 fatty acids (DHA+EPA) or placebo for 15-18months in a double blind placebo controlled trial. Erythrocyte enrichment with DHA and EPA was measured by gas chromatography. PNPLA3 and TM6SF2 genotypes were measured by PCR technologies. Multivariable linear regression and analysis of covariance were undertaken to test the effect of genotypes on omega-3 fatty acid enrichment, end of study liver fat percentage and serum triglyceride concentrations. All models were adjusted for baseline measurements of each respective outcome. Fifty-five men and 40 women (Genotypes PNPLA3 I148M, 148I/I=41, 148I/M=43, 148M/M=11; TM6SF2 E167K 167E/E=78, 167E/K+167K/K=17 participants) (mean ± SD age, 51 ± 11 years) completed the trial. Adjusting for baseline measurement, measured covariates and confounders, PNPLA3 148M/M variant was independently associated with percentage of DHA enrichment (B coefficient -1.02 (95% CI -1.97, -0.07), p=0.036) but not percentage of EPA enrichment (B coefficient -0.31 (95% CI -1.38, 0.75), p=0.56). This genotype was also independently associated with end of study liver fat percentage (B coefficient 9.5 (95% CI 2.53, 16.39), p=0.008), but not end of study triglyceride concentration (B coefficient -0.11 (95% CI -0.64, 0.42), p=0.68). PNPLA3 148M/M variant influences the changes in liver fat and DHA tissue enrichment during the trial but not the change in serum triglyceride concentration. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

PubMed

Mudaliar, Sunder; Henry, Robert R; Sanyal, Arun J; Morrow, Linda; Marschall, Hanns-Ulrich; Kipnes, Mark; Adorini, Luciano; Sciacca, Cathi I; Clopton, Paul; Castelloe, Erin; Dillon, Paul; Pruzanski, Mark; Shapiro, David

2013-09-01

Obeticholic acid (OCA; INT-747, 6α-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Effects of an oxacephem antibiotic on liver function in orthopedic surgery].

PubMed

Kuroyama, M; Otori, K; Yokota, S; Aoto, H; Sawada, M; Yago, K; Fujita, T; Kumagai, Y

1999-07-01

The subjects were 531 patients who underwent orthopedic surgery. Flomoxef was administered, and liver function was examined before and after administration. Abnormal liver function after administration of flomoxef was found in 14.3% of patients. In male patients, a high rate of 18.8% was observed. A particularly high rate of 37.0% was obtained among patients who showed GOT values of more than 40 U/L before treatment with flomoxef. The prevalence of abnormal GOT and GPT values after administration of flomoxef was 3.6% and 13.2%, respectively. These values were significantly higher than those obtained with other cephem antibiotics. These rates of occurrence of abnormally high GOT and GPT are obviously higher than those submitted at the time of approval and reported in the drug use investigation. The prevalence of abnormal liver function values was high in patients receiving flomoxef, and particularly high in male patients and patients whose GOT was high before administration of flomoxef. Therefore, sufficient check of liver function appears important when administration of flomoxef to these types of patients is intended.

In vitro differentiated hepatic oval-like cells enhance hepatic regeneration in CCl4 -induced hepatic injury.

PubMed

Awan, Sana Javaid; Baig, Maria Tayyab; Yaqub, Faiza; Tayyeb, Asima; Ali, Gibran

2017-01-01

Hepatic oval cells are likely to be activated during advanced stage of liver fibrosis to reconstruct damaged hepatic tissue. However, their scarcity, difficulties in isolation, and in vitro expansion hampered their transplantation in fibrotic liver. This study was aimed to investigate the repair potential of in vitro differentiated hepatic oval-like cells in CCl 4 -induced liver fibrosis. BMSCs and oval cells were isolated and characterized from C57BL/6 GFP + mice. BMSCs were differentiated into oval cells by preconditioning with HGF, EGF, SCF, and LIF and analyzed for the oval cells-specific genes. Efficiency of oval cells to reduce hepatocyte injury was studied by determining cell viability, release of LDH, and biochemical tests in a co-culture system. Further, in vivo repair potential of differentiated oval cells was determined in CCl 4 -induced fibrotic model by gene expression analysis, biochemical tests, mason trichrome, and Sirius red staining. Differentiated oval cells expressed hepatic oval cells-specific markers AFP, ALB, CK8, CK18, CK19. These differentiated cells when co-cultured with injured hepatocytes showed significant hepato-protection as measured by reduction in apoptosis, LDH release, and improvement in liver functions. Transplantation of differentiated oval cells like cells in fibrotic livers exhibited enhanced homing, reduced liver fibrosis, and improved liver functions by augmenting hepatic microenvironment by improved liver functions. This preconditioning strategy to differentiate BMSCs into oval cell leads to improved survival and homing of transplanted cells. In addition, reduction in fibrosis and functional improvement in mice with CCl 4 -induced liver fibrosis was achieved. © 2016 International Federation for Cell Biology.

Bioartificial liver devices: Perspectives on the state of the art.

PubMed

Ding, Yi-Tao; Shi, Xiao-Lei

2011-03-01

Acute liver failure remains a significant cause of morbidity and mortality. Bioartificial liver (BAL) devices have been in development for more than 20 years. Such devices aim to temporarily take over the metabolic and excretory functions of the liver until the patients' own liver has recovered or a donor liver becomes available for transplant. The important issues include the choice of cell materials and the design of the bioreactor. Ideal BAL cell materials should be of good viability and functionality, easy to access, and exclude immunoreactive and tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet these requirements. One of the challenges in BAL development is the improvement of current materials; another key point concerning cell materials is the coculture of different cells. The bioreactor is an important component of BAL, because it determines the viability and function of the hepatocytes within it. From the perspective of bioengineering, a successful and clinically effective bioreactor should mimic the structure of the liver and provide an in vivo-like microenvironment for the growth of hepatocytes, thereby maintaining the cells' viability and function to the maximum extent. One future trend in the development of the bioreactor is to improve the oxygen supply system. Another direction for future research on bioreactors is the application of biomedical materials. In conclusion, BAL is, in principle, an important therapeutic strategy for patients with acute liver failure, and may also be a bridge to liver transplantation. It requires further research and development, however, before it can enter clinical practice.

Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats.

PubMed

Pestel, Sabine; Martin, Hans-Juergen; Maier, Gerd-Michael; Guth, Brian

2006-01-01

Solubility is often a limiting factor when testing new compounds in animal experiments. Various solubilizing agents may be used, but each have their own pharmacological effects. We investigated the effects of selected vehicles having different chemical characteristics on gastrointestinal, renal, and liver function. Rats were treated orally, intravenously or intraperitoneally and gastric emptying, intestinal transit, renal, and liver function were investigated. Gastrointestinal motility was influenced by hydroxyethylcellulose, hydroxypropyl-beta-cyclodextrin (HPbetaCD), HPgammaCD, DMSO, polyethylene glycol 400 (PEG 400), fat emulsion, and the corresponding emulsifier. Liver function was affected by HPbetaCD, HPgammaCD, DMSO, PEG 400, Polysorbate 80, Cremophor RH 40, and fat emulsion. An increase in liver enzymes was observed after PEG 400 and Polysorbate 80. DMSO interfered with clinical chemistry measurements in serum. Urinary function was modified by HPgammaCD, DMSO, PEG 400, and Polysorbate 80, while enhanced urine enzyme excretion was observed after HPbetaCD, HPgammaCD, DMSO, PEG 400, and Polysorbate 80. Most of the investigated vehicles changed gastrointestinal, renal, and/or liver parameters after application of a certain threshold dose for each assay. No "best" vehicle could be identified that may be used in each test system. Thus, vehicles must be selected not only on their chemical characteristics but also on their potential pharmacological activity in a given test system.

Influence of Prescribed Herbal and Western Medicine on Patients with Abnormal Liver Function Tests: A Retrospective Quasi-Experimental Study

PubMed Central

Lee, Ah-Ram; Yim, Je-Min; Kim, Won-Il

2012-01-01

Objectives: The aim of this study was to investigate the safety and the efficacy of Korean herbal, western and combination medicine use in patients with abnormal liver function tests. Methods: We investigated nerve disease patients with abnormal liver function tests who were treated with Korean herbal, western and combination medicine at Dong-Eui University Oriental Hospital from January 2011 to August 2011. We compared aspartic aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (T-bil) levels before and after taking medicine and excluded patients who had liver-related disease when admitted. Results: AST and ALT were decreased significantly in patients who had taken herbal, western medicine. AST, ALT and ALP were decreased significantly in patients who had taken combination medicine. Compare to herbal medicine, AST, ALT and ALP were decreased significantly in patients who had taken western medicine, and ALT and ALP were decreased significantly in patients who had taken combination medicine. There were no significant differences between western and combination medicine. Conclusions: This study suggests that prescribed Korean herbal medicine, at least, does not injure liver function for patients’, moreover, it was shown to be effective in patients with abnormal liver function tests. PMID:25780634

Protective effects of ACLF sera on metabolic functions and proliferation of hepatocytes co-cultured with bone marrow MSCs in vitro

PubMed Central

Shi, Xiao-Lei; Gu, Jin-Yang; Zhang, Yue; Han, Bing; Xiao, Jiang-Qiang; Yuan, Xian-Wen; Zhang, Ning; Ding, Yi-Tao

2011-01-01

AIM: To investigate whether the function of hepatocytes co-cultured with bone marrow mesenchymal stem cells (MSCs) could be maintained in serum from acute-on-chronic liver failure (ACLF) patients. METHODS: Hepatocyte supportive functions and cytotoxicity of sera from 18 patients with viral hepatitis B-induced ACLF and 18 healthy volunteers were evaluated for porcine hepatocytes co-cultured with MSCs and hepatocyte mono-layered culture, respectively. Chemokine profile was also examined for the normal serum and liver failure serum. RESULTS: Hepatocyte growth factor (HGF) and Tumor necrosis factor; tumor necrosis factor (TNF)-α were remarkably elevated in response to ACLF while epidermal growth factor (EGF) and VEGF levels were significantly decreased. Liver failure serum samples induced a higher detachment rate, lower viability and decreased liver support functions in the homo-hepatocyte culture. Hepatocytes co-cultured with MSCs could tolerate the cytotoxicity of the serum from ACLF patients and had similar liver support functions compared with the hepatocytes cultured with healthy human serum in vitro. In addition, co-cultured hepatocytes maintained a proliferative capability despite of the insult from liver failure serum. CONCLUSION: ACLF serum does not impair the cell morphology, viability, proliferation and overall metabolic capacities of hepatocyte co-cultured with MSCs in vitro. PMID:21633639

The use of a projection method to simplify portal and hepatic vein segmentation in liver anatomy.

PubMed

Huang, Shaohui; Wang, Boliang; Cheng, Ming; Huang, Xiaoyang; Ju, Ying

2008-12-01

In living donor liver transplantation, the volume of the potential graft must be measured to ensure sufficient liver function after surgery. Couinaud divided the liver into 8 functionally independent segments. However, this method is not simple to perform in 3D space directly. Thus, we propose a rapid method to segment the liver based on the hepatic vessel tree. The most important step of this method is vascular projection. By carefully selecting a projection plane, a 3D point can be fixed in the projection plane. This greatly helps in rapid classification. This method was validated by applying it to a 3D liver depicted on CT images, and the result was in good agreement with Couinaud's classification.

Branched-chain amino acids to tyrosine ratio value as a potential prognostic factor for hepatocellular carcinoma.

PubMed

Ishikawa, Toru

2012-05-07

The prognosis of hepatocellular carcinoma (HCC) depends on tumor extension as well as hepatic function. Hepatic functional reserve is recognized as a factor affecting survival in the treatment of HCC; the Child-Pugh classification system is the most extensively used method for assessing hepatic functional reserve in patients with chronic liver disease, using serum albumin level to achieve accurate assessment of the status of protein metabolism. However, insufficient attention has been given to the status of amino acid (AA) metabolism in chronic liver disease and HCC. Fischer's ratio is the molar ratio of branched-chain AAs (BCAAs: leucine, valine, isoleucine) to aromatic AAs (phenylalanine, tyrosine) and is important for assessing liver metabolism, hepatic functional reserve and the severity of liver dysfunction. Although this ratio is difficult to determine in clinical situations, BCAAs/tyrosine molar concentration ratio (BTR) has been proposed as a simpler substitute. BTR correlates with various liver function examinations, including markers of hepatic fibrosis, hepatic blood flow and hepatocyte function, and can thus be considered as reflecting the degree of hepatic impairment. This manuscript examines the literature to clarify whether BTR can serve as a prognostic factor for treatment of HCC.

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

USDA-ARS?s Scientific Manuscript database

Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...