SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Cirrhosis

3

Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.

Concepts: Immune system, Inflammation, Gene expression, Bacteria, Infection, Cirrhosis, Organ transplant, Hepatitis C

3

In 2000, the World Health Organization estimated that, in developing and transitional countries, unsafe injections accounted for respectively 5%, 32% and 40% of new infections with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Safe injection campaigns were organized worldwide. The present study sought to measure the progress in reducing the transmission of these viruses through unsafe injections over the subsequent decade.

Concepts: AIDS, Immune system, Bacteria, Virus, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B

3

For mothers with chronic hepatitis B virus (HBV) infection, the Centers for Disease Control and Prevention recommends immunoprophylaxis to decrease perinatal transmission. However, its effectiveness and risk factors for failure have not been well-studied in community practice.

Concepts: Infection, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Hepatitis A

3

Background: The risks and benefits of metformin use in cirrhotic patients with diabetes are debated. Although data on a protective effect of metformin against liver cancer development have been reported, metformin is frequently discontinued once cirrhosis is diagnosed due to concerns about an increased risk of adverse effects of metformin in patients with liver impairment. This study investigated whether continuation of metformin after cirrhosis diagnosis improves survival of patients with diabetes. Methods: Diabetic patients diagnosed with cirrhosis between 2000 and 2010 who were on metformin at the time of cirrhosis diagnosis were identified (n=250). Data were retrospectively abstracted from the medical record. Survival of patients who continued versus discontinued metformin after cirrhosis diagnosis was compared using the log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox Proportional Hazards analysis. Results: 172 patients continued metformin while 78 discontinued metformin. Patients who continued metformin had a significantly longer median survival than those who discontinued metformin (11.8 vs. 5.6 years overall, P < 0.0001; 11.8 vs. 6.0 years for Child A patients, P = 0.006; and 7.7 vs. 3.5 years for Child B/C patients, P = 0.04, respectively). After adjusting for other variables, continuation of metformin remained an independent predictor of better survival with a HR of 0.43 (95%CI: 0.24-0.78, P = 0.005). No patients developed metformin-associated lactic acidosis during follow-up. Conclusion: Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication. (Hepatology 2014).

Concepts: Better, Cancer, Medical terms, Obesity, Cirrhosis, Hepatitis C, Adverse drug reaction, Lactic acidosis

3

Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.

Concepts: Clinical trial, Cirrhosis, Liver, Hepatology, Toxicology, Paracetamol, Liver transplantation, Liver dialysis

3

The detection of alcohol consumption in liver transplant candidates (LTCs) and recipients (LTRs) is required to enable a proper assessment of transplant eligibility and an early management of alcohol relapse, respectively. In this clinical setting, urinary ethyl glucuronide (uEtG), the Alcohol Use Disorders Identification Test for alcohol consumption (AUDIT-c), serum ethanol (sETOH), urinary ethanol (uETOH), carbohydrate-deficient transferrin (CDT), and other indirect markers of alcohol consumption were evaluated and compared prospectively in 121 LTCs and LTRs. Alcohol consumption was defined by a positive AUDIT-c or when it was confirmed by patient history in response to his/her abnormal results. Alcohol consumption was found in 30.6% of patients. uEtG was found to be the strongest marker of alcohol consumption (OR=414.5; p<0.0001) and showed a more accurate prediction rate of alcohol consumption when compared to CDT (area under the ROC=0.94 vs 0.63; p<0.0001) and AUDIT-c (AUROC=0.94 vs 0.73;p<0.0001). The combination of uEtG with AUDIT-c showed a higher accuracy in detecting alcohol consumption when compared to the combination of CDT and AUDIT-c (AUROC=0.98 vs 0.80; p<0.001). Furthermore, uEtG was the most useful marker for detecting alcohol consumption in patients with a negative AUDIT-c. In conclusion, the association of AUDIT-c and uEtG improves the detection of alcohol consumption in LTCs and LTRs. Therefore, they should be used routinely in these patients. Liver Transpl , 2014. © 2014 AASLD.

Concepts: Alcohol, Ethanol, Yeast, Cirrhosis, Alcoholic beverage, Beer, Vodka, Alcohol Use Disorders Identification Test

3

Background. It is unclear if the risk of liver disease associated with different levels of alcohol consumption is higher for patients infected with human immunodeficiency virus (HIV) or chronic hepatitis C virus (HCV). We evaluated associations between alcohol use categories and advanced hepatic fibrosis, by HIV and chronic HCV status. Methods. We performed a cross-sectional study among participants in the Veterans Aging Cohort Study who reported alcohol consumption at enrollment (701 HIV/HCV-coinfected; 1,410 HIV-monoinfected; 296 HCV-monoinfected; 1,158 HIV/HCV-uninfected). Alcohol use category was determined by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire and alcohol-related diagnoses and was classified as non-hazardous drinking, hazardous/binge drinking, or alcohol-related diagnosis. Advanced hepatic fibrosis was defined by FIB-4 index >3.25. Results. Within each HIV/HCV group, the prevalence of advanced hepatic fibrosis increased as alcohol use category increased. For each alcohol use category, advanced hepatic fibrosis was more common among HIV-infected than uninfected (non-hazardous: 6.7% versus 1.4%; hazardous/binge: 9.5% versus 3.0%; alcohol-related diagnosis: 19.0% versus 8.6%; p<0.01) and chronic HCV-infected than uninfected (non-hazardous: 13.6% versus 2.5%; hazardous/binge: 18.2% versus 3.1%; alcohol-related diagnosis: 22.1% versus 6.5%; p<0.01) participants. Strong associations with advanced hepatic fibrosis (adjusted odds ratio [95% confidence interval]) were observed among HIV/HCV-coinfected patients with non-hazardous drinking (14.2 [5.91-34.0]), hazardous/binge drinking (18.9 [7.98-44.8]), and alcohol-related diagnoses (25.2 [10.6-59.7]) compared to uninfected non-hazardous drinkers. Conclusion. Advanced hepatic fibrosis was present at low levels of alcohol consumption, increased with higher alcohol use categories, and was more prevalent among HIV-infected and chronic HCV-infected patients than uninfected individuals. All alcohol use categories were strongly associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients.

Concepts: HIV, AIDS, Epidemiology, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis A, Hepatitis C virus

3

Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide. HCV infection often results in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. No vaccine is available and current therapies are effective against some, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies. Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an antigen-binding fragment (Fab) at 2.4 Å resolution. The E2 core has a compact, globular domain structure, consisting mostly of β-strands and random coil with two small α-helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulphide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins, whereas sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements on exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.

Concepts: Protein, Virus, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Hepatitis C virus

3

Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-α/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12-88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5'-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment.

Concepts: Genome, RNA, Cirrhosis, Interferon, Alanine transaminase, Hepatitis C, Hepatitis B, Hepatitis C virus

3

Hepatic encephalopathy (HE) is associated with poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for primary prophylaxis of HE.

Concepts: Bacteria, Gut flora, Ammonia, Randomized controlled trial, Digestive system, Cirrhosis, Liver, Hepatic encephalopathy