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Concept: Cirrhosis

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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

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Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.

Concepts: Oxygen, Iron, Oxidative phosphorylation, Cirrhosis, Liver, Hydrogen peroxide, Knowledge, Human iron metabolism

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Racial and socioeconomic disparities exist in liver transplantation outcomes among adults, but little research exists in pediatric liver transplant populations. We examined racial differences in graft survival and mortality among a retrospective cohort of pediatric and young adult liver transplant recipients at a large children’s transplant center in the Southeast between 1998 and 2011. The association between race/ethnicity and the rate of graft failure and mortality was examined using Cox-Proportional Hazard models adjusting for demographic and clinical factors as well as individual- and census tract-level socioeconomic status. Among 208 liver transplant recipients, 51.0% were white, 34.6% black and 14.4% other races/ethnicities. Graft and patient survival was higher among whites vs. minorities at 1, 3, 5, and 10 years post-transplant, where 10-year graft survival was 84% (95% CI: 76-91%) among white, 60% (95% CI: 46- 74%) among black, and 49% (95% CI: 23- 77%) among other race/ethnicity patients. Ten-year patient survival was 92% (95% CI: 84-96), 65% (95% CI: 52-79%), and 76% (95% CI: 54-97%) among white, black, and other race/ethnicity groups respectively. In analyses that adjusted for demographic, clinical, and socioeconomic characteristics, the rates of graft failure [black: HR 2.59, 95% CI (1.29, 5.45); other HR 3.01, 95% CI (1.23, 7.35)] and mortality [black: HR 4.24, 95% CI (1.54, 11.69); other HR 3.09, 95% CI: (0.78, 12.19)] were higher among minority groups compared to whites. In a large pediatric transplant center in the Southeastern US, racial/ethnic disparities exist in pediatric and young adult liver transplant outcomes that are not fully explained by measured socioeconomic status and clinical factors. Liver Transpl , 2013. © 2013 AASLD.

Concepts: Cirrhosis, Liver, Black people, United Kingdom, Organ transplant, White people, Minority group, Liver transplantation

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Estrogens inhibit stellate cell activation and fibrogenesis. Thus, gender and reproductive states may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). To investigate the association between gender, menopause, and the severity of liver fibrosis in patients with NASH, we analyzed 541 adult patients enrolled from our Duke Liver Clinics (n=338) and the Duke Metabolic and Weight Loss Surgery Program (n=203) who had a histologic diagnosis of NASH. Multiple ordinal logistic regression models were used to assess the association between gender, menopause and severity of liver fibrosis. Overall, men, pre-menopausal and post-menopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. The mean age was 48 years and 22% had advanced fibrosis. After adjusting for covariates (enrolling site, grades of portal inflammation, and hepatocyte ballooning) and potential confounders (race, body mass index, diabetes/prediabetes, hypertension), adjusted cumulative odd ratio (ACOR) and 95% confidence interval (CI) for greater fibrosis severity was 1.4 [0.9, 2.1] (p=0.17) for post-menopausal women and 1.6 [1.0, 2.5] (p=0.03) for men, having pre-menopausal women as a reference. There was borderline interaction between gender and age group divided by age 50, the average age at menopause in the US (p=0.08): ACOR and 95% CI of having greater fibrosis severity in men compared to women was 1.8 [1.1, 2.9] for patients with age <50 years (p=0.02) and 1.2 [0.7, 2.1] for patients with age ≥ 50 years (p=0.59). Conclusion: Men are at a higher risk of having more severe fibrosis compared to women before menopause, while post-menopausal women have a similar severity of liver fibrosis compared to men. These findings may be explained by the protective effects of estrogen against fibrogenesis. (Hepatology 2013;).

Concepts: Logistic regression, Obesity, Menopause, Estrogen, Cirrhosis, Liver, Body mass index, UCI race classifications

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Management of pediatric chronic liver disease is limited by lack of validated noninvasive biomarkers of histologic severity. We demonstrate that magnetic resonance elastography is feasible and accurate in detecting significant hepatic fibrosis in a case series of 35 children with chronic liver disease, including severely obese children.

Concepts: Medicine, Cancer, Medical terms, Insulin, Cirrhosis, Evaluation methods, Liver function tests, Liver biopsy

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Incident ESRD after liver transplantation (LT) is associated with high post-transplant mortality. We constructed and validated a continuous renal risk index (RRI) to predict post-LT ESRD. Data for 43,514 adult recipients of deceased donor LT alone (February 28, 2002 to December 31, 2010) were linked from the Scientific Registry of Transplant Recipients and the Centers for Medicare and Medicaid Services ESRD Program. An adjusted Cox regression model of time to post-LT ESRD was fitted, and the resulting equation was used to calculate an RRI for each LT recipient. The RRI included 14 recipient factors: age, African-American race, hepatitis C, cholestatic disease, body mass index≥35, pre-LT diabetes, ln creatinine for recipients not on dialysis, ln albumin, ln bilirubin, serum sodium<134 mEq/L, status-1, previous LT, transjugular intrahepatic portosystemic shunt, and acute dialysis at LT. This RRI was validated and had a C statistic of 0.76 (95% confidence interval, 0.75 to 0.78). Higher RRI associated significantly with higher 5-year cumulative incidence of ESRD and post-transplant mortality. In conclusion, the RRI constructed in this study quantifies the risk of post-LT ESRD and is applicable to all LT alone recipients. This new validated measure may serve as an important prognostic tool in ameliorating post-LT ESRD risk and improve survival by informing post-LT patient management strategies.

Concepts: Regression analysis, Statistics, Cirrhosis, Liver, Hepatology, Organ transplant, Prediction interval, Centers for Medicare and Medicaid Services

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Hepatitis B virus (HBV) mutation leading to gender disparity in the progression of liver diseases has not been explored so far. We aimed to elucidate relationships of the novel preS1 mutation, W4P/R with the progression of liver diseases and male predominance from a Korean chronic cohort through a molecular epidemiologic study. We developed a fluorescence resonance energy transfer (FRET)-based real-time PCR (RT-PCR) assay for detection of W4P/R mutation and applied it to 292 chronic patients. The preS1 mutations from a total of 247 patients (84.6%) of 292 were detected by this assay. W4P/R mutants were significantly related to severe liver diseases [HCC and liver cirrhosis (12.4%, 19/153 patients) vs. chronic hepatitis and carrier (1.1%, 1/94 patients), P < 0.001]. All of the W4P/R mutants were found only in the male gender, not in the female gender. The novel HBV preS1 mutation, W4P/R, may be associated with disease severity in male chronic patients infected with genotype C. The W4P/R mutation may in part provide the likely explanation for the relatively high ratio of male to female incidence in HCC generation in Korean chronic patients.

Concepts: DNA, Epidemiology, Cancer, Cirrhosis, Hepatitis, Gender, Hepatitis C, Hepatitis B

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Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

Concepts: Immune system, Antibody, Cirrhosis, Liver, Humoral immunity, Immunity, Hepatitis B, Hepatitis A

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Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox’s proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 5% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control. (Hepatology 2013;).

Concepts: HIV, Immune system, Genetics, Male, Female, Cirrhosis, Sex, Hepatitis C