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Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

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Background The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score. MethodsIn this population-based study, we invited active participants of the ALSPAC cohort to our Focus@24+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7•1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI). Findings 10 018 active ALSPAC participants were invited to our Focus@24+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24•0 years (IQR 23•0-25•0). 3768 CAP scores were eligible for analysis. 780 (20•7% [95% CI 19•4-22•0]) participants had suspected steatosis (S1-S3; ≥248 dB/m), with 377 (10•0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5•17 [95% CI 4•11-6•50], p<0•0001; obese BMI: 27•27 [20•54-36•19], p<0•0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2•7% [95% CI 2•2-3•2]) had transient elastography values equivalent to suspected fibrosis (F2-F4; ≥7•9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11•7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4•02 [1•24-13•02]; p=0•02).Interpretation One in five young people had steatosis and one in 40 had fibrosis around the...

Background-Many patients with haemophilia have developed cirrhosis or hepatocellular carcinoma due to transfusion acquired chronic viral hepatitis. Aims-To assess the long term outcome of all haemophilic patients reported to have undergone orthotopic liver transplantation. Methods-Transplant centres of patients identified by medical database search were contacted and survival data assessed by Kaplan-Meier analysis. Results-Twenty six haemophilic men (median age 46 years, range 5-63 years) underwent orthotopic liver transplantation in 16 centres between 1982 and 1996. Indications for transplantation were hepatitis C cirrhosis (69%), hepatitis B with or without C cirrhosis (15%), viral hepatitis related hepatocellular carcinoma (12%), and biliary atresia (4%). Six patients (23%) were infected with human immunodeficiency virus (HIV). Postoperatively, the median time to normal clotting factor levels was 24 hours (range 0-48 hours) and exogenous clotting factors were stopped at a median of 24 hours (range 0-480 hours). Four patients (15%) had bleeding complications. The one and three year survival of HIV positive recipients (67% and 23%) was significantly poorer (p=0.0003) than that of HIV negative recipients (90% and 83%). Coagulopathy was cured in all patients surviving more than 12 days post-transplant. Six of the 20 patients (30%) with hepatitis C cirrhosis pretransplant had evidence of disease recurrence at a mean of nine months post-transplant. Conclusions-Hepatitis C cirrhosis is the most common indication for orthotopic liver transplantation in patients with haemophilia. Transplantation results in long term cure of haemophilia but may be complicated by the eVects of HIV infection or recurrent viral hepatitis. (Gut 1998;42:744-749)

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Background: Alpha‐4 integrins facilitate leucocyte migration across vascular endothelium. Aim: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha‐4 integrin, in patients with active ulcerative colitis. Methods: Ten patients with active ulcerative colitis, defined by a Powell‐Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end‐point was the change in Powell‐Tuck score at 2 weeks post‐infusion. Results Significant decreases in the median Powell‐Tuck score were observed at 2 and 4 weeks post‐infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell‐Tuck score of ≤ 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%), three (30%) and eight (80%) patients by weeks 2, 4 and 8, respectively (median, 34 days; range, 8–43 days). One patient remained in remission at 12 weeks. The median C‐reactive protein at 2 weeks (6 mg/L) was lower than that pre‐treatment (16 mg/L). Conclusions: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo‐controlled trials.