Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation(1-3). We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip(4). We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8 ؉ T cells. The role of CD4 ؉ CD25 ؉ T regulatory (T reg ) cells in priming and expanding virus-specific CD8 ؉ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virusspecific CD8؉ T-cell proliferation and gamma interferon (IFN-␥) frequency were analyzed with/without depletion of T reg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4؉ CD25 ؉ T reg cells inhibited anti-CD3/CD28 CD8 ؉ T-cell proliferation and perforin expression. Depletion of CD4؉ CD25 ؉ T reg cells from chronic HCV patients in vitro increased HCV and EBV peptidedriven expansion (P ‫؍‬ 0.0005 and P ‫؍‬ 0.002, respectively) and also the number of HCV-and EBV-specific IFN-␥-expressing CD8 ؉ T cells. Although stimulated CD8 ؉ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4 ؉ CD25 ؉ regulatory T cells on CD8 ؉ T-cell proliferation. In conclusion, marked CD4 ؉ CD25 ؉ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8 ؉ T-cell responses and viral persistence.

H epatocellular carcinoma (HCC), the fifth most common cancer worldwide with 564,000 new cases each year, is also the third most common cause of cancer-related death. 1 HCC arises most frequently in males with cirrhosis, which is most often a consequence of chronic hepatitis infection or alcohol abuse. 2 Recent reports from different countries suggest that the incidence of HCC is increasing, probably as a consequence of the increased prevalence of hepatitis C virus (HCV) infection, although increased alcohol consumption may be significant. 3 The only effective approaches for patients with HCC are resection or liver transplantation. Following transplantation, there is an 83% 4-year recurrence-free survival in highly selected patients (single tumor Ͻ5 cm in diameter or fewer than three tumors Ͻ3 cm in diameter). 4 However, the majority of patients do not meet such strict criteria or have other contraindications. Local therapies such as percutaneous ethanol injection, thermal ablation, and intra-arterial chemoembolization are less successful, 5 and less than 10% of patients with moderate disease (Okuda stage 2) survive for 3 years. 6 Immunological mechanisms are important in the surveillance of malignancy and control of tumor progression. Cytotoxic CD8 ϩ lymphocytes (CTLs) and natural killer cells are potential effector cells in the control of tumor growth, although both require CD4 ϩ T helper 1 immune responses for optimal function. 7 Tumor-infiltrating lym-

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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Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double‐blind, placebo‐controlled study, we tested the safety and efficacy of cilofexor (formerly GS‐9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large‐duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α‐hydroxy‐4‐cholesten‐3‐one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288‐439) and 0.7 mg/dL (0.5‐1.0), respectively. Dose‐dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction −21%; P = 0.029 versus placebo), gamma‐glutamyl transferase (−30%; P < 0.001), alanine aminotransferase (ALT) (−49%; P = 0.009), and aspartate aminotransferase (−42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid–treated and untreated patients. At week 12, cilofexor‐treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, tissue inhibitor of metalloproteinase 1, C‐reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo‐treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12‐week, randomized, placebo‐controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.