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Concept: Primary sclerosing cholangitis

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Background Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. Methods In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Results Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. Conclusions Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524 ; Current Controlled Trials number, ISRCTN89514817 .).

Concepts: Clinical trial, Cirrhosis, Liver, Hepatology, Bilirubin, Primary biliary cirrhosis, Primary sclerosing cholangitis, Jaundice

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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often leading to end-stage liver disease. Its pathogenesis remains largely unknown, although frequent concomitant IBD hints towards common factors underlying gut and bile duct inflammation. Considering the mounting evidence on the involvement of the intestinal microbiota in initiating and determining IBD phenotype, we investigated intestinal microbiota composition in patients with PSC.

Concepts: Digestive system, Cirrhosis, Hepatology, Bilirubin, Bile, Cholestasis, Primary biliary cirrhosis, Primary sclerosing cholangitis

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We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Concepts: Immune system, Cirrhosis, United Kingdom, Hepatology, Bilirubin, Autoimmune disease, Primary biliary cirrhosis, Primary sclerosing cholangitis

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Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease characterized by fibro-obliterative inflammation of the hepatic bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and in some cases, cholangiocarcinoma. Despite clinical trials of nearly 20 different pharmacotherapies over several decades, safe and effective medical therapy, albeit critically needed, remains to be established. PSC is pathogenically complex, with genetic, immune, enteric microbial, environmental and other factors being potentially involved and, thus, not surprisingly, it manifests as a clinically heterogeneous disease with a relatively unpredictable course. It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend. The authors herein provide a review of previously tested pharmacologic agents, discuss emerging fundamental concepts and present viewpoints regarding how identifying therapies for PSC may evolve over the next several years.

Concepts: Medicine, Cirrhosis, Liver, Therapy, Hepatology, Bilirubin, Bile duct, Primary sclerosing cholangitis

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Aim  Current guidelines recommend annual surveillance for colorectal cancer (CRC) in all patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). The aim of our study was to validate the need for annual surveillance for colon neoplasia in patients ≤ 45 of age with a combined diagnosis of PSC and IBD. Method  We identified patients, ≤ 45 years of age with a combined diagnosis of PSC and IBD, who were seen at the Mayo Clinic between 1995 and 2010. We then reviewed the medical records of the patients who developed colonic neoplasia defined as cancer, high-grade dysplasia (HGD) or dysplasia-associated lesion or mass (DALM). Results  In the population of 784 patients ≤ 45 years of age with a combined diagnosis of PSC and IBD, 10 (1.3%) of 784 developed colonic neoplasia during the follow-up period. Seven patients had colon cancer, one had HGD and two had a DALM. Conclusion  Colonic neoplasia is uncommon in young patients (≤ 45 years of age) with a combined diagnosis of PSC and IBD. We suggest delaying surveillance in young patients and propose that studies should be carried out to clarify the cost-effectiveness of annual or biannual surveillance colonoscopies according to patient age.

Concepts: Cancer, Colorectal cancer, Ulcerative colitis, Colon, Constipation, Inflammatory bowel disease, Primary sclerosing cholangitis, Ileostomy

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While referring to the evidence adopted in the Tokyo Guidelines 2007 (TG07) as well as subsequently obtained evidence, further discussion took place on terminology, etiology, and epidemiological data. In particular, new findings have accumulated on the occurrence of symptoms in patients with gallstones, frequency of severe cholecystitis and cholangitis, onset of cholecystitis and cholangitis after endoscopic retrograde cholangiopancreatography and medications, mortality rate, and recurrence rate. The primary etiology of acute cholangitis/cholecystitis is the presence of stones. Next to stones, the most significant etiology of acute cholangitis is benign/malignant stenosis of the biliary tract. On the other hand, there is another type of acute cholecystitis, acute acalculous cholecystitis, in which stones are not involved as causative factors. Risk factors for acute acalculous cholecystitis include surgery, trauma, burn, and parenteral nutrition. After 2000, the mortality rate of acute cholangitis has been about 10 %, while that of acute cholecystitis has generally been less than 1 %. After the publication of TG07, diagnostic criteria and severity assessment criteria were standardized, and the distribution of cases according to severity and comparison of clinical data among target populations have become more subjective. The concept of healthcare-associated infections is important in the current treatment of infection. The treatment of acute cholangitis and cholecystitis substantially differs from that of community-acquired infections. Cholangitis and cholecystitis as healthcare-associated infections are clearly described in the updated Tokyo Guidelines (TG13).Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html .

Concepts: Epidemiology, Gastroenterology, Hepatology, Endoscopic retrograde cholangiopancreatography, Endoscopy, Primary sclerosing cholangitis, Ascending cholangitis, Cholecystitis

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Ursodeoxycholic acid is administered to patients with primary biliary cirrhosis, a chronic progressive inflammatory autoimmune-mediated liver disease with unknown aetiology. Despite its controversial effects, the U.S. Food and Drug Administration has approved its usage for primary biliary cirrhosis.

Concepts: Cirrhosis, Liver, Hepatology, Bilirubin, Primary biliary cirrhosis, Primary sclerosing cholangitis, Liver biopsy, Ursodiol

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Patients with primary sclerosing cholangitis (PSC) are at increased risk of bacterial cholangitis due to biliary strictures and bile stasis. A subset of PSC patients suffer from repeated episodes of bacterial cholangitis, leading to frequent hospitalizations and impaired quality of life. Although PSC waitlist candidates with bacterial cholangitis frequently receive exception points, and/or are referred for living donor transplantation, the impact of bacterial cholangitis on waitlist mortality is unknown. We performed a retrospective cohort study of all adult PSC waitlist candidates listed for initial transplantation from February 27, 2002 to June 1, 2012 at the University of Pennsylvania and the University of Colorado-Denver. Over this period, 171 PSC patients were waitlisted for initial transplantation. Prior to waitlisting, 38.6% (66/171) of patients had a history of bacterial cholangitis, while 28.0% (44/157) of those with at least one MELD update experienced cholangitis on the waitlist. During follow-up, 30 (17.5%) patients were removed from the waitlist for death or clinical deterioration, with 46.7% (14/30) developing cholangiocarcinoma. Overall, 12/82 (14.6%) waitlist candidates who ever had an episode of cholangitis were removed for death or clinical deterioration, compared with 18/89 (20.2%) without cholangitis (P=0.34 comparing two groups). No patients were removed due to bacterial cholangitis. In multivariable competing risk models, a history of bacterial cholangitis was not associated with an increased risk of waitlist removal for death or clinical deterioration (subhazard ratio=0.67; 95% CI: 0.65-0.70, P<0.001). In summary, PSC waitlist transplant candidates with bacterial cholangitis do not have an increased risk of waitlist mortality. The data call into question the systematic granting of exception points or referral for living donor transplantation due to a perceived risk of increased waitlist mortality. © 2012 American Association for the Study of Liver Diseases.

Concepts: Cohort study, Actuarial science, Cirrhosis, Liver disease, Bile duct, Cholangiocarcinoma, Primary sclerosing cholangitis, Ascending cholangitis

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INTRODUCTION: Ischemic cholangitis in intensive care unit is a recently reported liver disease in patients who have had a prolonged mechanical ventilation and vasopressive drug support for multiple organ deficiency. Prognosis is usually poor and the only life-saving therapy is liver transplantation despite ursodesoxycholic acid treatment. CASE REPORT: We report a 63-year-old man who presented with a sclerosis cholangitis after a month in intensive care unit, effectively treated with fenofibrate and ursodesoxycholic acid. Recent reports underline fenofibrate efficacy in the treatment of primary biliary cirrhosis, especially in association with ursodesoxycholic acid. This treatment has prevented liver transplantation for our patient with a correct quality of life. CONCLUSION: The addition of fibrate to ursodesoxycholic acid improves persistent cholestasis in sclerosing cholangitis.

Concepts: Cirrhosis, Liver, Gastroenterology, Hepatology, Bilirubin, Cholestasis, Primary biliary cirrhosis, Primary sclerosing cholangitis

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Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD). The aim of this study was to assess the IBD phenotype associated with PSC in a large well-phenotyped population-based PSC cohort using endoscopic and histopathologic criteria.

Concepts: Inflammation, Ulcerative colitis, Colonoscopy, Gastroenterology, Inflammatory bowel disease, Autoimmune diseases, Primary sclerosing cholangitis