Summary Background The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Methods We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Findings Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Interpretation Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. Funding National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Acute liver failure (ALF) is a rare but challenging clinical syndrome with multiple causes; a specific etiology cannot be identified in 15% of adult and 50% of pediatric cases. The course of ALF is variable and the mortality rate is high. Liver transplantation is the only therapy of proven benefit, but the rapidity of progression and the variable course of ALF limit its use. Currently in the United States, spontaneous survival occurs in approximately 45%, liver transplantation in 25%, and death without transplantation in 30% of adults with ALF. Higher rates of spontaneous recovery (56%) and transplantation (31%) with lower rates of death (13%) occur in children. The outcome of ALF varies by etiology, favorable prognoses being found with acetaminophen overdose, hepatitis A, and ischemia (Ϸ60% spontaneous survival), and poor prognoses with drug-induced ALF, hepatitis B, and indeterminate cases (Ϸ25% spontaneous survival). Excellent intensive care is critical in management of patients with ALF. Nonspecific therapies are of unproven benefit. Future possible therapeutic approaches include N-acetylcysteine, hypothermia, liver assist devices, and hepatocyte transplantation. Advances in stem cell research may allow provision of cells for bioartificial liver support. ALF presents many challenging opportunities in both clinical and basic research. A cute liver failure (ALF) is a dramatic but rare clinical syndrome marked by the sudden loss of hepatic function in a person with no prior history of liver disease. The causes of ALF include viral hepatitis, drug-induced and toxin-induced liver disease, metabolic errors, ischemia, and miscellaneous rare causes. Currently, there are no specific therapies of proven benefit except for emergency liver transplantation. The many challenges in understanding and management of ALF led to the organization of a 2-day research workshop held on December 4-5, 2006 in Bethesda, Maryland, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) with support from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Office of Rare Diseases of the National Institutes of Health (NIH). This manuscript summarizes the presentations at that meeting and the recommendations arising therefrom. Overview of ALF Epidemiology and Etiology in AdultsThe sudden loss of hepatic function in a person without preexisting liver disease defines ALF. 1,2 The most reliable signs of severe acute liver injury are the presence of coagulopathy (international normalized ratio [INR] Ն 1.5) and any degree of hepatic encephalopathy, the length of illness being considered anything Յ 24 weeks. Many patients evolve to coma within 1 week or less. The term "acute liver failure" is preferable to fulminant hepatic failure 1 or acute hepatic necrosis. 2 ALF is rare and represents a syndrome rather than a specific disease, having multiple causes that vary in course and outcome. 1401The rarity of ALF and its unpredictable, severe course make it a challenging entity for prospec...

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsyproven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study. (HEPATOLOGY 2004;39:188 -196.)

Chronic hepatitis B is caused by persistent infection with the hepatitis B virus (HBV),

In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.

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Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with "more than mild" in adults were older age (P < 0.0001), female gender (P ‫؍‬ 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P ‫؍‬ 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P ‫؍‬ 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). "More than mild" in the pediatric biopsies correlated with younger age (P ‫؍‬ 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with "more than mild" were steatosis amount (P ‫؍‬ 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, "more than mild" was associated with steatosis location (P ‫؍‬ 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009;49:809-820.)

Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis and need for liver transplantation in a high proportion of cases. The disease occurs in approximately 1 per 100,000 population per year, usually presents in adulthood, and affects men more often than women. Typical serum biochemical results, autoantibodies and liver biopsy are suggestive but not diagnostic of PSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of the intra-and/or extra-hepatic bile ducts. The natural history of PSC is variable, the average survival being 12 to 17 years. The cause of PSC is still unknown. Although considered an autoimmune disease, PSC has several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory. Standard doses of ursodeoxycholic acid (UDCA) lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearance or survival. Several innovative therapies have been tried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopic dilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC and improves survival. PSC may recur after transplantation but is rarely progressive. The most dreaded complication of PSC is cholangiocarcinoma. Diagnosis of this highly malignant tumor is difficult, and there are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has an exceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holds promise in selected patients. Thus, significant opportunities remain for basic and clinical research into the cause, natural history, and therapy of PSC. 44:746-764.)