New developments in the treatment of primary biliary cholangitis - role of obeticholic acid.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that predominantly affects women in early to middle age. It is typically associated with autoantibodies to mitochondrial antigens and results in immune-mediated destruction of small and medium-sized intrahepatic bile ducts leading to cholestasis, hepatic fibrosis and may progress to cirrhosis or hepatic failure and, in some cases, hepatocellular carcinoma. The clinical presentation and the natural history of PBC have improved over the years due to recognition of earlier widespread use of ursodeoxycholic acid (UDCA); about one-third of patients show suboptimal biochemical response to UDCA with poor prognosis. Until recently, UDCA was the only US Food and Drug Administration approved agent for this disease for more than two decades; obeticholic acid was approved in 2016 for treatment of patients with PBC with a suboptimal response or intolerance to UDCA. Currently, liver transplantation is the most effective treatment modality for PBC patients with end-stage liver disease. This review will focus on the recent advances in therapy of primary biliary cholangitis, with emphasis on obeticholic acid

Primary Sclerosing Cholangitis: Epidemiology, Genetics, Diagnosis, and Current Management.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-gochanour a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-kowdley an interview with the author

Current perspectives into the evaluation and management of hepatitis B: a review.

Hepatitis B is a widespread disease which affects millions of people worldwide. Chronic hepatitis B (CHB) can lead to significant morbidity and mortality due to complications such as cirrhosis and hepatocellular carcinoma. The pathophysiology of hepatitis is critical to diagnosing CHB. Deciding which patients with CHB should be treated is an important decision as treatment can often lead to better outcomes in the appropriate patient population. The nucleos(t)ide analog inhibitors entecavir and tenofovir are currently the mainstay of treatment as they are able to successfully suppress the virus and lead to fewer complications. Novel therapies are currently being developed which may offer a potential cure for this disease in the future

Nutritional Approaches to Achieve Weight Loss in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) can range in spectrum from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by lipotoxicity, hepatocellular ballooning, and inflammation and can progress to cirrhosis. Weight loss is the cornerstone treatment for NAFLD and NASH. Various randomized controlled trials have shown that weight loss of ≥5-10% leads to significant improvements in hepatic steatosis. Diets high in sodium and fructose have been implicated in the pathogenesis of NAFLD. Although some clinical studies suggest that an isocaloric high-fructose diet does not worsen NAFLD, these clinical studies are often short in duration. More recently, the Dietary Approaches to Stop Hypertension diet, a sodium-restricted diet, has been associated with less prevalence of NAFLD and has been shown to improve NAFLD. In addition, the Mediterranean diet has been promising in improving hepatic steatosis, and a larger randomized controlled trial is currently enrolling subjects. For those who are unable to pursue weight loss through dietary approaches, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis. This method has been variable in improving hepatic fibrosis. In conclusion, weight loss is crucial to the improvement of NAFLD and NASH, and patients should attempt various diets in an attempt to achieve weight loss

Curcumin and Turmeric Modulate the Tumor-Promoting Effects of Iron In Vitro.

Free or loosely chelated iron has tumor-promoting properties in vitro. Curcumin, a polyphenol derived from the food spice turmeric (Curcuma longa), is a potent antioxidant that binds iron. The primary aim of this study was to investigate whether curcuminoids prevent tumor-promoting effects of iron in T51B cells, a non-neoplastic rat liver epithelial cell line. Purified curcuminoids (curcumin) or a standardized turmeric extract similarly reduced oxidative stress and cytotoxicity associated with iron overload (I

Sofosbuvir, Velpatasvir, and Voxilaprevir for Treatment of Recurrent Hepatitis C Virus Infection After Liver Transplantation.

There are limited data on direct-acting antiviral (DAA) treatment options for previously treated patients with recurrent genotype 3 (GT3) hepatitis C virus (HCV) after liver transplantation. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is currently approved for treatment of HCV in patients with prior treatment with DAAs. We report the first published experience using SOF/VEL/VOX after liver transplantation for a DAA-experienced patient with severe hepatitis due to early recurrent GT3 HCV. The patient was treated with SOF/VEL/VOX that was extended to a total duration of 16 weeks and was intensified with ribavirin (RBV) starting at week 8 due to persistent viremia during treatment. Sustained virologic response at 12 weeks (SVR12) after treatment completion was achieved. SOF/VEL/VOX was well tolerated, and immediate drug-drug interaction (DDI) with tacrolimus (TAC) was not evident. Due to improvement in liver metabolic function with increasing TAC clearance, TAC dose adjustment was required throughout the treatment course

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS) and is characterized by steatosis in the absence of significant alcohol consumption. However, MetS and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD. AIM: To assess the clinical characteristics of patients with both alcoholic and NAFLD (BAFLD) in a large cohort in the United States. METHODS: Adults from the National Health and Nutrition Examination Survey between 2003-2014 were included. NAFLD was diagnosed based on elevated alanine aminotransferase (ALT) and being overweight or obese in the absence of other liver diseases. BAFLD patients met the criteria for NAFLD but also had either MetS or type 2 diabetes and consumed excessive amounts of alcohol. Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score (FIB4 index). RESULTS: The prevalence of NAFLD was at 25.9% (95%CI; 25.1-26.8) and that of BAFLD was 0.84% (0.67, 1.02) which corresponds to an estimated 1.24 million Americans affected by BAFLD. Compared to NAFLD, patients with BAFLD were more likely to be male, smokers, have higher ALT, aspartate aminotransferase, triglycerides, and lower platelets; CONCLUSION: A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis

Primis : design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC.MethodsAdults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint-chosen in conjunction with guidance from the U.S. Food and Drug Administration-is the proportion of patients with >= 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor.ConclusionThe phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC.Trial Registration: ClinicalTrials.gov NCT03890120; registered 26/03/2019.Peer reviewe

Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry

Background : It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. Methods : The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using Χ 2 tests. Results : Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma ( P =0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis ( P <0.001) and hepatitis C ( P <0.001). Conclusions : Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75573/1/j.1478-3231.2007.01596.x.pd