No abstract

No abstract

on behalf of the Liver Forum Case Definitions Working GroupIdentifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials. (Hepatology 2019;70:1841-1855).

BACKGROUND & AIMS:The association between physical activity (PA) and all-cause and cause-specific mortality from nonalcoholic fatty liver disease (NAFLD) requires investigation. We studied whether PA, measured by accelerometer, is associated with all-cause and cause-specific mortality among individuals with NAFLD. METHODS:We performed a longitudinal analysis using the 2003 to 2006 US National Health and Nutrition Examination Survey data of adults (age, ‡20 y) and collecting mortality data through December 2015. NAFLD was defined based on the hepatic steatosis index or US fatty liver index scores, in the absence of other causes of chronic liver disease. PA was measured from participants who wore accelerometers 10 h/d for a minimum of 4 days over a 7-day period and were classified as total PA, moderate to vigorous PA (MVPA), and sedentary behavior. RESULTS:Over an average follow-up period of 10.6 years, increasing the duration of total PA was associated with a reduced risk of death, from any cause, in an age-and sex-adjusted model (hazard ratio [HR], 0.52; 95% CI, 0.32-0.86 for highest quartile vs lowest quartile; P for trend [ .001) and multivariable model (HR, 0.46; 95% CI, 0.28-0.75; P for trend < .001) among individuals with NAFLD. Increasing the duration of MVPA was associated with a lower risk of death from any cause in individuals with NAFLD. Furthermore, longer total PA was associated with a lower risk for cardiovascular disease-related death in individuals with NAFLD (HR, 0.28; 95% CI, 0.08-0.98 for highest quartile vs lowest quartile; P for trend [ .007). We did not find this association for cancer-related mortality in individuals with NAFLD. Increasing the duration of sedentary behavior did not affect all-cause or cause-specific mortality in individuals with NAFLD. CONCLUSIONS:Longer total PA and MVPA, measured by accelerometers over a 7-day period, are associated with lower all-cause and cardiovascular mortality in individuals with NAFLD.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an increasingly dominant cause of liver disease worldwide. The progressive subtype, nonalcoholic steatohepatitis, is a leading indication for liver transplantation and a noteworthy cause of hepatocellular carcinoma. The overall prevalence of NAFLD is on the rise, and even more concerning data modeling predicts that an increasing percentage of those with NAFLD will develop advanced disease. This increased volume of patients with advanced liver disease will impose a significant health care burden in terms of resources and cost. Thus, the identification of patients with established fibrosis or at high risk of developing advanced liver disease is critical to effectively intervene and prevent overall and liver-related morbidity and mortality. Herein, we provide a framework to consider for the identification of patients with NAFLD at high risk of nonalcoholic steatohepatitis with advanced fibrosis and provide a critical assessment of currently accessible diagnostic and treatment modalities.

No abstract

Liver transplantation (LT) is definitive treatment for end‐stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty‐two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol‐associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait‐listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non‐Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End‐Stage Liver Disease (MELD)‐Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF‐C) score >51.5 (OR, 1.26; P = 0.03), acute‐on‐chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3‐month mortality included CLIF‐C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD‐Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non‐Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF‐C score predicted being declined for LT and mortality.