Background & Aims The appropriate alanine aminotransferase (ALT) threshold value to use for diagnosis of chronic liver disease in children is unknown. We sought to develop sex-specific, biology-based, pediatric ALT thresholds. Methods The screening ALT for elevation in today’s youth (SAFETY) study collected observational data from acute care children’s hospitals, the national health and nutrition examination survey (NHANES, 1999–2006), overweight children with and without non-alcoholic fatty liver disease (NAFLD), and children with chronic Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. The study compared the sensitivity and specificity of ALT thresholds currently used by children’s hospitals versus study-derived, sex-specific, biology-based, ALT thresholds for detecting children with NAFLD, HCV, or HBV. Results The median upper limit of ALT at children’s hospitals was 53 U/L (range, 30–90). The 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free, NHANES pediatric participants were 25.8 U/L (boys) and 22.1 U/L (girls). The concordance statistics of these NHANES-derived thresholds for liver disease detection were 0.85 (95% confidence interval [CI] 0.74–0.96) in boys and 0.91 (95% CI 0.83–0.99) in girls for NAFLD, 0.80 (95% CI 0.70–0.91) in boys and 0.79 (95% CI 0.69–0.89) in girls for HBV, and 0.86 (95% CI 0.77–0.95) in boys and 0.84 (95% CI 0.75–0.93) in girls for HCV. Using current children’s hospitals ALT thresholds, the median sensitivity for detection of NAFLD, HBV, and HCV ranged from 32% to 48%; median specificity was 92% (boys) and 96% (girls). Using NHANES-derived thresholds, the sensitivities were 72% (boys) and 82% (girls); specificities were 79% (boys) and 85% (girls). Conclusions The upper limit of ALT used in children’s hospitals varies widely and is set too high to reliably detect chronic liver disease. Biology-based thresholds provide higher sensitivity and only slightly less specificity. Clinical guidelines for use of screening ALT and exclusion criteria for clinical trials should be modified.

Assessing severity of disease in patients with alcoholic hepatitis (AH) is useful for predicting mortality, guiding treatment decisions, and stratifying patients for therapeutic trials. The traditional disease-specific prognostic model used for this purpose is the Maddrey discriminant function (

Background Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). Methods We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. Results Of the 978 patients in our cohort, 867 patients (mean age 56.9±14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. Conclusions The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and nonalcoholic steatohepatitis(NASH), among subjects with NAFLD. Methods In a Cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as 1) drinking > 20gm/day, 2) binge drinkers, or 3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression. Results The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to nondrinkers had lower odds of having a diagnosis of NASH (Summary odds ratio 0.56, 95%CI 0.39–0.84, p=0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95%CI 0.41–0.77) and ballooning hepatocellular injury (OR 0.66 95%CI 0.48–0.92) than lifetime non-drinkers. Conclusions In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD.

Objective Case series suggest that Nonalcoholic Fatty Liver Disease (NAFLD) is associated with increased all-cause and cardiovascular mortality. The current study compared the survival of subjects with and without suspected NAFLD in a population-based cohort, and placed the finding in the context of previously published case series. Methods Primary analysis assessed mortality for NHANES-III participants with and without suspected NAFLD using the National Death Index. Suspected NAFLD was based upon unexplained ALT elevation. The Olmsted County and Cleveland Clinic case series were also used for comparison. Survivals were compared using Proportional Hazards Model and direct age standardization. Results The NHANES cohort included 980 with and 6594 subjects without suspected NAFLD. Over a mean of 8.7 years, suspected NAFLD had a hazards ratio of 1.37 (95%CI 0.98–1.91) for all-cause mortality. In the 45–54 age group, suspected NAFLD had significantly higher all-cause (4.40 95%CI 1.27–13.23) and cardiovascular mortality (8.15 , 95%CI 2.00–33.20) after adjusting for conventional cardiovascular risk factors. The age-standardized rate per 10,000 per year was 129 (95%CI 118–140) for the NHANES non-NAFLD cohort, 154 (95%CI 116–198) for the NHANES suspected NAFLD cohort, 214 (95%CI 157–279) for the Olmsted County series, and 426 (95%CI 298–573) for the Cleveland Clinic series. Conclusion The magnitude of mortality risk in NAFLD depends on the setting and method of ascertainment. Suspected NAFLD in the 45–54 age group is a strong independent risk factor for cardiovascular death and warrants further cardiovascular risk management guidelines.

People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT > 43) and the cut point based on the 95th percentile of healthy subjects (ALT > 30 for men; ALT > 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05-0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33-0.79). Conclusion: Modest wine consumption is associated with reduced prevalence of suspected NAFLD. The current study supports the safety of one glass of wine per day for cardioprotection in patients at risk for both coronary heart disease and NAFLD. (HEPATOLOGY 2008;47:1947-1954

Alcoholic Liver Disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of ALD can be conceptually divided into 1) Ethanol mediated liver injury, 2) Inflammatory Immune response to injury, 3) Intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including IL22, anakinra, and others. These studies provide hope for better future outcomes for this difficult disease.

Background Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplant (LT) recipients with COVID-19 is not defined. Approach and Results We conducted a multicenter study in the US of 112 adult LT recipients with COVID-19. The median age was 61 years (IQR 20), 54.5% (n=61) were male, and 39.3% (n=44) Hispanic. The mortality rate was 22.3% (n=25); 72.3% (n=81) were hospitalized and 26.8% (n=30) admitted to the ICU. Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5x ULN) in 22.2% (n= 18) and severe liver injury (ALT > 5x ULN) in 12.3% (n= 10). Compared to age and gender matched non-transplant patients with CLD and COVID-19 (n=375), the incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; p=0.037). Variables associated with liver injury in LT recipients were younger age (p= 0.009, odds ratio (OR) 2.06 [1.20-3.54]), Hispanic ethnicity (p= 0.011; OR 6.01 [1.51-23.9]), metabolic syndrome (p= 0.016; OR 5.87 [1.38-24.99]), vasopressor use (p= 0.018; OR 7.34 [1.39-38.52]) and antibiotic use (p= 0.046; OR 6.93 [1.04-46.26]). Reduction in immunosuppression (49.4%) was not associated with liver injury (p= 0.156) or mortality (p= 0.084). Liver injury during COVID-19 was significantly associated with mortality (p= 0.007; OR 6.91 [95% CI: 1.68-28.48]) and ICU admission (p=0.007; OR 7.93[1.75-35.69]) in LT recipients. Conclusion Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.