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Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

ABSTRACT: BACKGROUND & AIMS:Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ?2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response. METHODS:We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve. RESULTS:The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ? 154 mg/dL, baseline international normalized ratio ? 1, baseline aspartate aminotransferase level ? 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001). CONCLUSIONS:In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.

SUBMITTER: Loomba R

PROVIDER: S-EPMC6696948 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

Loomba Rohit R Sanyal Arun J AJ Kowdley Kris V KV Terrault Norah N Chalasani Naga P NP Abdelmalek Manal F MF McCullough Arthur J AJ Shringarpure Reshma R Ferguson Beatrice B Lee Lois L Chen Jianfen J Liberman Alexander A Shapiro David D Neuschwander-Tetri Brent A BA

Gastroenterology 20180915 1

<h4>Background & aims</h4>Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid ...[more]

PMID: 30222962

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Project description:Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1-point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group-adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96-week biopsies, and in FLINT 200 subjects had baseline and 72-week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

Project description:Background & aimsObese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH.MethodsTwenty-one patients with early hepatic fibrosis (81% female; mean age, 54 years; average body mass index, 44 kg/m2) underwent magnetic resonance elastography (MRE) and endoscopic ultrasound with core liver biopsy collection at time IGB placement and removal at a single center from October 2016 through March 2018. The primary outcome measure was the changes in liver histology parameters after IGB, including change in nonalcoholic fatty liver disease activity score (NAS) and fibrosis score. We also evaluated changes in weight, body mass index, waist to hip ratio, aminotransaminases, fasting levels of lipids, fasting glucose, glycosylated hemoglobin, and MRE-detected liver stiffness.ResultsSix months after IGB, patients' mean total body weight loss was 11.7% ± 7.7%, with significant reductions in HbA1c (1.3% ± 0.5%) (P = .02). Waist circumference decreased by 14.4 ± 2.2 cm (P = .001). NAS improved in 18 of 20 patients (90%), with a median decrease of 3 points (range, 1-4 points); 16 of 20 patients (80%) had improvements of 2 points or more. Fibrosis improved by 1.17 stages in 15% of patients, and MRE-detected fibrosis improved by 1.5 stages in 10 of 20 patients (50%). Half of patients reached endpoints approved by the Food and Drug Administration of for NASH resolution and fibrosis improvement. Percent total body weight loss did not correlate with reductions in NAS or fibrosis. Other than post-procedural pain (in 5% of patients), no serious adverse events were reported.ConclusionIn a prospective study, IGB facilitated significant metabolic and histologic improvements in NASH. IGB appears to be safe and effective for NASH management when combined with a prescribed diet and exercise program. ClinicalTrials.gov no: NCT02880189.

Project description:BACKGROUND & AIMS:Cross-sectional studies of patients with nonalcoholic fatty liver disease (NAFLD) have reported a lower prevalence of severe disease among modest drinkers compared with nondrinkers. We collected data from adult participants in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network to evaluate the longitudinal association between modest use of alcohol and histology findings in patients with NAFLD, using paired liver biopsies collected more than 1 year apart. METHODS:We studied NASH Clinical Research Network participants 21 years or older, not receiving pharmacologic therapy, from whom 2 or more liver biopsies and data on alcohol use within 2 years of the initial biopsy were available. Alcohol consumption was evaluated at study entry using the Alcohol Use Disorders Identification Test and Skinner Lifetime Drinking History questionnaires. At each follow-up visit participants were asked about alcohol use frequency, number of drinks on a typical day, and frequency of heavy drinking. The association between baseline drinking status and changes in fibrosis stage, NASH histology, and the NAFLD Activity Score and its individual components were evaluated by analysis of covariance. The association between change in drinking status and change in histology was evaluated using adjusted logistic regression. RESULTS:Of 285 participants (82% white, 70% female, mean age, 47 y) meeting entry criteria, 168 (59%) were modest alcohol users (?2 drinks/d) and the remaining 117 were abstinent. At baseline, a higher proportion of modest alcohol users were white (86% vs 76% nonwhite) (P = .04) and a lower proportion of modest alcohol users were diagnosed with definite NASH (57% vs 74% without NASH; P = .01). During a mean follow-up period of 47 months between biopsies, nondrinkers had a greater mean reduction in steatosis grade (reduction, 0.49) than modest drinkers (reduction, 0.30; P = .04) and a greater reduction in mean level of aspartate transaminase (reduction, 7 U/L vs an increase of 2 U/L in modest drinkers; P = .04). Modest drinkers had significantly lower odds of NASH resolution compared with nondrinkers (adjusted odds ratio, 0.32; 95% CI, 0.11-0.92; P = .04) on adjusted analysis. CONCLUSIONS:In a longitudinal analysis of liver biopsies from patients with NAFLD not receiving pharmacologic therapy, modest alcohol use was associated with less improvement in steatosis and level of aspartate transaminase, as well as lower odds of NASH resolution, compared with no use of alcohol.

Project description:Background and aimsPredictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial.Approach and resultsThis study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52 weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P < 0.0001) retained baseline and change in GGT (area under the receiver operating characteristic [AUROC], 0.79; 95% confidence interval [CI], 0.71-0.87). For borderline zone 1 NASH, the model (P = 0.0004) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). For fibrosis, the model (P < 0.001) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). Additional clinical parameters were added to the models using Akaike's information criterion selection, and significantly boosted performance: improvement in histology with AUROC of 0.89 (95% CI, 0.82-0.95), borderline zone 1 NASH with AUROC of 0.91 (95% CI, 0.83-0.99), and fibrosis with AUROC of 0.89 (95% CI, 0.82-0.94). Models were validated using data from the TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial.ConclusionsIn children with NAFLD, dynamic changes in serum ALT and GGT are associated with change in liver histology and appear to be powerful indicators of histological response.

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Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

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Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

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