A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children, and currently, there are no FDA-approved therapies. Plasminogen activator inhibitor-1 (PAI-1) is elevated in children with NAFLD and associated with increased disease severity. Losartan potassium (losartan) is an angiotensin II receptor blocker (ARB) that reduces PAI-1 production and improves insulin sensitivity that has been proposed as a treatment for pediatric NAFLD but has not previously been tested. Methods This was an 8-week randomized, double-blind, placebo-controlled, phase 2a, crossover study (with a 6-week washout between conditions) for safety and preliminary efficacy of losartan 50 mg a day taken orally in 12 normotensive children with biopsy proven nonalcoholic steatohepatitis (NASH). Results Twelve children enrolled in the study, and nine completed all visits. No changes in blood pressure or serious adverse events occurred during the study. Trends in improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and homeostatic model assessment insulin resistance (HOMA-IR) were seen with losartan treatment compared to the placebo time-period. More participants decreased ALT on losartan as compared to placebo (89% [8 out 9] vs. 56% [5 out of 9], respectively). Conclusions This data provides preliminary evidence that losartan treatment is safe over 8 weeks in children with NAFLD and supports consideration of larger studies to test its efficacy. Trial registration URL and trial identification number: https://clinicaltrials.gov/show/NCT01913470, NCT01913470. Date registered: August 1, 2013

Alanine Aminotransferase as a Monitoring Biomarker in Children with Nonalcoholic Fatty Liver Disease: A Secondary Analysis Using TONIC Trial Data

Background: Validated noninvasive biomarkers to assess treatment response in pediatric nonalcoholic fatty liver disease (NAFLD) are lacking. We aimed to validate alanine aminotransferase (ALT), a monitoring biomarker for change in liver histology. Methods: A retrospective analysis using data from the TONIC trial. NAFLD histologic assessments were defined by: Fibrosis score, NAFLD activity score (NAS), nonalcoholic steatohepatitis (NASH), and a combination of NASH resolution and fibrosis (NASH + fibrosis). Analysis was performed using classification and regression trees (CART) as well as logistic regression. Results: Mean ALT for the child over 96 weeks and percent change of ALT from baseline to 96 weeks were significant predictors of progression of NAFLD for each histologic assessment (p < 0.001 for fibrosis score, NASH, and NASH + fibrosis and p < 0.05 for NAS). Mean ALT adjusted for age, sex and ethnicity was a better predictor for change in NASH (81.8 (11.0) ROC (receiver operating characteristic curve) mean (SD (Standard derivation))) and NASH + fibrosis (77.8 (11.2)), compared to change in NAS (63 (17.7)) and fibrosis (58.6 (11.1)). Conclusion: Mean ALT over 96 weeks is a reasonable proxy of histologic improvement of NASH and NASH + fibrosis. These findings support ALT as a valid monitoring biomarker of histologic change over time in children with NASH and fibrosis