Abstract
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.
Highlights
There is an urgent need for effective therapies for nonalcoholic fatty liver disease (NAFLD)because of its high prevalence, affecting approximately 25% of the global population [1,2]
While liver biopsies are commonly performed and histology is recommended as the best primary outcome for phase 3 clinical trials in pediatric NAFLD [6,9], they are both invasive and costly [10,11] and biopsies are typically avoided in early phase studies
Mean ALT was higher in the group that progressed versus the group that improved at each time point with the exception of NAFLD activity score (NAS) Score and nonalcoholic steatohepatitis (NASH) at baseline
Summary
Because of its high prevalence, affecting approximately 25% of the global population [1,2] It is currently the second leading indication for liver transplant in the US [3]. Clinical trials for potential therapies have been conducted in children with NAFLD [5,6] and new studies are needed to test novel therapeutic approaches [7]. While liver biopsies are commonly performed and histology is recommended as the best primary outcome for phase 3 clinical trials in pediatric NAFLD [6,9], they are both invasive and costly [10,11] and biopsies are typically avoided in early phase studies. Validated noninvasive biomarkers to assess treatment response in pediatric nonalcoholic fatty liver disease (NAFLD) are lacking. 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)
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