Efficacy of Weight Reduction on Pediatric Nonalcoholic Fatty Liver Disease: Opportunities to Improve Treatment Outcomes Through Pharmacotherapy.

Chance S. Friesen,Jonathan B. Wagner,Sherwin S. Chan,Alec Friesen,Iván L. Csanaky,Jason D. Fraser,Chelsea Hosey-Cojocari,Brooke R. Sweeney,Valentina Shakhnovich

doi:10.3389/fendo.2021.663351

Abstract

Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low. Bariatric surgery, though effective, is invasive and can worsen NAFLD postoperatively. Thus, there is an evolving and underutilized role for pharmacotherapy in children, both for weight reduction and NAFLD management. In this perspective article, we provide an overview of the efficacy of weight reduction on pediatric NAFLD treatment, discuss the pros and cons of currently approved pharmacotherapy options, as well as drugs commonly used off-label for weight reduction in children and adolescents. We also highlight gaps in, and opportunities for, streamlining obesity trials to include NAFLD assessment as a valuable, secondary, therapeutic outcome measure, which may aid drug repurposing. Finally, we describe the already available, and emerging, minimally-invasive biomarkers of NAFLD that could offer a safe and convenient alternative to liver biopsy in pediatric obesity and NAFLD trials.

Highlights

With 340 million children worldwide affected by obesity [1], the rate of nonalcoholic fatty liver disease (NAFLD) is expected to rise because obesity remains the single most significant risk factor for NAFLD [2]
In addition to effective childhood weight management strategies, readily available non-invasive diagnostic and monitoring modalities are needed for NAFLD management, in order to prevent obesity-associated NAFLD progression from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure in adulthood
The present work aims to review the efficacy of weight reduction on pediatric NAFLD and to illustrate opportunities for improving NAFLD diagnosis, monitoring, and treatment outcomes through pharmacologic interventions

Summary

INTRODUCTION

With 340 million children worldwide affected by obesity [1], the rate of nonalcoholic fatty liver disease (NAFLD) is expected to rise because obesity remains the single most significant risk factor for NAFLD [2]. In a large national prospective registry of children participating in non-surgical, multicomponent, intensive behavioral clinical treatment for obesity (n=6,454), the mean change in %BMIp95 after lifestyle modification was -1.88% at 4 to 6 months, -2.5% at 7 to 9 months, and -2.86% at >12 months – showing a modest decline in weight loss over time Those patients who achieved -5.2% change in %BMIp95 showed improvement in alanine aminotransferase (ALT), a clinical biomarker of liver injury [23]. Though weight-reduction is an important first-line treatment for children with NAFLD, and may be achieved through lifestyle modifications, bariatric surgery or pharmacotherapy, each approach is associated with substantial variability in treatment response This leaves a gap in universally effective treatments for pediatric NAFLD, and a potential role for precision therapeutics and pharmacotherapy. Total fasting and postprandial primary BAs, and the ratios of taurine- and glycine-conjugated BAs, are consistently higher in the sera of adults with nonalcoholic

DATA AVAILABILITY STATEMENT

Findings

DISCUSSION