Nonalcoholic steatohepatitis Fitness Intervention in Thrombosis (NASHFit): Study protocol for a randomized controlled trial of a supervised aerobic exercise program to reduce elevated clotting risk in patients with NASH

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide affecting upwards of one third the global population. For reasons not fully understood, individuals with NAFLD and its more severe variant, nonalcoholic steatohepatitis (NASH), are at increased risk for venous thromboembolism which significantly increases morbidity and mortality. Lifestyle changes centering around exercise training are the mainstay of treatment for NAFLD/NASH. While exercise training can lessen venous thromboembolic risk in healthy persons and those with cardiovascular disease, whether or not this benefit is seen in patients with NAFLD/NASH remains unknown. In order to better understand how exercise training impacts thrombosis risk in NAFLD, we present the design of a thirty-two week randomized controlled clinical trial of 42 sedentary subjects age 18-69 with biopsy proven NASH. The main aim is to determine the impact of an aerobic exercise training program on the abnormal hemostatic system unique to NAFLD/NASH. The main outcome is change in plasminogen activator inhibitor one level, an established marker for venous thromboembolism. Secondary outcomes include body composition, cardiorespiratory fitness, control of comorbid metabolic conditions (e.g., obesity, hypertension, hyperlipidemia, diabetes), dietary composition, health related quality of life, liver enzymes and histology, NAFLD/NASH disease activity (e.g., biomarkers, clinical decision aids), microbiome, other markers of hemostasis, and PNPLA3 gene expression. The study represents the first clinical trial of an exercise training program to reduce elevated clotting risk in subjects with NAFLD/NASH.