NASH Fitness Intervention in Thrombosis Trial (NASHFit)

Often comorbid with obesity, nonalcoholic fatty liver disease (NAFLD) is the leading cause of
chronic liver disease in the United States affecting 75-100 million adults, of which 15-20
million have the more severe variant nonalcoholic steatohepatitis (NASH). Conservative
estimates project a doubling in NASH by 2025.The most advanced forms of NAFLD are associated
with increased liver-related mortality and lower overall survival. The most effective
treatment for NAFLD remains adopting healthy dietary and exercise patterns, however NAFLD
patients are among the least physically active individuals. Predicting exercise behavior on
an individual level is highly complex due to differing motivation, physiologic response to
and subjective experience of exercise as well as emerging genetic evidence. The human genome
and regulation of gene expression is influenced by physical activity. Patatin like
phospholipase-3 (PNPLA3) rs738409 polymorphism (GG, GC and CC genotypes) plays a crucial role
in the development of NAFLD. The GG genotype is both associated with advanced NAFLD, and
predicts response to physical activity. Patients with NASH have extensive extrahepatic
disease and are hypercoagulable. NASH is a prothrombotic state with fibrinolytic dysfunction
through elevated plasminogen activator inhibitor (PAI-1), an independent risk factor for
venous thromboembolism (VTE). Consequently, patients with NASH are predisposed to VTE; the
risk of portal vein thrombosis (PVT) in NASH is 210% greater than in other liver disease.
NASH patients are also at increased risk for pulmonary embolism (PE) and deep vein thrombosis
(DVT).The most advanced forms of NASH have the greatest thrombotic risk. While studies
observe that change in diet, weight and physical activity patterns improve NASH, it is not
clear whether these lifestyle changes also reduce the elevated clot risk, however,
moderate-intensity exercise leads to improved fibrinolysis in healthy persons.The NASHFit
study is being done to find out if exercise is beneficial in decreasing the risk of clotting
problems in patients with NASH. Exercise has been shown to decrease markers of clotting in
healthy individuals as well as in those with cardiovascular disease.

Inclusion Criteria Adults age >=18 or <70 years Liver biopsy <= 6months prior to enrollment
Biopsy proven NASH(79)

Lack of secondary causes of hepatic fat accumulation:

Significant alcohol consumption (<21 drinks/week for men and <14 drinks/week for women)
Chronic hepatitis C Wilson disease Lipodystrophy Parenteral nutrition Long-term use of
steatogenic medications (mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen,
corticosteroids) Monogenic hereditary disorders

Exclusion Criteria >90 minutes/week of at least moderate intensity exercise over the
previous three months Pregnancy BMI <18 or >40 kg/m2(16) Uncontrolled diabetes (changes in
medication dosing over the previous three months or hemoglobin A1c >9%)(12) Active cardiac
symptoms Severe medical comorbidities/psychiatric illness Decompensated cirrhosis (history
of esophageal varices, ascites or hepatic encephalopathy) Abdominal hernia Cancer with life
expectancy <6 months MRI contraindications (severe claustrophobia, implanted ferrous metal)
Other liver disease (positive hepatitis B surface antigen, antinuclear antibody titer
>1:160) Active weight-loss program participation or weight-loss supplement use Active
substance abuse/smoking Inability to provide informed consent Institutionalized/prisoner
Inability to walk > 2 blocks or ¼ mile. Physical Activity Readiness Questionnaire (PAR-Q)
score >=1 at the discretion of the study PI