NASH Fitness Intervention in Thrombosis Trial (NASHFit)
NASH Fitness Intervention in Thrombosis Trial (NASHFit)
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the
 United States. The most advanced forms of NAFLD are associated with increased liver-related
 mortality and lower overall survival. The current standard of care for NAFLD is lifestyle
 changes through diet and exercise. The human genome and regulation of gene expression is
 influenced by physical activity. NAFLD is a prothrombotic state with derangements in all
 three phases of hemostasis leading to clinically important clotting events. Exercise can
 improve coagulation in healthy persons. In this proposal, we seek to begin a line of work to
 answer the question "Can lifestyle changes effectively mitigate the increased risk of
 clotting in patients with NAFLD?" focusing initially on the at-risk population genetically
 susceptible to advanced disease.
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