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  The Liver Meeting
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November 13 - 16 - 2021
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Exercise for 20 Weeks Tied to Lower
Clotting Risk in Randomized NASH Trial

  AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
People with nonalcoholic steatohepatitis (NASH) randomized to 20 weeks of supervised aerobic exercise had a significant drop in a clotting marker compared with NASH patients who got standard care in a small trial [1]. Exercisers enjoyed this anticlotting benefit independent of weight loss or changes in diet.
Researchers from Penn State College of Medicine noted that physical inactivity boosts chances of nonalcoholic fatty liver disease (NAFLD) and NASH, which can lead to morbidity and mortality from nonliver causes like nonliver cancer, cardiovascular disease, and venous thromboembolism. The last of these complications in people with NAFLD can be traced to higher rates of deep vein thrombosis, portal vein thrombosis, and pulmonary embolism. Prior research found that exercise training can cut risk of venous thromboembolism in healthy people and in those with peripheral vascular disease. But the impact of exercise on venous thromboembolism has not been studied in people with NAFLD.
To address this issue a Penn State team conducted the NASHFit trial, which included 18- to 69-year-old people with biopsy-confirmed NASH within the past 6 months. Trial participants had to be sedentary, defined as fewer than 90 minutes of physical activity per week over the past 3 months. No one could have active cardiac symptoms, ongoing substance dependence including smoking, decompensated cirrhosis, or excessive alcohol use. And no one could be taking anticoagulants (except 81-mg aspirin) or have an active weight loss program.
Researchers randomized participants in a 2-to-1 ratio to 20 weeks of aerobic exercise or standard care. Supervised exercise with real-time heart-rate monitoring took place for 45 minutes 5 days a week at a heart rate corresponding to 45% to 55% of maximal oxygen uptake (VO2 peak), which can be achieved with walking or light cycling. Standard-care participants continued usual clinical care. Both groups got standard dietary counseling with energy expenditure- and Mediterranean diet-informed macronutrient goals and instructions to avoid processed foods.
The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1), an established marker of clotting risk. Sample size calculation determined the trial would need 42 participants to detect a 23% difference in PAI-1. The trial's Data and Safety Monitoring Board (DSMB) recommended an interim analysis with two thirds of target participants enrolled. Reviewing findings at that point, the DSMB unanimously recommended stopping the trial.
At that point researchers had randomized 28 participants, 18 to the exercise program and 10 to standard care. Participants had completed 82% of exercise sessions, and 89% met the definition of exercise adherence set before the trial began.
Overall these 28 people averaged 50 years in age, 61% were women, 92% were white, and body mass index averaged 34.6 kg/m2 (in the obese range). Two thirds had hypertension, and 39% had diabetes. Magnetic resonance imaging proton density fat fraction (MRI-PDFF) averaged 22.1%.
Average age was nonsignificantly older in the exercise group (52.9 vs 45.0, P = 0.082). The two groups did not differ significantly in proportion of women, body mass index, diabetes, high lipids, hypertension, average hemoglobin A1c (a diabetes marker), VO2peak, liver fat by MRI-PDFF, or proportions with liver fibrosis stage F0, F1, F2, F3, or F4.
In two analyses PAI-1, the clotting marker, fell in the exercise group while rising in the no-exercise control group (P = 0.02 and P = 0.04). MRI-PDFF-measured percent absolute liver fat dropped in the exercise group while rising in controls (-4.7 +/- 5.6 vs 1.2 +/- 2.8%, P = 0.01). Among exercisers versus nonexercisers, 40% versus 13% had at least a 30% relative drop in MRI-PDFF (P < 0.01), which is the threshold for histologic response.
Hemoglobin A1c, the diabetes marker, fell in the exercise group (-0.4 +/- 0.6) while rising in the control group (0.4 +/-0.7%) (P < 0.01). Absolute fasting glucose also dropped with exercise while climbing in nonexercising controls (P = 0.04). Exercise yielded significant declines in body fat and visceral adipose tissue, compared with small gains in controls (P = 0.02 for both).
These changes were independent of clinically significant (7% or greater) weight loss (1 exerciser and no controls), dietary change (no change in macronutrients, sodium, or fiber), or adverse events (no adverse events during VO2peak fitness testing).
The researchers noted that the drop in MRI-PDFF absolute liver fat and improvement in cardiorespiratory fitness with aerobic exercise exceeded threshold levels needed for histologic response and improved overall and cardiovascular mortality. The Penn State investigators cautioned that the analysis suffers from the small study size and lack of long-term outcomes. A well-appreciated limitation of short-term supervised exercise programs is the willingness or ability of sedentary people to continue exercising on their own when a trial ends.
1. Stine JG, et al. Nonalcoholic steatohepatitis fitness intervention in thrombosis (NASHFit): a randomized controlled trial of an exercise training program to reduce elevated clotting risk in patients with NASH. AASLD, The Liver Meeting, November 12-15, 2021. Parallel session 17: NAFLD and NASH: Predicting Outcomes and Response to Interventions.