In a large multicenter study with patients from across the United States, we assessed the cross-sectional relationship between meeting or exceeding US national guidelines for physical activity and histological severity of NAFLD. There was no association between meeting moderate-activity guidelines and histological severity of NAFLD. In contrast, meeting the minimum guidelines for vigorous activity was associated with a significant reduction in the adjusted odds of having NASH. Furthermore, exceeding the vigorous-activity guidelines, which is recommended for additional health benefits, was associated with a decreased odds of fibrosis.
These data, based on a large population with biopsy-proven NAFLD and a careful examination of liver histology, substantially extend the knowledge base of physical activity and severity of NAFLD. Two cross-sectional studies have evaluated the association between physical activity or fitness level and the presence or absence of suspected NAFLD based on liver biochemistry (elevated AST, ALT) and/or liver imaging (ultrasonography or computed tomography). These technologies are limited both by being unreliable for the detection of mild steatosis and by their inability to assess for the presence of steatohepatitis or stage of fibrosis. Zelber-Sagi et al
), found that subjects with suspected NAFLD (identified by ultrasonography) reported a lower weekly duration of exercise than did those without suspected NAFLD. In a study by Church et al
), adults with suspected NAFLD had a lower cardiorespiratory fitness level than did those without suspected NAFLD. Other studies have examined changes in liver biochemistry in response to multimodal interventions incorporating both diet and exercise in subjects with suspected NAFLD. In a study by Suzuki et al
), 348 subjects with elevated ALT were identified and counseled on exercise and nutrition. Beginning or continuing an exercise routine was associated with a greater change in ALT compared with performing no exercise. A similar study by Kim et al
., included subjects identified by ultrasonography during a regular health checkup as having NAFLD. Those subjects were advised to increase physical activity and to reduce calorie intake (17
). At 5-year follow-up, a greater proportion of subjects exercising ≥3 times a week had a decrease in ultrasonographic abnormalities than did those who exercised <3 times a week. St George et al
), randomized subjects with suspected NAFLD (ALT >30 for males or >19 for females) to one of three different intensity counseling groups (low intensity: three sessions; moderate: six sessions; moderate plus: six sessions plus phone follow-up) or to a control group. Subjects who increased their physical activity by at least 60 min (n
=85), or who maintained their physical activity at ≥150 min per week (n
=29) had the greatest improvements in liver biochemistry than did those who were inactive (n
=25). In another small study (n
=16) that included subjects with biopsy-proven NASH, subjects received diet counseling and were encouraged to walk or jog for 30 min a day (11
). Improvements were seen in weight and serum aminotransferases; however, post-treatment histology was not assessed.
We expected to find that both moderate and vigorous physical activities were inversely associated with disease severity. However, the finding that only vigorous-intensity physical activity was associated with histological severity is consistent with a large body of literature on all-cause mortality, cardiovascular disease, and colon cancer (27
). Epidemiological studies on exercise intensity and cardiovascular outcomes are better developed for men than for women. In men, the preponderance of evidence suggests that physical activity of vigorous intensity, but not of moderate intensity, is associated with a decreased frequency of coronary heart disease (29
). For example, The Health Professionals’ Follow-up Study, with a sample of 44,452 men and 12 years follow-up, demonstrated that, adjusted for exercise volume, vigorous but not moderate physical activity was associated with a decreased risk for myocardial infarction (31
). In addition to cardiovascular disease, large long-term studies of men have shown that vigorous- but not moderate-intensity physical activity was associated with decreased risk for all-cause mortality (32
). Less is known about the effect of exercise intensity on health outcomes in women because there are fewer published data and the available studies have much shorter follow-up duration. However, a large study reported a similar risk reduction for coronary events for moderate and vigorous activities (35
). Thus, data obtained from men suggest important differences between exercise intensity and risk for coronary heart disease, whereas more data with longer follow-up are required in women. In the current study, no gender interaction was found in the analysis of meeting vigorous recommendations and odds of NASH.
The biological basis for observed differences in the association between moderate and vigorous physical activities and the severity of NAFLD are not known. One potential explanation is the effect of exercise on AMP-activated protein kinase (AMP-kinase), a regulator of intracellular energy metabolism. AMP-kinase activation in the liver increases fatty acid oxidation and decreases glucose production (36
). Activation of AMP-kinase leads to phosphorylation of many downstream targets that regulate mitochondrial biogenesis and hepatic gluconeogenesis (37
). Furthermore, AMP-kinase not only regulates energy but may also have a key role in hepatic fibrogenesis, as it has been shown to suppress hepatic stellate cell proliferation. Under normal conditions, AMP-kinase is activated when the ratio of AMP is greater than ATP. Exercise can increase the AMP-to-ATP ratio; however, only vigorous activity results in a large enough shift of the AMP-to-ATP ratio required to activate AMP-kinase. Thus, observed differences in the association between exercise intensity and histological severity could be due to differences in the ability of exercise to modulate cellular pathways controlling metabolism, inflammation, and matrix deposition (38
The multicenter design of the NASH CRN makes these results generalizable to adults in the United States with a clinical (i.e., biopsy-proven) diagnosis of NAFLD. An additional strength of this study was the inclusion of liver histology on all patients with a rigorous, standardized, central biopsy review. A limitation was the cross-sectional nature of this study; thus, these data do not establish a causal relationship between exercise and disease severity. In addition, self-report of physical activity may result in error and misclassification. In particular, better reliability and validity has been demonstrated for recall of vigorous- vs. moderate-intensity activity (39
). The present measure was limited to leisure-time physical activity, and it is likely activities in occupation, transport, and household domains that were not assessed are more likely to be moderate than vigorous (26
). Measurement limitations and misclassification due to reporting bias could have reduced power to detect associations with moderate physical activity. Furthermore, this analysis included a large sample of individuals with NASH, but without cirrhosis, who qualified for the PIVENS trial. However, sensitivity analyses excluding the clinical trial participants (no. 3) showed similar results. Longitudinal studies with objective measures of physical activity and randomized clinical trials are required to further examine the relationship between physical activity intensity and histological severity in individuals with NAFLD. Moderate exercise may still be beneficial over time, if only by attenuating further weight gain, but longitudinal studies are necessary to address this possibility.
In conclusion, we found an inverse relationship between vigorous-intensity physical activity and NAFLD severity. Moderate-intensity physical activity and total volume of physical activity were not related to outcomes. Thus, intensity may be an important dimension of physical activity to consider when counseling patients and planning interventions. Intervention studies with objective measures of physical activity are required to confirm the differential effects of vigorous compared with moderate physical activity on NAFLD severity.