The benefits of exercise for patients with non-alcoholic fatty liver disease

Abstract

As exercise is now an established therapy for the management of non-alcoholic fatty liver disease (NAFLD), recent investigations have sought to identify the optimal dose (type, intensity and amount) of exercise for hepatic benefit. Here, the authors discuss the following: the role of aerobic exercise for the modulation of hepatic steatosis; the limited evidence for the role of resistance training in reducing liver fat; the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis; and the benefits of exercise for patients with NAFLD, beyond steatosis. Based on current evidence, the authors provide recommendations for exercise prescription for patients with NAFLD.

Keywords:

• aerobic training
• exercise
• hepatic steatosis
• non-alcoholic fatty liver disease
• resistance training

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in many countries [1] and encompasses disorders ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH presents as steatosis with inflammatory changes, hepatocyte ballooning and a variable degree of fibrosis, and is strongly associated with both liver-related and cardiovascular disease morbidity and mortality. NAFLD is also associated with dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension [1]. Given the high prevalence of NAFLD in populations with obesity and type 2 diabetes and the fact that weight gain is a major determinant of NAFLD development [2], a multidisciplinary lifestyle intervention approach involving diet and exercise therapy is the cornerstone of management. The strongest hepatic benefit occurs with weight loss [3], and ≥7–10% reduction in body weight can lead to significant reduction in hepatic steatosis, improved NAFLD activity score and the reversal of NASH [3]. However, weight loss is typically an unsustainable outcome of clinical intervention with only 50% of individuals achieving the amount associated with histological improvement [3]. It is generally accepted that regular exercise leads to non-significant or small amounts of weight loss, but there are multiple benefits nonetheless. Human data clearly demonstrate that regular exercise itself reduces liver fat and can do so in the absence of clinically significant weight loss [4–7]. These data are supported by cross-sectional analyses which collectively demonstrate an inverse relationship between physical activity, physical fitness and NAFLD [8].

The optimal ‘dose’ of exercise for patients with NAFLD

Aerobic exercise training

Since the efficacy of exercise per se for the reduction of liver fat is now acknowledged, the emphasis of clinical investigation has centered on the optimal ‘dose’ of exercise required for benefit. In the absence of specific exercise guidelines for NAFLD, most studies have conformed to doses recommended by the American College of Sports Medicine for the development and maintenance of cardiorespiratory, musculoskeletal and neuromuscular fitness in apparently healthy adults [9]. With respect to aerobic exercise, these guidelines promote moderate-intensity cardiorespiratory exercise training for ≥30 min on at least 5 days per week, or vigorous cardiorespiratory exercise training for ≥20 min on 3 days per week, or a combination of both and align with global recommendations for health, fitness and disease prevention [10]. Exercise interventions meeting these guidelines consistently demonstrate reduction in liver fat of 10–43% in patients with NAFLD [5,6,11–16]. We recently observed significant reduction in intrahepatic lipid (IHL) with exercise training doses which emphasized volume over intensity (45–60 min of aerobic exercise at 50% VO_2peak on 4 days per week, mean relative IHL reduction of 28%) or intensity over volume (30–45 min of aerobic exercise at 70% VO_2peak on 3 days per week, mean relative IHL reduction of 29%) in previously inactive obese adults [14]. These observations are congruent with the options provided in current guidelines (i.e., that people can undertake either vigorous aerobic exercise with lower time commitment or lower-intensity aerobic exercise requiring greater time commitment). Interestingly, a mean 18% relative reduction in IHL was also observed with prescription of low-to-moderate intensity and low-volume aerobic exercise (30 min at 70% VO_2peak on 3 days per week), demonstrating that significant reductions can occur below the doses advocated in the current guidelines.

Progressive resistance training

Exercise guidelines for health and fitness also recommend that adults undertake progressive resistance training (PRT) on 2–3 non-consecutive days per week [9]. PRT involves the repetitive movement of strenuous weights/loads in short bursts for all major muscle groups, typically with specialized equipment. To date, there is sparse evidence for the efficacy of PRT as per these guidelines for liver fat reduction. Of the nine studies employing PRT in isolation, five observed a significant reduction in liver fat [5,13,17–19], three of which conformed with the abovementioned guidelines [5,13,18], while four showed no benefit [12,20–22] with discrepancies in outcomes likely due to the large heterogeneity in study design. These differences include the use of circuit-based training (which has a concurrent ‘aerobic’ exercise stimulus) [19,22], the use of home-based prescription [17], and variation in training intensities and study populations, all of which combined limit the ability to generalize findings and draw practical conclusions.

The largest study to date which has directly compared aerobic exercise with PRT observed significant reduction in liver fat score (assessed via attenuation of computed tomography) with 8 months of aerobic exercise training but not with PRT in overweight adults [20]. Moreover, despite performing double the training load of the aerobic alone or PRT alone groups, aerobic exercise combined with PRT led to a non-significant reduction in liver fat. A superior hepatic benefit of aerobic exercise training was also demonstrated in obese adolescent girls [12]; however, comparable reductions between aerobic and resistance training have been observed in NAFLD patients with type 2 diabetes [5] and in obese adolescent boys [13].

Exercise for patients with NASH

There is no evidence to suggest that exercise has an effect on NASH. The only human interventional trial employed 6 months of circuit-type training in nine patients with NAFLD and found no significant reduction in NAFLD activity score or fibrosis when compared with dietary intervention, despite a mean 18% reduction in visceral adipose tissue and a mean (non-significant) 24% reduction in biopsy-determined steatosis level [22]. Cross-sectional data suggest that vigorous exercise intensity per se is required for histological improvement in the liver [23]; however, this is based on self-report data. Recent research from obese rodent models also suggests a superior benefit of high-intensity training compared with moderate-intensity continuous exercise on liver fat and markers of liver injury typically associated with NASH [24]. However, until further evidence is available from human clinical trials, exercise for patients with NASH should be prescribed at similar exercise levels, cognizant of co-morbidities and in conjunction with lifestyle changes and pharmacotherapy [9].

Safety of vigorous exercise in clinical populations

Vigorous physical activity may be contraindicated in patients with, or at risk of, cardiovascular disease, which includes those with NAFLD. Vigorous exercise should only be initiated after appropriate pre-screening. Available evidence suggests that vigorous exercise is safe in patients with coronary artery disease [25], but pre-medical evaluation should include 12-lead electrocardiography (stress testing) and appropriate specialist review if indicated.

Benefits for patients with NAFLD: beyond steatosis

Regular exercise training provides panoply of health benefits and is justifiably touted as a ‘polypill’ for chronic disease management. Given that cardiovascular disease is the primary cause of mortality in patients with NAFLD, the benefits of exercise extend beyond steatosis. There is substantial evidence for exercise benefiting the secondary vascular and metabolic co-morbidities associated with NAFLD, including insulin resistance, dyslipidemia, inflammation, hypertension [9] and endothelial dysfunction [16,26], which reduces the risk of liver-related and cardiovascular morbidity and mortality. Indeed, a one Metabolic Equivalent improvement in cardiorespiratory fitness (3.5 ml/kg/min) is associated with a 13 and 15% reduction in all-cause mortality and risk of cardiovascular events, respectively [27]. As there is currently no established association between the degree of reduction in hepatic steatosis and reduction in cardiovascular events, these extrahepatic benefits should be underscored when promoting exercise for obese patients with bland steatosis and co-morbid metabolic dysfunction.

Recommendations for exercise prescription

Based on current evidence, we advocate the prescription of 150–300 min per week of moderate- to vigorous-intensity (50–70% VO_2peak) aerobic exercise, performed on a minimum of 3 days per week, for hepatic benefits in patients with NAFLD. Although volume should be emphasized for the modulation of body composition including IHL, vigorous-intensity aerobic exercise may lead to superior improvement in cardiorespiratory fitness and glycemic control. While evidence supports the prescription of aerobic exercise in the first instance, performing PRT for 2–3 days per week following a prescription of two to three sets of 8–12 repetitions at an intensity of 70–85% 1-repetition maximum may provide additional benefit for optimizing insulin sensitivity and improving muscle strength and function. Ideally, participation in resistance training would be in addition to performing regular aerobic exercise at the level promoted in the guidelines. Ultimately, exercise prescription should be individualized to promote adoption and long-term adherence to the exercise regimen, which may be facilitated by behavioral and cognitive strategies [28]. While the benefits of exercise are apparent, from a clinical perspective, a multidisciplinary lifestyle approach with combined diet and exercise therapy is regarded as ‘best practice’ given that the strongest hepatic benefit occurs with weight loss.

Financial & competing interests disclosure

J George is supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) program grant (grant number: 1053206); and a project grant (grant number: 1049857). NA Johnson has received honoraria for speaking engagements for Merck Sharp & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.