Aerobic Exercise in the Management of Metabolic Dysfunction Associated Fatty Liver Disease

Figures & data

Table 1 Observational Studies Evaluating the Effect of Physical Activity on MAFLD

Reference	Country	Study Design	N	Evaluation of Physical Activity	Diagnosis of MAFLD	Main Results
Perseghin G, 2007^Citation23	Italy	Cross-sectional, Cohort	191	Questionnaire	^1H-MRS	● Inverse correlation between hepatic fat content and PA. ● ↓ prevalence of MAFLD according to quartile of PA: 25 > 11 < 25 >2%
Zelber-Sagi S, 2008^Citation24	Israel	Cross-sectional, Cohort	349	Self-reported PA in the last year	Abdominal US	● The MAFLD group engaged in less aerobic or resistance PA
Kistler KD, 2011^Citation42	USA	Cross-sectional, Cohort	813 MAFLD patients	Self-reported PA questionnaire from the NHANES	Liver biopsy	● Moderate-intensity PA did not associate with steatohepatitis or fibrosis stage ● Vigorous PA ↓ risk of steatohepatitis: OR 0.65 [0.43–0.98] ● Doubling recommended time spent in vigorous PA ↓ risk of advanced fibrosis: OR 0.53 [0.29–0.97]
Gerber L, 2012^Citation32	USA	Cross-sectional, Cohort	3056	Activity counts from accelerometer readings for 7 days	FLI >60	● Patients with MAFLD spent less time participating in activity at any level ● Average PA was 28.7 counts/minute/day lower in MAFLD patients than controls
Bae JC, 2012^Citation37	Korea	Cross-sectional, Cohort	72359	Self-reported questionnaires	Abdominal US	● Subjects who exercised >3x/week, ≥30 min/session, for 3 consecutive months presented lower risk of MAFLD: OR 0.53–0.72
Miyake T, 2015^Citation38	Japan	Cross-sectional, Cohort	6370	Questionnaire	Abdominal US	● Periodical exercise ↓ risk of having MAFLD: OR 0.707 [0.546–0.914]
Kwak MS, 2015^Citation20	Korea	Cross-sectional, Cohort	3718	PA questionnaire from the NHANES	Abdominal US	● PA was inversely associated with MAFLD:  ● 4th vs 1st quartile: OR 0.68 [0.54–0.85]  ● 3rd vs 1st quartile: OR 0.74 [0.59–0.93]
Ryu S, 2015^Citation6	Korea	Cross-sectional, Cohort	139056	International PA Questionnaire Short Form (Korean version)	Abdominal US	● Prevalence of MAFLD ↓ in physically active vs inactive:  ● Minimally active group: OR 0.94 [0.02–0.95]  ● HEPA group: OR 0.8 [0.78–0.82] ● Prevalence of MAFLD ↑ with increasing sitting time:  ● 5–9 hours/day: OR 1.04 [1.02–1.07]  ● ≥ 10 hours/day: OR 1.09 [1.06–1.11]
Hallsworth K, 2015^Citation33	UK	Cross-sectional, Case-control	37 MAFLD, 37 controls	Sedentary behaviour, PA and E expenditure were assessed by a multisensor array over 7 days	^1H-MRS	● MAFLD patients compared to controls:  ● Spent an hour extra per day being sedentary  ● Walked 18% fewer steps  ● ↓ active E expenditure by 40%  ● ↓ total E expenditure by 8%
Tsunoda K, 2016^Citation43	Japan	Prospective cohort, FU 4.2 years	1149	Questionnaire	MAFLD: by US; steatohepatitis by ↑ ALT or AST	● Vigorous PA prevented progression to steatohepatitis: OR 0.55 [0.32–0.94] ● Moderate or low intensity PA presented no association with progression to steatohepatitis
Sung KC, 2016^Citation40	Korea	Prospective cohort, FU 4.95 years	169347	International PA Questionnaire Short Form (Korean version)	Abdominal US	● ≥5x/week exercise vs no exercise:  ● ↓ risk of incident steatosis: OR 0.86 [0.80–0.92]  ● ↑ likelihood of steatosis resolution: OR 1.40 [1.25–1.55]
Wei H, 2016^Citation28	China	Cross-sectional, Cohort	2054 male	Self-reported questionnaire	FLI ≥60	● Dose-dependent ↑ prevalence of MAFLD across the tertiles of sitting time. ● Sitting time >7.1 hours/day associated with ↑ prevalence of MAFLD (OR 1.09 [1.04–1.67])
Keating SE, 2016^Citation34	Australia	Cross-sectional, Cohort	82	Activity counts from accelerometer readings for 4 days	^1H-MRS	● No associations between PA and sedentary behavior and the prevalence of MAFLD
Kwak MS, 2017^Citation21	Korea	Prospective cohort, FU 4.2 years	1373	PA questionnaire from the NHANES	Incident MAFLD by US	● Total and leisure PA was inversely associated with incident MAFLD ● ↓ PA at FU associated with ↑ incident MAFLD: 4th quartile vs 1st quartile of ↓ PA OR 1.45 [1.04–2.02]
Byambasukh O, 2019^Citation22	Netherlands	Cross-sectional, Cohort	42661	Self reported questionnaire to evaluate HEPA	FLI ≥60	● Higher moderate/vigorous PA was dose-dependently associated with ↓ risk of MAFLD: OR for PA quintiles: 0.78 [0.71–0.86] > 0.64 [0.58–0.70] > 0.53 [0.48–0.59] > 0.51 [0.46–0.56] ● Even PA lower than recommendations was better than inactivity ● Occupational PA offers no clear health benefits
Li YF, 2019^Citation26	China	Cross-sectional, Case-control	543 MAFLD, 543 controls	International PA Questionnaire Short Form (Chinese version)	Abdominal US	● Both moderate (OR 0.62 [0.41–0.92]) or vigorous (OR 0.60 [0.40–0.91]) intensity PA associated with ↓ risk of MAFLD in men, independently of sedentary time or E expenditure
Jang DK, 2019^Citation27	Korea	Cross-sectional, Case-control	32391	Self reported questionnaire to evaluate HEPA	Hepatic steatosis index	● PA negatively associated with MAFLD (most vs least active: OR 0.7 [0.6–0.8]) and lean MAFLD (OR 0.5 [0.4–0.7])
Gerage AM, 2019^Citation41	Brazil	Prospective cohort, FU 2.5 years	5860	International PA Questionnaire	Abdominal US	● Lower likelihood of improving steatosis in subjects who remained inactive (OR 0.64) or became inactive (OR 0.66) ● Lower risk of acquiring MAFLD in subjects who remained active (OR 0.75) or became active (OR 0.75)
Bhatt SP, 2019^Citation25	India	Cross-sectional, Case-control	342	Questionnaire	Abdominal US	● Mean PA was lower in cases than controls (33.3±3.6 vs 36.2±0.5 MET/min) ● Total E expenditure was lower in cases than controls (2707.6±505.6 vs 2904.3±690.3 kcal)
Croci I, 2019^Citation29	Australia	Cross-sectional, Cohort	15781	Self-reported questionnaire	FLI ≥60	● For each additional 1 hour/day of sedentary behavior, the risk of having MAFLD ↑ 4% [3–6] ● High cardiorespiratory fitness attenuated the negative role of sedentary behavior up to 7 hours/day on MAFLD.
Joo JH, 2020^Citation30	Korea	Cross-sectional, Cohort	13518	International PA Questionnaire (Korean version)	Hepatic steatosis index	● The offs of having MAFLD increased across quartiles of sitting hours: 1.07 [0.88–1.31] < 1.16 [1.06–1.41] < 1.34 [1.11–1.61]
Kim D, 2021^Citation52	USA	Prospective cohort, FU 10.6 years	5207 MAFLD patients	PA questionnaire	Abdominal US	● ↑ duration of PA inversely associated with all-cause mortality (higher vs lower quartile: OR 0.46 [0.28–0.75]) and cardiovascular mortality (OR 0.28 [0.008–0.98]) in patients with MAFLD

Abbreviations: E, energy; FLI, Fatty Liver Index; HEPA, health-enhancing physically active; NHANES, National Health and Nutrition Examination Survey; PA, physical activity; US, ultrasound.

Figure 1 The anti-steatogenic mechanisms of exercise.

Abbreviations: VAT, visceral adipose tissue; WAT, white adipose tissue; NEFA’s, non-esterified fatty acids; ER, endoplasmic reticulum.

Table 2 Randomized Controlled Studies Evaluating the Effect of Aerobic Exercise on MAFLD

Reference	Country	N	Intervention			Controls	Main Findings
			Intensity	Sessions/Week	Duration
Sullivan S, 2012^Citation131	USA	19 obese MAFLD patients	45–55 VO2 peak, 30–60 minutes	5	16	No exercise	● Exercise ↓ IHLC (10.3±4.6%) ● Exercise had no effect on weight or % of body fat
Hallsworth K, 2015^Citation33	UK	23 MAFLD patients	H-I interval training	3	12 weeks	Standard of care	● Exercise associated with:  ● ↓ liver fat and whole body fat mass  ● ↓ ALT and AST  ● ↑ early diastolic filling rate ● No effect on glucose or lipid metabolism
Keating SE, 2015^Citation58	Australia	48 inactive overweight/ obese adults	1. L/M-I (50% VO2 peak), 60 min, 4x/week 2. H-I (70% VO2 peak), 45 min, 3x/week 3. L/M-I (50% VO2 peak), 45 min, 3x/week		8 weeks	No exercise	● L/M-I, 60 min, 4x/week: ↓ IHLC 2.62±1.00%, ↓ VAT 386.8±119.5 cm^2 ● H-I, 45 min, 3x/week: ↓ IHLC 2.38±0.73%, ↓ VAT 258.4±87.2 cm^2 ● L/M-I, 45 min, 3x/week: ↓ IHLC 0.84±0.45%, ↓ VAT 212.9±105.5 cm^2 ● Placebo: ↑ IHLC 1.10±0.62%, ↑ VAT 92.6±83.5 cm^2
Zhang HS, 2016^Citation126	China	220 MAFLD patients with central obesity	1. H-I: 65–80% maximal HR 2. M-I: 45–55% maximal HR	150 minutes	6 months	No exercise	● No difference on IHLC in M-I vs H-I exercise, even though H-I exercise associated with higher decrease in body weight ● No effect on aminotransferases
Shojaee-Moradie F, 2016^Citation127	UK	27 sedentary MAFLD patients	1 hour at 40–60% HR reserve	4–5	16 weeks	Conventional life-style advice	● Exercise versus control ↓ IHLC, visceral fat and subcutaneous abdominal fat and ↑ VLDL clearance
Cuthbertson DS, 2016^Citation140	UK	69 MAFLD patients	30% HR reserve 30 minutes → 60% HR reserve 45 minutes	3 → 5	16 weeks	Counseling	● Greater ↓ of IHLC in intervention group (4.7% [0.01–9.4]), improvement on insulin sensitivity and SC abdominal fat
Rezende R, 2016^Citation132	Brazil	40 sedentary post-menopausal women	Treadmill aerobic exercise	120 minutes	24 weeks	No exercise	● Exercise associated with ↓ waist circumference ● Exercise did not associate with improvements on steatosis (by CAP-Fibroscan) or glucose metabolism
Cheng S, 2017^Citation139	China	115 patients with MAFLD and IR, 50–65 years	60–75% VO2 max, 30–60 minutes ± fiber-enriched diet	2–3	8.6 months	No intervention	● Effect on IHLC:  ● exercise alone: ↓ 24.4%  ● diet alone: ↓ 23.2%  ● exercise + diet: ↓ 47.9%  ● no intervention: ↓ 20.9% ● Only exercise associated with ↓ HbA1c
Winn NC, 2018^Citation133	USA	23 obese adults	H-I interval (4 min 80%VO2 peak/3 min, 50%VO2 peak) or M-I continuous (55%VO2 peak, 60 min). Duration calculated to spend 400 kcal		4 weeks	No exercise	● Both exercises similarly ↓ IHLC (H-I −37.0±12.4% and M-I 20.1±6.6%) ● Exercise ↓ postprandial insulin and lipid peroxidation levels ● Exercise did not ↓ BMI, visceral AT or liver enzymes
Abdelbasset WK, 2019^Citation135	Saudi Arabia	32 obese MAFLD patients	H-I interval training, 40 minutes	3	8 weeks	No exercise	● Exercise associated with:  ● ↓ IHLC (12.4±4.5% to 10.1±1.3%)  ● ↓ visceral AT (184.5±12.3 to 160.4±11.6 cm^2)  ● ↓ BMI (36.3±4.5 to 34.1±3.1 kg/m^2)  ● improvement in glucose and lipid metabolism
Abdelbasset WK, 2020^Citation136	Saudi Arabia	72 obese diabetic MAFLD patients	H-I interval vs M-I continuous	3	8 weeks	No exercise	● No differences between H-I interval or M-I continuous on IHLC, visceral AT, BMI or glucose metabolism
O’Gorman P, 2020^Citation157	Ireland	24 biopsy-proven MAFLD patients	Supervised and unsupervised sessions	3–5	12 weeks	Standard of care	● Exercise associated with ↓ hepatocyte ballooning and fibrosis for one stage, but showed no effect on steatosis, lobular inflammation or NAFLD activity score

Abbreviations: AT, adipose tissue; BMI, body mass index; H, high; HR, heart rate; IHLC, intra-hepatic liver content; IR, insulin resistance; L, low; M, moderate, VLDL, very-low density lipoproteins.

Table 3 International Guidelines on Exercise for Patients with MAFLD

	AGA 2021	AASLD 2018	EASL, EASD, EASO 2016	NICE 2016	WGO 2016
Type of exercise	Aerobic ± resistance	Aerobic ± resistance	Aerobic ± resistance	Aerobic	Aerobic
Intensity	Moderate or vigorous	Moderate	Moderate	Moderate	Moderate
Exercise examples			Brisk walking, stationary cycling	Brisk walking, cycling or gardening	Achieving heart rate 60–75% of the age-based maximum
Duration and frequency	150–300 min /week if moderate or 75–150 min/week if vigorous 2–3x /week	150 min/week or increase 60 min /week	150 min /week 2–3x /week	45–60 min /day	3–4x /week

Abbreviations: AGA, American Gastroenterological Association; AASLD, American Association for the Study of the Liver; EASL, European Association for the Study of the Liver; EASD, European Association for the Study of Diabetes; EASO, European Association for the Study of Obesity; NICE, National Institute for Health and Care Excellence; WGO, World Gastroenterology Organization.

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