Front. Endocrinol. Frontiers in Endocrinology Front. Endocrinol. 1664-2392 Frontiers Media S.A. 10.3389/fendo.2023.1081096 Endocrinology Systematic Review Effects of lifestyle intervention on adults with metabolic associated fatty liver disease: A systematic review and meta-analysis Chai Xiao-Ni 1 † Zhou Bing-Qian 1 Ning Ni 1 Pan Ting 1 Xu Fan 1 He Si-Han 2 Chen Ni-Ni 3 Sun Mei 1 4 * † 1 Xiangya Nursing School, Central South University, Changsha, China 2 School of Nursing, Hunan Traditional Chinese Medical College, Zhuzhou, China 3 Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China 4 School of Nursing, Changsha Medical University, Changsha, China

Edited by: Yun Shen, Shanghai Jiao Tong University, China

Reviewed by: Ammar Salehi, Shahid Beheshti University of Medical Sciences, Iran; Tianhui Zou, Shanghai Jiao Tong University, China

*Correspondence: Mei Sun, smnjw2008@126.com

†ORCID: Xiao-Ni Chai, orcid.org/0000-0002-0261-3797; Mei Sun, orcid.org/0000-0002-0261-3797

This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology

 16 02 2023 2023 14 1081096 27 12 2022 06 02 2023 Copyright © 2023 Chai, Zhou, Ning, Pan, Xu, He, Chen and Sun 2023 Chai, Zhou, Ning, Pan, Xu, He, Chen and Sun

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Introduction

This systematic review and meta-analysis evaluates the overall effects of lifestyle interventions upon hepatic fat content and metabolism-related indicators among adults with metabolic associated fatty liver disease.

 Methods

It was registered under PROSPERO (CRD42021251527). We searched PubMed, EMBASE, MEDLINE, Cochrane, CINAHL, Scopus, CNKI, Wan-fang, VIP, and CBM from the inception of each database to May 2021 for RCT studies of lifestyle interventions on hepatic fat content and metabolism-related indicators. We used Review Manager 5.3 for meta-analysis and used text and detailed tabular summaries when heterogeneity existed.

 Results

Thirty-four RCT studies with 2652 participants were included. All participants were obesity, 8% of whom also had diabetes, and none was lean or normal weight. Through subgroup analysis, we found low carbohydrate diet, aerobic training and resistance training significantly improved the level of HFC, TG, HDL, HbA1c, and HOMA-IR. Moreover, low carbohydrate diet is more effective in improving HFC than low fat diet and resistance training is better than aerobic training in reduction in HFC and TG (SMD, -0.25, 95% CI, -0.45 to -0.06; SMD, 0.24, 95% CI, 0.03 to 0.44, respectively).

 Discussion

Overall, this is the first review that systematically synthesizes studies focused on the effects of various lifestyle on adults with MAFLD. The data generated in this systematic review were more applicable to obesity MAFLD rather than lean or normal weight MAFLD.

 Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier (CRD42021251527).

 MAFLD diet exercise lifestyle systematic review meta-analysis Fundamental Research Funds for Central Universities of the Central South University10.13039/501100012476 Hunan Provincial Innovation Foundation for Postgraduate10.13039/501100010083 Introduction

Metabolic associated fatty liver disease (MAFLD) is a chronic liver disease characterized by the excessive accumulation of fat in liver cells and metabolic dysfunction (1, 2). MAFLD, formerly known as non-alcoholic fatty liver disease (NAFLD), is redefined in the guidelines of the Asia-Pacific Society of Liver Diseases in October 2020. The new definition of MAFLD is based on the presence of fatty liver as indicated by liver biopsy or imaging or blood biomarkers, along with one of three conditions: overweight/obesity, type 2 diabetes, and metabolic dysfunction. New definition attaches importance to the pathogenesis of MAFLD and makes change to end points of study, which differ from NAFLD that excludes alcohol consumption (3). MAFLD affects approximately one quarter of the global population, which not only causes liver inflammation, fibrosis, and malignant tumors, but also often merges with a variety of metabolic disorders, causing major diseases such as gout, type 2 diabetes, hypertension, and atherosclerosis and posing a major health and economic burden to all societies (1, 4–6). Therefore, an effective approach to address such a serious situation is urgently needed.

The high prevalence of MAFLD is fueled by the rapid rise in unhealthy lifestyle including sedentary behavior and unreasonable dietary structure (7). Currently, lifestyle interventions are the primary recommended therapy for MAFLD, especially in the absence of approved pharmaceutical agents (1, 8). However, lifestyle interventions for MAFLD patients vary widely among studies, which focus on diet and/or exercise, mainly encompassing Mediterranean diet, Dietary Approaches to Stop Hypertension, high-dietary-fiber diet, aerobic exercise, and resistance exercise (9–15). In addition, the effects of lifestyle interventions differ in the available studies. The effects regarding lifestyle interventions on MAFLD are reflected in the hepatic fat content (HFC) and metabolism-related indicators, such as body mass index (BMI), waist circumference (WC), blood pressure (BP), plasma triglycerides (TG), plasma high-density lipoprotein cholesterol (HDL), fasting blood glucose (FBG), HbA1c, homeostasis model assessment of insulin resistance score (HOMA-IR), and plasma high-sensitivity C-reactive protein (CRP) level, yet these indicators are not fully included in the respective studies (10, 12, 16–18).

Although reviews focus on NAFLD(19–23), to date, none have applied systematic approaches to examine the efficacy or effectiveness of various lifestyle interventions on MAFLD after the name changed and the new diagnostic criteria were redefined. Therefore, we conducted a systematic review and meta-analysis to integrate and evaluate the relevant evidence of various lifestyle interventions in adults with MAFLD and to provide reference for clinical care teams.

 Methods

This study protocol was registered on PROSPERO (CRD42021251527). The study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (24).

Eligibility criteria for this study Types of participants

NAFLD adults who met the diagnostic criteria of MAFLD and adults diagnosed with MAFLD were included in this review. The diagnostic criteria for MAFLD were based on histological, imaging, or blood biomarker evidence of liver fat accumulation, combined with one of the following three conditions: overweight/obesity, type 2 diabetes, or lean/normal weight but presence of at least two metabolic risk abnormalities (2).

 Types of interventions

Interventions included lifestyle interventions, such as diet, physical activity, sleeping, or a combination of two or three. Studies designed to prove the effectiveness of dietary supplements or herbal preparations were excluded.

 Types of comparators

Comparators included no intervention, standard/usual care, or other lifestyle interventions.

 Types of outcomes

The primary outcomes of interest were changes in HFC assessed by histological, imaging, or blood biomarkers. The secondary outcomes included BMI, WC, BP, plasma TG, plasma HDL, FBG, HbA1c, HOMA-IR, and plasma high-sensitivity CRP level.

 Types of study

Only randomized clinical trials were included in this review.

 Search strategy and study selection

Searches were performed in English and Chinese databases, such as PubMed, EMBASE, MEDLINE, Cochrane, CINAHL and Scopus for English literature and CNKI, Wanfang, VIP, and CBM for Chinese literature. The search period was from the inception of each database to May 2021. The Medical Subject Headings and related free words were widely used to capture the literature, including non-alcoholic fatty liver disease, metabolic associated fatty liver disease, lifestyle, diet, exercise, sleep, and all synonyms of these keywords. The detailed search strategy of PubMed is shown in Table 1 . Other database search strategies are listed in the Appendix. Articles that satisfied the eligibility criteria and studies published in English or Chinese were included. The screening process included four steps and is shown in Figure 1 . First, all titles and abstracts retrieved were downloaded to the Endnote X9 library, and duplicate articles were removed. Second, articles were excluded based on titles and abstracts. Third, the full text of the article was reviewed to determine eligibility based on the inclusion criteria. Finally, the reference lists of the included articles and related reviews were screened for potentially relevant articles. The searching and screening processes were conducted by two independent researchers, and disagreements were resolved by a third researcher.

Search strategy of PubMed.

Main Concept Search Formula Results
1. MAFLD Non-alcoholic Fatty Liver Disease[Mesh] OR Metabolic associated fatty liver disease OR MAFLD OR Metabolic-dysfunction-associated fatty liver disease OR Non alcoholic Fatty Liver Disease OR NAFLD OR Nonalcoholic Fatty Liver Disease OR Fatty Liver, Nonalcoholic OR Fatty Livers, Nonalcoholic OR Liver, Nonalcoholic Fatty OR Livers, Nonalcoholic Fatty OR Nonalcoholic Fatty Liver OR Nonalcoholic Fatty Livers OR Nonalcoholic Steatohepatitis OR Nonalcoholic Steatohepatitides OR Steatohepatitides, Nonalcoholic OR Steatohepatitis, Nonalcoholic 34802
2. Lifestyle Healthy Lifestyle[Mesh] OR Life Style[Mesh] OR Sedentary Behavior[Mesh] OR Life Styles[Title/Abstract] OR (Lifestyle[Title/Abstract] OR Lifestyles[Title/Abstract] OR Life Style Induced Illness[Title/Abstract] OR Lifestyle Factors[Title/Abstract] OR Factor, Lifestyle[Title/Abstract] OR Lifestyle Factor[Title/Abstract] OR Lifestyle, Healthy[Title/Abstract] OR Lifestyles, Healthy[Title/Abstract] OR Healthy Life Styles[Title/Abstract] OR Healthy Lifestyles[Title/Abstract] OR Healthy Life Style[Title/Abstract] OR Life Style, Healthy[Title/Abstract] OR Life Styles, Healthy[Title/Abstract] OR Behavior, Sedentary[Title/Abstract] OR Sedentary Behaviors[Title/Abstract] OR Sedentary Lifestyle[Title/Abstract] OR Lifestyle, Sedentary[Title/Abstract] OR Physical Inactivity[Title/Abstract] OR Inactivity, Physical[Title/Abstract] OR Lack of Physical Activity[Title/Abstract] OR Sedentary Time[Title/Abstract] OR Sedentary Times[Title/Abstract] OR Time, Sedentary[Title/Abstract] OR Exercise[Mesh] OR Exercises[Title/Abstract] OR Physical Activity[Title/Abstract] OR Activities, Physical[Title/Abstract] OR Activity, Physical[Title/Abstract] OR Physical Activities[Title/Abstract] OR Exercise, Physical[Title/Abstract] OR Exercises, Physical[Title/Abstract] OR Physical Exercise[Title/Abstract] OR Physical Exercises[Title/Abstract] OR Acute Exercise[Title/Abstract] OR Acute Exercises[Title/Abstract] OR Exercise, Acute[Title/Abstract] OR Exercises, Acute[Title/Abstract] OR Exercise, Isometric[Title/Abstract] OR Exercises, Isometric[Title/Abstract] OR Isometric Exercises[Title/Abstract] OR Isometric Exercise[Title/Abstract] OR Exercise, Aerobic[Title/Abstract] OR Aerobic Exercise[Title/Abstract] OR Aerobic Exercises[Title/Abstract] OR Exercises, Aerobic[Title/Abstract] OR Exercise Training[Title/Abstract] OR Exercise Trainings[Title/Abstract] OR Training, Exercise[Title/Abstract] OR Trainings, Exercise[Title/Abstract] OR Diet[Mesh] OR diets[Title/Abstract] OR Sleep[Mesh] OR Sleeping Habits[Title/Abstract] OR Sleep Habits[Title/Abstract] OR Habit, Sleep[Title/Abstract] OR Habits, Sleep[Title/Abstract] OR Sleep Habit[Title/Abstract] OR Sleeping Habit[Title/Abstract] OR (Habit, Sleeping[Title/Abstract] OR (Habits, Sleeping[Title/Abstract] 887252
3. RCT randomized controlled trial [Publication Type] OR randomized [Title/Abstract] OR placebo[Title/Abstract] 888684
#1 AND #2 AND #3 503

PRISMA flow diagram.

 Assessment of methodological quality

The quality of the included articles was assessed by two independent researchers using the Joanna Briggs Institute Critical Appraisal tools for Checklist for RCTs, which contain 13 entries ( Figure 2 ). Each entry was answered with yes, no, or unclear.

Methodological quality of included studies.

 Data extraction

All data were extracted by two independent researchers by using standardized forms, and disagreements were resolved by a third researcher. The standard form included authors and year of publication, country, study design, subject, diagnosis methods, sample size, the intervention of experimental and control groups, duration, outcomes, results, and conclusion. Among the articles included in the systematic review, those studies that provided intervention values of HFC, BMI, WC, BP, TG, HDL, FG, HbA1c, and HOMA-IR were included in the meta-analysis.

 Data synthesis

ReviewManager 5.3 version was used for data consolidation, heterogeneity test, sensitivity analysis, forest map mapping, and subgroup analysis. First, clinical heterogeneity was determined, and if heterogeneity existed, meta-analysis was discarded, and the results were presented in the form of text and detailed tabular summaries. Secondly, statistical heterogeneity could be explored by chi-square test after excluding clinical heterogeneity. The results were presented as standardized mean difference (SMD) with 95% confidence intervals (CIs), and P<0.05 was considered statistically significant. A fixed-effects model was applied when the heterogeneity test indicated no significant difference (P>0.1 and I2<50%); otherwise, a random-effects model was used. Meta-analysis was abandoned, and descriptive methods were used when the source of heterogeneity could not be determined.

 Results Study selection and study characteristics

The PRISMA flow diagram summarized the selection process of the systematic review and meta-analysis (as shown in Figure 1 ). A total of 8469 studies were identified through search in nine databases. Duplicate references were identified and removed (N=3620). After examining the titles and abstracts, 252 full texts were further screened, and 34 studies met the inclusion criteria and were included in the systematic review and meta-analysis. The reasons for exclusion at this full-text level (N=218) are listed in Figure 1 .

The characteristics of the included studies are shown in Table 2 . The 34 included studies reported 2929 adults with MAFLD, and 27 of them reported information about participants lost at follow-up; the final total number was 2652. For diagnosis of MAFLD, 93% of them were based on imaging-detected liver fat accumulation combined with obesity; the remaining 7% were biopsy-proven liver fat accumulation combined with obesity. Moreover, all participants were obesity, and 8% of them had a diagnosis of type 2 diabetes. The sample size of the participants ranged from 18 to 461, and the age of participants ranged from 27 to 68 years. We classified these articles into three categories on the basis of the form of lifestyle interventions: diet interventions, exercise interventions, and diet combined with exercise interventions, which are detailed in Tables 3 – 5 , respectively.

Characteristics of the included articles.

Reference Clinical group Country N Age M/F BMI Intervention form
(25) Obesity and biopsy-proven NASH USA 31/28 35–60 22/9 34(25~40) Diet combined with exercise
(26) Obesity and ultrasonography-proven NAFLD Iran 44 30–49 22/22 28.99 ± 2.72/29.21 ± 2.61 Diet
(9) Obesity and MRI-proven NAFLD USA 33/18 44–50 5/13 38.1 ± 4.6 Exercise
(27) Obesity, DM2, and biopsy-proven steatosis Saudi Arabia 100 35–55 100/0 32.11 ± 3.54/32.37 ± 3.92 Diet combined with exercise
(28) Obesity, DM2, and MRI scan-proven NAFLD Italy 32/31 53–58 22/9 30.5 ± 1.0/28.8 ± 1.1 Exercise
(10) Obesity and ultrasonography-proven NAFLD Israel 82/64 36–58 34/30 30.75 ± 4.52/31.3 ± 4.14 Exercise
(29) Obesity and fibrosis scan-proven NAFLD UK 29/23 44–64 U 31 ± 4/31 ± 5 Exercise
(30) Obesity and ultrasonography-proven NAFLD Egypt 32 33–56 15/17 33.99 ± 2.57/33.13 ± 2.11 Exercise
(16) Obesity and ultrasonography-proven NAFLD Greece 55/44 40–61 23/32 29.5 ± 4.3/28.2 ± 3.7 Diet
(11) Obesity and ultrasonography-proven NAFLD Iran 60/60 32–53 30/30 28.5 ± 3.2/28.3 ± 3.3 Diet
(12) Obesity and ultrasonography-proven NAFLD China 220/211/208 46–62 71/149 27.9 ± 2.7/28.1 ± 3.3/28.0 ± 2.7 Exercise
(31) Obesity and ultrasonography-proven NAFLD Saudi Arabia 100 45–57 70/30 32.35 ± 2.54/31.76 ± 2.92 Diet combined with exercise
(32) Obesity and fibrosis scan-proven NAFLD Brazil 44/40 48–63 0/40 34.1 ± 4.4/32.0 ± 5.0 Exercise
(33) Obesity and biopsy-proven NASH Australia 26/24 42–67 U 33 ± 7/33 ± 5 Exercise
(34) Obesity and fibrosis scan-proven NAFLD Japan 61/52 46–53 52/0 27.2 ± 0.9/28.4 ± 0.9/28.8 ± 1.1 Exercise
(13) Obesity and ultrasonography-proven NAFLD Greece 63/63 38–60 43/20 30.04/31.67/32.44 Diet combined with exercise
(35) Obesity and ultrasonography-proven NAFLD China 474/461 48–62 230/231 75.28 ± 10.18/74.94 ± 10.37/74.69 ± 10.3 Exercise
(14) Obesity and MRI scan-proven NAFLD Australia 51/50/50/49/48 38–62 25/26 30.2 ± 5.6/31.5 ± 4.1 Diet
(36) Obesity and ultrasonography-proven NAFLD Iran 70/64 36–56 19/45 30.90 ± 3.62/31.36 ± 3.74 Diet
(37) Obesity and ultrasonography-proven NAFLD Iran 66/54(66) 32–60 29/37 30.6 ± 3.6/29.6 ± 3.9 Diet
(38) Obesity and ultrasonography-proven NAFLD Iran 66/62 36–56 19/43 30.85 ± 3.53/31.29 ± 3.77 Diet
(39) Obesity and ultrasonography-proven NAFLD Iran 60/54 31–49 12/48 32.77 ± 3.63/31.09 ± 3.24 Diet
(40) Obesity and MRI-proven NASH Germany 26/22 40–68 13/9 32.2 ± 3.4/32.4 ± 3.7 Diet combined with exercise
(17) Obesity and ultrasonography-proven NAFLD China 271/264 27–41 87/184 26.76 ± 1.59/26.12 ± 2.21/26.34 ± 2.73 Diet
(41) Obesity, DM2, and MRI scan-proven NAFLD Saudi Arabia 32/32 49–61 19/13 36.3 ± 4.5/35.9 ± 5.3 Exercise
(15) Obesity and ultrasonography-proven NAFLD Iran 112/94 34–52 39/55 32.5 ± 4.1/31.8 ± 4.4 Diet
(18) Obesity, DM2, and MRI scan-proven NAFLD Saudi Arabia 48/47 46–63 27/20 36.3 ± 4.5/36.7 ± 3.4/35.9 ± 5.3 Exercise
(42) Obesity and ultrasonography-proven NAFLD Singapore 108/101(108) 35–57 68/40 30.1 ± 4.0/30.8 ± 4.8 Diet combined with exercise
(43) Obesity and fibrosis scan-proven NAFLD China 158/147 30–55 113/34 27.63 ± 3.46/28.39 ± 2.69/27.11 ± 2.73 Exercise
(44) Obesity and ultrasonography-proven NAFLD Turkey 32/31 36–54 12/19 32.74 ± 4.78/33.17 ± 4.91 Exercise
(45) Obesity and ultrasonography-proven NAFLD Serbia 27/24 28–39 U 30.43 ± 1.81/30.17 ± 2.28 Diet
(46) Obesity and imaging-proven NAFLD Sweden 74/64 47–67 33/41 32.1 ± 3.8/32.3 ± 2.7/32.9 ± 5.2 Diet
(47) Obesity and ultrasonography-proven NAFLD Iran 80/75 33–54 36/39 32.02 ± 4.57/30.06 ± 3.81 Diet
(48) Obesity and ultrasonography-proven NAFLD Spain 98/76/72/58 41–60 55/43 33.7 ± 4/33.3 ± 4 Diet

The subjects were included in studies and analysis. M/F, male/female; BMI, body mass index; NAFLD, non-alcoholic fatty liver disease; DM2, type-2 diabetes mellitus; MRI, magnetic resonance imaging; CT, computerized tomography; NASH, non-alcoholic steatohepatitis.

Diet interventions.

Reference Interventions Interveners Control Duration Outcomes Measurer Results
(26) Low carbohydrate diet:carbohydrate:fat:protein: 40:40:20500 kcal less than energy requirement Dietitians Low fat diets:carbohydrate:fat:protein: 55:25:20500 kcal less than energy requirement 6 weeks HFC, BMI, TG, HDL Same trained assessor TG decreased 18.09% in low carbohydrate diet.HFC and BMI decreased in both groups.Low carbohydrate diet. is better than low fat diet in improving HFC
(14) Low carbohydrate diet:carbohydrate:fat:protein:40:40:20 Dietitians Low-fat diets:carbohydrate:fat:protein: 50:30:20 12 weeks HFC, BMI, WC, SBP, DBP, TG, HDL, FBG, HbA1c, HOMA-IR Unmentioned TG and HbA1c decreased in low carbohydrate diet.HFC decreased in both groups.Low carbohydrate diet. is better than low fat diet in improving HFC
(45) Low carbohydrate diet:carbohydrate:fat:protein: 50:30+:15,600–800 kcal less than energy requirement Nutritionists Low-fat diets:carbohydrate:fat:protein: 60:25:15600–800 kcal less than energy requirement 3 months HFC, BMI, WC, TG, HDL, FBG, HOMA-IR, CRP Unmentioned HFC and TG decreased in low carbohydrate diet.HDL increased in low carbohydrate diet.WC, FBG, and HOMA-IR decreased in both groups.
(46) Low carbohydrate diet:carbohydrate:fat:protein: 5–10:50–80:10–40 Dietitians Low-fat diets:carbohydrate:fat:protein: 45–60:20:10–20 12 weeks HFC, BMI, SBP, DBP, TG, HDL, HbA1c, HOMA-IR Unmentioned HFC decreased 7.2% in LCHF diet.HFC decreased 6.1% in 5:2 diet.
(48) Low carbohydrate diet:carbohydrate:fat:protein: 40–45:30–35:25,7 meals/day, 30% less than energy requirement Unmentioned Low-fat diets:carbohydrate:fat:protein: 55:30:15,3–5 meals/day, 30% less than energy requirement 24 months HFC, BMI, WC, SBP, DBP, TG, HDL, HbA1c, HOMA-IR Unmentioned HFC, WC, and HOMA-IR decreased in FLiO group.
(16) Currant replacing snacks of similar caloric content and dietary counseling Dietitians Dietary counseling 24 weeks HFC, BMI, WC, SBP, DBP, TG, HDL, HbA1c Unmentioned WC and FBG reduced in the currant arm.HFC, BMI, HbA1c, and CRP reduced in both arms.
(11) Rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fats, cholesterol, refined grains, and sweets350–700 kcal less than energy requirement Dietitians Usual diets350–700 kcal less than energy requirement 8 weeks HFC, BMI, WC, TG, HDL, FBG, HOMA-IR, CRP Same trained examiner BMI, WC, HOMA-IR, TG, and CRP decreased in DASH diet.
(37) Olive oil 20 g per day500 kcal less than energy requirement Dietitians Sunflower oil 20 g per day500 kcal less than energy requirement 12 weeks HFC, BMI, WC, SBP, DBP, TG, HDL, FBG, HOMA-IR Unmentioned HFC and TG reduced in olive group.WC, SBP, and DBP reduced in both groups.
(36) Soy milk instead of 1 serving of grains and fats500 kcal less than energy requirement Unmentioned Usual diets500 kcal less than energy requirement 8 weeks HFC, BMI, WC, TG, HDL, CRP Unmentioned CRP decreased in soy milk group.
(38) Soy milk instead of 1 serving of grains and fats500 kcal less than energy requirement Unmentioned Usual diets500 kcal less than energy requirement 8 weeks SBP, DBP, FBG, HOMA-IR Unmentioned DBP and HOMA-IR reduced in soy milk group.
(39) Purslane seeds 10 g/day before breakfast and dinner500 kcal less than energy requirement Unmentioned Usual diets500 kcal less than energy requirement 8 weeks SBP, DBP, TG, HDL, FBG, HOMA-IR Unmentioned FBG and HOMA-IR reduced in purslane seed group
(15) At least half of cereal servings from whole-grain foods each day Dietitians Usual cereals 12 weeks HFC, SBP, DBP, TG, HDL, FBG, HOMA-IR Same trained assessor HFC, SBP, and DBP decreased in whole-grain foods
(17) A fast day with 25% of energy requirement and a feed day with ad libitum food Unmentioned Control: 80% of energy requirement 12 weeks HFC, BMI, WC, TG, HDL, FBG Unmentioned BMI and TG decreased in both ADF and TRF groups.
An 8-h window for food intake and a 16-h window of fasting
(47) Protein restraining in meat products,500 kcal less than energy requirement Unmentioned Protein freely500 kcal less than energy requirement 3 months HFC, BMI, WC, SBP, DBP, TG, HDL, FBG, HOMA-IR Same trained assessor HFC, BMI, WC, SBP, TG, FBG, and HOMA-IR decreased in LOV-D.

HFC, hepatic fat content; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; HDL, high density lipoprotein; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; HOMA-IR, homoeostasis model of assessment-estimated insulin resistance; CRP, high-sensitivity C-reactive protein.

 Methodological quality

The quality assessment details of each study are presented in Figure 2 . Twenty studies did not specify whether allocation concealment was performed, which may cause selection bias. Fifteen studies did not perform intention to treat analysis, potentially leading to follow-up bias. Participants, interveners, and outcome assessors were not fully blinded, probably causing performance bias.

 Effects of interventions Effects of diet interventions

The diet interventions were divided into two categories in this article, as shown in Table 3 : 1) the first five studies were reduction in the proportion of carbohydrates, and 2) the last nine studies were food serving replacement under isocaloric conditions. A meta-analysis of the diet interventions was deemed inappropriate due to the heterogeneity of the diet forms. We found that low carbohydrate diet significantly improved the level of HFC, TG, HDL, HbA1c, and HOMA-IR, but not BMI, BP, FBG, and CRP when compared to low fat diet. In addition, food serving replacement under isocaloric conditions was most significant in improving HOMA-IR in MAFLD, followed by HFC, WC, TG, FBG, BMI, BP, and CRP, but not HDL and HbA1c.

 Effects of exercise interventions

The exercise interventions were divided into aerobic training and resistance training, as shown in Table 4 . According to the different types of exercise, we will conduct meta-analysis in three subgroups: 1) the effects of aerobic training on MAFLD, 2) the effects of resistance exercise on MAFLD, and 3) the difference between aerobic and resistance exercise, which are shown in Figures 3 – 5 , respectively. Aerobic training was associated with the improvement of the indicator of MAFLD including HFC, BMI, WC, TG, FBG, HbA1c, and HOMA-IR (SMD, -0.25, 95% CI, -0.43 to -0.07; SMD, -0.22, 95% CI, -0.39 to -0.05; SMD, -0.36, 95% CI, -0.55 to -0.17; SMD, -0.46, 95% CI, -0.67 to -0.25; SMD, -0.44, 95% CI, -0.63 to -0.26; SMD, -0.59, 95% CI, -0.95 to -0.23; SMD, -0.44, 95% CI, -0.65 to -0.24, respectively). Resistance training was associated with the improvement of the indicator of MAFLD including HFC, BMI, WC, DBP, TG, FBG, and HOMA-IR (SMD, -0.25, 95% CI, -0.45 to -0.06; SMD, -0.25, 95% CI, -0.56 to -0.15; SMD, -0.36, 95% CI, -0.56 to -0.15; SMD, -0.52, 95% CI, -0.73 to -0.32; SMD, -0.58, 95% CI, -0.78 to -0.38; SMD, -0.57, 95% CI, -0.79 to -0.35; SMD, -0.55, 95% CI, -0.77 to -0.33, respectively). Resistance training was better than aerobic training in reduction in HFC and TG (SMD, -0.25, 95% CI, -0.45 to -0.06; SMD, 0.24, 95% CI, 0.03 to 0.44, respectively). Aerobic and resistance training had no effect on HDL and BP.

Exercise interventions.

Reference Types Intervention Control Duration Outcome Result
Types Intensity Supervision Types Intensity
(9) Aerobic training Aerobic training:30–60 min×5 times/week 45%–55% of VO2 peak Under supervision:1 time/week Daily activities Unmentioned 16 weeks HFC, BMI, TG, HDL HFC decreased in aerobic training group.
(28) Both Aerobic training:60 min×3 times/week 45%–55% of VO2 peak Under supervisionAll Resistance training:10repetitions×3×3times/week 70%–80% 1RM 4 months HFC, BMI, TG, HDL, HbA1c HFC and HbA1c decreased in both groups.
(10) Resistance training Resistance training:8–12 repetitions×3×3 times/week Unmentioned Under supervision≥2 times Daily activities Unmentioned 3 months HFC, BMI, WC, BP, TG, HDL, FBG, HbA1c HFC, BMI, and WC decreased in resistance training group.
(29) Aerobic training Aerobic training:30–40min×3 times/week Unmentioned Under supervisionfirst 2 sessions Daily activities Unmentioned 12 weeks HFC, BMI, TG, FBG, HbA1c, HOMA-IR HFC and BMI decreased in HIIT group.
(30) Both Resistance exercise:10 repetitions×2–3×3 times/week 70%–80% 1RM,RPE: 13–14 Under supervisionClosely Aerobic training:20–30 min×3times/week 75% of max HR 12 weeks HFC, BMI, WC, TG, HDL HFC and WC decreased in resistance training group.
(12) Aerobic training Aerobic training I:Moderate 6month; 30 min×5 times/week and vigorous 6months30 min×5times/week×6months 60%–80% of max HR for vigorous exercise;45%–55% of max HR for moderate exercise Under supervision1 time/week Daily activities Unmentioned 12 months HFC, BMI, WC, BP, TG, HDL WC and SBP reduced in aerobic training I group.HFC reduced in both aerobic training groups.
Aerobic training II:30min×5times/week×12months 45%–55% of max HR
(32) Aerobic training Aerobic training:30–50 min×2times/week 10% below RCP Under supervision Daily activities Unmentioned 24 weeks HFC, BMI, WC, TG, HDL,HbA1c,HOMA-IR WC decreased and HDL increased in aerobic group.
(34) Both Aerobic trainingI: 3min×3vigorous +2 min×2 rests)×3 times/week 80%–85% of VO2 peak Unmentioned Resistance training: 3times/week 1RM 12 weeks HFC, TG, HOMA-IR HFC reduced in both aerobic groups.
Aerobic training II: 40min×3times/week 60%–65% of VO2 peak
(33) Both Aerobic training and/or Resistance training:45–60 min×3 times/week Aerobic training: RPE: 16–18; Resistance training: RPE: 14–16 Under supervision Daily activities Unmentioned 12 weeks HFC, TG, HbA1c, HOMA-IR, CRP HFC and TG reduced in interventions group.
(35) Both Aerobic training: 45 min×5 times/week, 50%–70% of max HR Unmentioned Daily activities Unmentioned 6 months HFC, BMI, WC, BP, TG,HLD,FBG,HOMA-IR HFC, WC, DBP, TG, FBG, and HOMA-IR reduced in both interventions groups.
Resistance training:: 10–15 repetitions×3×3/week Unmentioned
(41) Aerobic training Aerobic training: 4 min×3vigorous+2 min ×2 rests)×3/week 80%–85% of VO2 peak Unmentioned Daily activities Unmentioned 8 weeks HFC, BMI, TG, FBG, HbA1c, HOMA-IR HFC, FBG, and HbA1c decreased in the aerobic group.
(44) Resistance training: Resistance training:: 40 min×4 times/week 60%–80% of max HR Under supervision Usual activities Unmentioned 8 weeks HFC, TG, HDL, FBG, HbA1c, HOMA-IR HOMA-IR decreased in resistance training group.
(43) Aerobic training Aerobic training30–60 min×5 times/week 60%–80% of max HR Under supervision1 time/week Daily activities Unmentioned 3 months HFC, BMI, WC, BP, TG, FBG HFC, WC, and TG reduced in aerobic training group.
(18) Both Aerobic training I:(4 min×3 vigorous+2 min×2rests)×3times/week 80%–85% of VO2 peak Under supervision Daily activities Unmentioned 8 weeks HFC, BMI, TG, HDL, HbA1c, HOMA-IR HFC reduced in both intervention groups.
Aerobic training II:(4 min×3 ME at +2 min×2rests)×3 times/week 60%–70% of max HR

HFC, hepatic fat content; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; HDL, high-density lipoprotein; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; HOMA-IR, homoeostasis model of assessment-estimated insulin resistance; CRP, high-sensitivity C-reactive protein; RPE, rating of perceived exertion; CWT, circuit weight training; HR, heart rate; RCP, respiratory compensation point.

Effect of aerobic training vs. control group on MAFLD.

Effect of resistance training vs. control group on MAFLD.

Effect of aerobic training vs. resistance training on MAFLD.

 Effects of diet combined with exercise interventions

A meta-analysis of diet combined with exercise interventions was deemed inappropriate due to the heterogeneity of the intervention forms. As shown in Table 5 , diet combined with exercise interventions was most significant in improving HFC, followed by BMI, HOMA-IR, WC, BP, TG, and HDL. However, diet combined with exercise interventions was not significant in improving FBG and HbA1c.

Diet combined with exercise interventions.

Reference Intervention Control Duration Outcome Measures Result
(25) Diet: 1000–1500 kcal/day, 25% from fatExercise: 10,000 steps/day, 200 min/week Usual lifestyle 48 weeks HFC, BMI, WC, TG, HDL, HbA1c, HOMA-IR HFC reduced in intervention group.
(27) Diet: 1200 kcal/day, Carbohydrate:fat:protein: 55:30–35:15Exercise: 40 min×36 times, 65%–75% of maximum HR No intervention 3 months BMI, HOMA-IR BMI and HOMA-IR reduced in intervention group.
(31) Diet: 1200 kcal/day, carbohydrate:fat:protein: 55:30–35:15Exercise: 40 min×3 times/week, 65%–75% of maximum HR No intervention 3 months BMI, TG, HDL, HOMA-IR BMI, TG, and HOMA-IR reduced in intervention group.HDL increased in intervention group.
(13) Diet: 1500 kcal/day for women, 1800 kcal/day for men,carbohydrate:fat:protein: 45:35:20,Exercise: 30min/day, optimal sleep Usual lifestyle 6 months HFC, BMI, TG, HDL, FBG, HOMA-IR HFC decreased in both intervention groups.
Diet: 1500 kcal/day for women, 1800 kcal/day for men,carbohydrate:fat:protein: 45:35:20
(40) Diet: first 6 weeks: 2 daily meals replace soy–yogurt–honeyFollowing 18 weeks, 1 daily meal replace soy–yogurt–honey Usual lifestyle 24 weeks HFC, BMI, WC, HG, HDL, FBG, HbA1c HFC reduced in intervention group.
(42) Individualized caloric goal10,000 steps/day Usual lifestyle 6 months BMI, WC, SBP, DBP WC, SBP, and DBP reduced in intervention group.

HFC, hepatic fat content; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; HDL, high-density lipoprotein; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; HOMA-IR, homoeostasis model of assessment-estimated insulin resistance.

 Discussion

To our knowledge, this is the first systematic review and meta-analysis examining the effects of lifestyle interventions on adults with MAFLD after the name NAFLD changed to MAFLD and the diagnostic criteria redefined. We find that the intervention effects of low carbohydrate diet are significant on MAFLD. After comparing the effects of aerobic exercise and resistance exercise, resistance exercise is more effective than aerobic exercise in improving HFC and TG on MAFLD in our meta-analysis. We also find diet combined with exercise interventions are significant on MAFLD. However, there are insufficient evidence about the effects of lifestyle intervention on lean/normal weight (49)MAFLD and the effects of lifestyle intervention on certain metabolism-related indicators.

We find the intervention effects of low carbohydrate diet are significant on MAFLD. Our results suggest that low carbohydrate diet is more effective in improving HFC than low fat diet in adults with MAFLD. Although meta-analysis was abandoned for the different proportions of carbohydrates, all the five articles showed significant effects. However, the results of a meta-analysis about the effect of low carbohydrate diet on NAFLD showed no significant difference between low carbohydrate diet group and low-fat diet group (50). The possible reason for the discrepancy would be the changed definition and redefined criteria. The inclusion criteria of participants with MAFLD are based on the new diagnostic criteria, which excludes participants with NAFLD unrelated to metabolic dysfunction, therefore, the participants are more homogeneous. A recent randomized controlled trial on Type 2 Diabetes combined with NAFLD showed that low carbohydrate diet had greater clinically meaningful improvements in glycemic control and weight compared with low fat diet, which is in line with our results. The participants in this RCT meet the diagnostic criteria for MAFLD (49). However, the participants in this RCT are part of the MAFLD, which are not representative of the MAFLD as a whole. Furthermore, the RCT also showed the changes were not sustained 3 months after intervention. The Mechanisms maybe that carbohydrate, the main raw material for liver’s fat synthesis, reduced in diets would inhibit the fat accumulation in hepatocytes, while initiating lipolysis to reduce HFC (51). In a word, it deserves our attention that the results are different after MAFLD redefinition and more researches about comparing low carbohydrate diet with low fat diet are needed.

Our meta-analysis compares the intervention effects of aerobic and resistance training in adults with MAFLD. We find that resistance exercise is more effective than aerobic exercise in improving HFC and TG. This result is supported by a previous meta-analysis (52). Their results showed that resistance exercise leads to more effective outcomes in improving the metabolic syndrome and cardiovascular risk parameters compared to aerobic exercise. Resistance exercise was the most significant effective training method in ameliorating body fat while aerobic exercise was best in improving BMI significantly. The possible reason is that resistance exercise increases muscular strength, endurance, and muscle mass. Muscle mass engaged during exercise stimulates more IL-6 release that has a direct impact on glucose and lipid metabolism (53). However, a recent RCT showed that aerobic training and resistance training with dietary modification are equally effective for reducing HFC and improving underlying insulin resistance among patients with NAFLD (54). The possible reason for the discrepancy would be the different interventions. Hence, future research should distinguish aerobic and resistance exercise and focus on the advantages of resistance exercise in improving HFC and TG.

We also find diet combined with exercise interventions are significant on MAFLD. This finding is consistent with a published systematic review, which shows that a range of lifestyle interventions significantly improve NAFLD (19). Meanwhile, this finding is similar to two other systematic reviews in children with NAFLD, which reports that lifestyle interventions significantly improve NAFLD (22, 23). The results are also in line with a recent RCT study, which shows lifestyle intervention with diet and regular exercise improved functional fitness in middle-aged patients with NAFLD and Metabolic Syndrome (55). However, none studies have compared the differences of diet, exercise and diet combined exercise interventions on MAFLD. Hence, further research should consider diet combined exercise interventions, and comparing their effects from diet only or exercise only intervention on MAFLD.

Our results remind evidence about lean/normal weight MAFLD is insufficient. According to the new diagnostic criteria of MAFLD, MAFLD could be divided into three subgroups, including overweight/obesity, type 2 diabetes and lean/normal weight. We find that all the participants included in this article are obesity, 8% of them have diabetes together, but none is lean or normal weight, which makes the results more applicable to obesity MAFLD rather than lean or normal weight MAFLD. A retrospective cohort study shows improvement in histological liver steatosis on liver biopsy in non-obese patients with NAFLD treated with diet combined with exercise after a mean of 10 weeks (56). A Japanese meta-analysis showed lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality (57). A recent meta-analysis also found that a higher mortality in patients with lean NAFLD than those with non-lean NAFLD (58). The results remind that further research about the risk factors and effective interventions of lean NAFLD is warranted. Hence, we suggest that future research should focus not only on obesity MAFLD, but also on lean or normal weight MAFLD.

Our results also remind evidence about certain metabolism-related indicators is needed. NAFLD focus on glutathione aminotransferase, aspartate aminotransferase and fatty fibrosis, while MAFLD focus on HFC and metabolism-related indicators. The outcomes of interest in our study include HFC, WC, BP, TG, HDL, FBG, HbA1c, HOMA-IR, and CRP. However, not all metabolism-related indicators were analyzed in each included study, especially CRP. We could not analysis the effects of lifestyle interventions on CRP in MAFLD according to available data. These suggest that certain metabolism-related indicators deserve attention in future research.

Limitations

This review has several limitations. First, there is moderate heterogeneity among the analyzed studies, in part due to the differences in inclusion criteria and type and duration of lifestyle interventions. Second, not all interesting end points are reported in the included studies. For example, CRP is not reported in a majority of included studies, and the effect of lifestyle on CRP could not be evaluated. Third, selection bias, performance bias, and follow-up bias in some of the analyses could be another limitation. Therefore, the results should be taken with caution, and more studies on the effect of lifestyle interventions are required to reinforce the recommendations of lifestyle in the treatment and prevention of MAFLD.

 Implications for practice

The recommendations for future research are provided as follows. First, the MAFLD subjects can be divided into overweight/obesity, type 2 diabetes, or lean/normal weight, and subjects with lean/normal weight MAFLD should be focused more because they are more likely to be overlooked and there is insufficient evidence from existing studies. Second, lifestyle interventions should include both diet and exercise and respect for preferences of MAFLD; for example, resistance training may be more feasible than aerobic training for MAFLD patients who are less fit or unable to tolerate aerobic training. Lastly, future studies should focus more on all metabolism-related indicators, especially CRP.

 Conclusion

This systematic review and meta-analysis examine the effects of lifestyle interventions on adults MAFLD for the first time after the name changed. Low carbohydrate diet is more effective in improving HFC than low fat diet in adults with MAFLD. Resistance exercise is more effective than aerobic exercise in improving HFC and TG in adults MAFLD. Diet combined with exercise interventions are significant on MAFLD. However, our results more applicable to obesity MAFLD rather than lean or normal weight MAFLD.

 Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

 Author contributions

X-NC: Data Curation, Formal analysis, Writing - original draft. B-QZ: Data Curation, Validation, Investigation. NN: Data Curation, Validation. TP: Formal analysis. FX: Formal analysis. S-HH: Formal analysis. N-NC: Formal analysis. MS: Conceptualization; Methodology; Writing - review and editing. All authors contributed to the article and approved the submitted version.

 Funding

This work was supported by the Hunan Provincial Innovation Foundation for Postgraduate (CX20210348), the Fundamental Research Funds for the Central Universities of Central South University (No. 2021zzts1008), the Fundamental Research Funds for the Central Universities of Central South University (No. 2021zzts1016). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

 Acknowledgments

We would like to thank Jacqueline Wah for their help in polishing our paper.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1081096/full#supplementary-material

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