Diet and Exercise in NAFLD/NASH: Beyond the Obvious

Georg Semmler; Christian Datz; Thomas Reiberger; Michael Trauner

Liver International. 2021;41(10):2249-2268.

Abstract and Introduction

Abstract

Lifestyle represents the most relevant factor for non-alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of the metabolic syndrome. Although a tremendous body of clinical and preclinical data on the effectiveness of dietary and lifestyle interventions exist, the complexity of this topic makes firm and evidence-based clinical recommendations for nutrition and exercise in NAFLD difficult. The aim of this review is to guide readers through the labyrinth of recent scientific findings on diet and exercise in NAFLD and non-alcoholic steatohepatitis (NASH), summarizing "obvious" findings in a holistic manner and simultaneously highlighting stimulating aspects of clinical and translational research "beyond the obvious". Specifically, the importance of calorie restriction regardless of dietary composition and evidence from low-carbohydrate diets to target the incidence and severity of NAFLD are discussed. The aspect of ketogenesis—potentially achieved via intermittent calorie restriction—seems to be a central aspect of these diets warranting further investigation. Interactions of diet and exercise with the gut microbiota and the individual genetic background need to be comprehensively understood in order to develop personalized dietary concepts and exercise strategies for patients with NAFLD/NASH.

Introduction

Non-alcoholic fatty liver disease (NAFLD) may present as "simple" steatosis or with a potentially progressive inflammatory phenotype of non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis and/or hepatocellular cancer, thus being expected to become the leading cause of liver-related morbidity and mortality.^[1] Since no drug has yet been approved specifically for the treatment of NASH and/or associated cirrhosis,^[2] dietary interventions and physical activity (PA) and exercise are generally regarded the cornerstones of NAFLD/NASH treatment. These interventions might be specifically effective to target the "triple hit" of modern-day lifestyle (ie sedentary behaviour, low PA and poor diet) that contributes to the "multiple-hit" pathogenesis of NAFLD.^[3,4] The aim of this review is to provide an overview of recent research findings covering diet and PA "beyond the obvious", thereby presenting stimulating aspects of this topic complimentary to state-of-the-art reviews (eg Refs.^[5–7]).

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Table 1. Comparison of guideline recommendations of the EASL-EASD–EASO guideline 2016, AASLD guidance 2018, ESPEN guideline 2019 and APASL guideline 2020. Modified after Miller (2020) ¹
	EASL-EASD–EASO 2016⁸	AASLD 2018⁹	ESPEN 2019¹⁰	APASL 2020¹¹
Recommendations	• In overweight/obese NAFLD, a 7%-10% weight loss is the target of most lifestyle interventions, and results in improvement of liver enzymes and histology (B1). • Dietary recommendations should consider energy restriction and exclusion of NAFLD-promoting components (processed food, and food and beverages high in added fructose). The macronutrient composition should be adjusted according to the Mediterranean diet (B1). • Both aerobic exercise and resistance training effectively reduce liver fat. The choice of training should be tailored based on patients' preferences to be maintained in the long-term (B2).	• Weight loss generally reduces hepatic steatosis, achieved either by hypocaloric diet alone or in conjunction with increased physical activity. A combination of a hypocaloric diet (daily reduction by 500–1,000 kcal) and moderate-intensity exercise is likely to provide the best likelihood of sustaining weight loss over time. • Weight loss of at least 3%-5% of body weight appears necessary to improve steatosis, but a greater weight loss (7%-10%) is needed to improve the majority of the histopathological features of NASH, including fibrosis. • Exercise alone in adults with NAFLD may prevent or reduce hepatic steatosis, but its ability to improve other aspects of liver histology remains unknown. • Patients with NAFLD should not consume heavy amounts of alcohol. • There are insufficient data to make recommendations with regard to nonheavy consumption of alcohol by individuals with NAFLD.	• In overweight/obese NAFL/NASH patients a 7%-10% weight loss shall be aimed for to improve steatosis and liver biochemistry; a weight loss of >10% shall be aimed for in order to improve fibrosis. (A) • In overweight/obese NASH patients, intensive lifestyle intervention leading to weight loss in conjunction with increased physical activity shall be used as first-line treatment. (A). • In normal weight NAFL/NASH patients, increased physical activity to improve insulin resistance and steatosis can be recommended (GPP). • Overweight and obese NAFL/NASH patients shall follow a weight reducing diet to reduce the risk of comorbidity and to improve liver enzymes and histology (necroinflammation) (A) • In order to achieve weight loss, a hypocaloric diet shall be followed according to current obesity guidelines irrespective of the macronutrient composition (A) • A Mediterranean diet should be advised to improve steatosis and insulin sensitivity. (B) • NAFL/NASH patients shall be advised to exercise in order to reduce hepatic fat content, but there are no data regarding the efficacy of exercise in improving necroinflammation. (A) • NAFL/NASH patients shall be encouraged to abstain from alcohol in order reduce risk for comorbidity and to improve liver biochemistry and histology. (A)	• Lifestyle change towards a healthy diet and physical activity norms via structured programs are recommended for MAFLD (C2). • Patients without steatohepatitis or fibrosis should receive counselling for a healthy diet and physical activity and no pharmacotherapy for their liver disease (B2). • Both overweight/obese and nonobese MAFLD can benefit from weight loss. In the former, a 7%-10% weight loss is the target of most lifestyle interventions and results in improvement of liver enzymes and histology (B1). • Dietary recommendations should consider energy restriction and exclusion of MAFLD-mediating components (processed food, food and beverages high in added fructose). A Mediterranean type diet is advisable (B1). • Combined diet/exercise strategies are more effective in normalization of liver enzymes levels and reducing liver fat and improving histology (B1). • Both aerobic exercise and resistance training effectively reduce liver fat and should be tailored based on patient preferences to ensure long-term adherence. Resistance exercise may be more feasible than aerobic exercise for MAFLD patients with poor fitness (B2).
Energy restriction	500–1000 kcal energy deficit/day to induce a weight loss of 500–1000 g/week	Decrease caloric intake by at least 30% or by approximately 750–1000 kcal/day	Hypocaloric diet	Hypocaloric diet (500-1000 kcal deficit/day).
Weight loss	7%-10% total weight loss target	≥5% for steatosis improvement, ≥7% for histological improvement	7%-10% in overweight/obese patients >10% to improve fibrosis	7%-10% weight loss, gradual weight loss (up to 1 kg/week)
Macronutrient composition	• Low-to-moderate fat and moderate-to-high carbohydrate intake • Low-carbohydrate ketogenic diets or high-protein	NS	• Irrespective of macronutrient composition • Mediterranean diet to improve steatosis and insulin sensitivity	• No strong evidence to support a particular dietary approach. • Plans should encourage low-carbohydrate, low-fat and Mediterranean-type diets
Fructose	Avoid fructose-containing beverages and foods	NS	NS	Exclusion of beverages high in added fructose
Alcohol	• Strictly keep alcohol below the risk threshold (30 g, men; 20 g, women) • Moderate alcohol intake (namely, wine) below the risk threshold is associated with lower prevalence of NAFLD, NASH and even lower fibrosis	• Should not consume heavy amounts of alcohol. • Insufficient data on nonheavy consumption of alcohol	Abstain	• The "cut-off" values of alcohol intake in MAFLD should be set lower than the apparent "threshold levels". • Patients with MAFLD should be advised to avoid alcohol and if that is not possible, to consume the lowest amount possible.
Coffee	No liver-related limitations.	NS	More likely to benefit health than harm	NS
Physical activity	• 150–200 min/week of moderate intensity aerobic physical activities in 3–5 sessions are generally preferred (brisk walking, stationery cycling) • Resistance training is also effective and promotes musculoskeletal fitness, with effects on metabolic risk factors • High rates of inactivity-promoting fatigue and daytime sleepiness reduce compliance with exercise	• Physical activity more than 150 minutes/week • Moderate intensity exercise	Increase physical activity	• Aerobic exercise and resistance training effectively should be tailored based on patient preferences to ensure long-term adherence. • Resistance exercise may be more feasible than aerobic exercise for patients with poor fitness.

Note: Bold-letters indicate the grade of evidence according to the respective guidelines.
Abbreviations: MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, non-alcoholic fatty liver disease; NAFLD, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; NS, not specified.

Table 2. Overview and characterization of individual studies on dietary interventions discussed in this manuscript
Study	Type of study	Duration of intervention	Types of diet (± calorie intake)	Macronutrient composition	Individuals analysed*	Patients	Outcome measure (liver-related)	Outcome (liver-related)
Mediterranean diet (MED)
Ryan (2013)²⁴	RCT	6w	MED vs LFD/HCD (both diets after one another)	MED: 40% C, 20% P, 40% F LFD/HCD: 50% C, 20% P, 30% F	6 vs 6	Biopsy-proven NAFLD	¹H-MRS	-39% vs -7% reduction in IHLC after MED compared to LFD/HCD
Trovato (2015)²³	Single-arm	6m	Increase the adherence to Mediterranean Diet Score and reduce sedentary habits	NS	90	Non-diabetic NAFLD	Bright Liver Score (BLS)	Adherence to MED independently explain considerable variance of BLS
Misciagna (2017)²⁵	RCT	6m	Low Glycemic Index MED vs CD	NS	44 vs 46	Moderate or severe NAFLD (US)	US (semi-quantitatively)	Negative interaction between time and MED on NAFLD (semi-quantitatively)
Abenavoli (2017)²⁶	RCT	6m	Hypocaloric MED± antioxidant supplementation (1400-1600 kcal/d) vs CD	MED: 50%-60% C, 15%-20% P, <30% F	20 vs 20 vs 10	Overweight NAFLD	US (semi-quantitatively), FLI, LSM (FibroScan)	Decrease in FLI and LSM following both diets
Katsagoni (2018)²⁹	RCT	6m	Hypocaloric diets (1500 kcal/d ♀, 1800 kcal/d ♂) MED vs MED +lifestyle intervention vs CD	45% C, 20% P, 35% F	21 vs 21 vs 21	Overweight/obese NAFLD	LSM (Aixplorer)	Decrease in LSM following both diets, improvement in ALT only in MED +lifestyle intervention-group
Marin-Alejandre (2019)²⁷	RCT	6m	Personalized hypocaloric diets (−30%): FLiO-diet vs CD (AHA-recommendations)	FLiO: 40%-45% C, 25% P, 30%-35% F CD: 50%-55% C, 15% P, 30% F	37 vs 39	Overweight/obese NAFLD	MRI, LSM (ARFI)	Reduction in IHLC +FLI following both diets
Yaskolka Meir (2020)²⁸	RCT	18m	Hypocaloric MED +28g/d walnuts ± green tea/Mankai (1500-1800 kcal/d ♂, 1200–1400 kcal/d ♀) vs healthy diet	MED: <35% F	89 vs 84 vs 91	Abdominal obesity/dyslipidemia	¹H-MRS	IHLC reduced following all diets, greater following green-MED compared to MED
Diets focussing on proteins
Markova (2017)³²	RCT	6w	Isocaloric animal-protein vs plant-protein diet	40% C, 30% P, 30% F	18 vs 19	T2DM + NAFLD	¹H-MRS	-48.0% vs −35.7% reduction in IHLC
Xu (2020)³³	RCT	3w	Hypocaloric LPD vs HPD vs reference-protein diet	LPD: 55%-65% C, 10% P, 25%-35% F HPD: 35%-45% C, 30% P, 25%-30% F Ref.-prot: 20%-22% P	10 vs 9 vs 10	Morbid obesity	¹H-MRS	-36.7% vs −42.6% reduction in IHLC vs no changes in IHLC
Hypocaloric diet
De Luis (2008)³⁷	Single-arm	3m	Hypocaloric diet (1520 kcal/d)	52% C, 23% P, 25% F	142	Non-diabetic and obese	Serum biomarkers	Improved ALT/AST
Krik (2009)³⁸	RCT	48h	Hypocaloric LCD vs HCD (~1100 kcal/d)	LCD: ~10% C (≤50g), 15% P, 75% F HCD: ~65% C (≥180g), 15% P, 20% F	11 vs 11	Non-diabetic and obese	¹H-MRS	-29.6% vs −8.9% reduction in IHLC
Haufe (2011)³⁵	RCT	6m	Hypocaloric LCD vs LFD (−30%)	LCD: ≤90g C, 0.8g/kg BW P, ≥30% F LFD: 0.8g/kg BW P, ≤20% F	52 vs 50	Overweight/obese and otherwise healthy (non-diabetic)	¹H-MRS	-42% vs −47% reduction in IHLC
Vilar-Gomez (2015)³⁹	Single-arm	52w	Hypocaloric LFD ( −750 kcal/d) + PA	64% C, 14% P, 22% F	261	Histological NASH w/o cirrhosis	Liver biopsy	Correlations between weight loss and histological improvement
Low-carbohydrate diet (LCD)/Very-low-carbohydrate diet (VLCD)
Browning (2011)⁵¹	Non-randomized controlled trial	2w	VLCD vs hypocaloric (1200 kcal/d ♀, 1500 kcal/d ♂) diet	LCD: 8% C, 33% P, 59% F Cal-restr.: 50% C, 16% P, 34% F	9 vs 9	NAFLD w/o cirrhosis	¹H-MRS	-55% vs −28% reduction in IHLC
Mardinoglu (2018)⁵⁴	Single-arm	2w	Isocaloric VLCD (~3115 kcal/d)	4% C (23-30g), 24% P, 72% F	10	Obese NAFLD	¹H-MRS	-43.8% reduction in IHLC
Gepner (2019)⁵³	RCT	18m	LFD w/o PA vs LFD with PA vs MED/LCD w/o PA vs MED/LCD with PA (MED +28g walnuts/d); all diets hypocaloric	LFD: <30% F; LCD/MED: <35% F(<40g C in first 2m, then up to 70g/d)	76 vs 63 vs 73 vs 66	Abdominal obesity/dyslipidaemia	MRI	-7.3% (MED/LCD) vs −5.8% (LFD) reduction in IHLC after 6 months; −4.2% vs −3.8% after 18 months
Luukkonen (2020)⁵⁷	Single-arm	6d	Hypocaloric VLCD (~1440 kcal/d)	~6% C (≤25 g), 28% P, ~64% F	10	Overweight/obese NAFLD	¹H-MRS	-31% reduction in IHLC
Goss (2020)⁵⁸	RCT	8w	LCD vs LFD	LCD: ≤25% C, 25% P, ≥50% F LFD: 55% C, 25% P, 20% F	14 vs 11	Obese NAFLD (9–17 years)	MRI	LCD: −6.2% absolute decrease in IHLC, LFD: −1.0% absolute decrease in IHLC; no significant difference
Intermittent calorie restriction (ICR)
Johari (2019)⁶⁹	RCT	8w	Modified alternate-day calorie restriction (MACR) vs CD; MACR: 70% calorie-restriction on fasting day, ad libitum on non-fasting day; CD: no changes	NS	30 vs 9	NAFLD +elevated ALT/AST	Serum biomarkers, US (semiquantitatively), LSM (Aixplorer)	ALT reduced; reduction in steatosis and LSM scores
Cai (2019)⁷⁰	RCT	12w	ADF vs TRF vs. CD ADF: −75% calorie-restriction on fasting day, ad libitum on non-fasting day TRF: 8h ad libitum eating CD: −20% calorie-restriction	ADF: 55 C, 15% P, 30% F; TRF: NS	90 vs 95 vs 79	Overweight/obese NAFLD (BMI >24kg/m²), ≥9.6kPa, 18–65y	LSM (FibroScan)	LSM not different
Holmer (2021)⁷¹	RCT	12w	LCD vs 5:2 diet vs CD; LCD: 1600 kcal/d ♀, 1900 kcal/d ♂; 5:2 diet: 500 kcal/d ♀ and 600 kcal/d ♂ on 2 non-consecutive days; 2000 kcal/d ♀ and 2400 kcal/d ♂ on other days CD: healthy diet	LCD: 5%-10% C, 15%-40% P, 50%-80% F; 5:2 diet: 45%-60% C, 10%-20% P, 25% F	20 vs 24 vs 20	NAFLD	¹H-MRS; LSM (FibroScan) with CAP	-53.1% vs −50.9% vs −16.8% reduction in IHLC; −61.9% vs −63.8% vs −20.2% reduction in CAP; change in IHLC 3.9% greater in LCD compared to CD and 2.6% in 5:2 diet compared to CD; reduction in LSM in 5:2 diet and CD compared to LCD
Fructose-restriction
Geidl-Flück (2021)⁹⁰	RCT	7w	SSB with 80g/day of fructose vs sucrose vs glucose vs no SSB	45%-56% C, 15%-19% P, 30%-37% F	32 vs 31 vs 32 vs 31	Healthy men	Fatty acid-synthesis	2-fold increase in basal hepatic fractional fatty acid-secretion rates compared to controls in fructose/sucrose group; no diff in glucose group
Simons (2021)⁹¹	RCT	6w	Dietary fructose-restriction; control-group: supplemented with fructose powder; intervention group: supplemented with glucose powder	35%-40% C, 15%-20% P, 35%-40% F	21 vs 16	Overweight +FLI ≥ 60	¹H-MRS	IHLC reduction greater by −0.7% absolute difference in the intervention group; IHLC reduction in both groups

*per protocol; ADF, alternate date fasting; BLS, bright liver score; BW, body weight; C, carbohydrates; CAP, controlled attenuation parameter; CD, control diet; F, fat; FLI, fatty liver index; ¹H-MRS, proton magnetic resonance spectroscopy; HFF, hepatic fat fraction; HPD, high-protein diet; ICR, intermittent calorie restriction; IHLC, intrahepatic lipid content; LCD, low-carbohydrate diet; LFD, low-fat diet; LPD, low-protein diet; LSM, liver stiffness measurement; m, months; MED, Mediterranean diet; MRI, magnetic resonance imaging (Dixon techniques); NS, not specified; P, protein; PA, physical activity; RCT, randomized controlled trial; SSB, sugar-sweetened beverages; TRF, time-restricted feeding; US, ultrasonography; w, weeks; w/o, without; WL, weight loss.

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Diet and Exercise in NAFLD/NASH: Beyond the Obvious

Abstract and Introduction

Abstract

Introduction

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Tables

References

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