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Treatment of NAFLD with diet, physical activity and exercise
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Summary & conclusions
Lifestyle change, including dietary habits and physical activity, are and should be the first line of treatment in NAFLD and NASH. Weight reduction is the most established treatment for both NAFLD and NASH, with a clear dose-response association. Generally, any form of healthy diet (low fat or low carbohydrates or Mediterranean diet), which will lead to caloric reduction and is acceptable by the patient, should be encouraged. For those who find caloric restriction difficult, changing dietary composition without necessarily reducing caloric intake may offer a more feasible alternative, although the benefit to liver health is not as marked as weight reduction. The importance of weight loss is highlighted in people with NASH, where weight loss >7% is associated with a clinically meaningful regression of disease status. Exercise produces significant but modest changes in liver fat (vs. weight loss). However, given the strong cardiovascular benefits of exercise, the optimal placement for exercise is likely as an adjunct to dietary manipulation, whether in NAFLD or NASH. Combined, this evidence strongly supports the role of lifestyle as a primary therapy for the management of NAFLD and NASH. The question is no longer whether lifestyle is an effective clinical therapy; the question is now how do we implement lifestyle as a therapy in everyday clinical care.
⋅ A 'triple hit behavioural phenotype' of: i) sedentary behaviour, ii) low physical activity, and iii) poor diet have been defined
⋅ The primary approach to treat NAFLD focuses on the control of the underlying risk factors like diabetes, hyperlipidaemia, obesity and other comorbidities. Lifestyle changes through diet and physical activity modifications are well-established therapeutic strategies for conditions such as diabetes and cardiovascular disease.
⋅ Weight reductions of ≥10% are required for inducing near universal NASH resolution or fibrosis improvement by at least one stage....a 7-10% weight loss is the target of most lifestyle interventions, and results in an improvement of liver enzymes and histology
⋅ Losing weight decreases cardiovascular and diabetes risk and also regresses liver disease.....weight loss can also have a favourable impact on abdominal obesity,[144], [145] cardiovascular disease146 and extrahepatic malignancies.147 Most studies conclude that at least 7-10% of weight loss is required to induce an improvement in NAFLD activity score (NAS) and its components (steatosis, lobular inflammation and ballooning).[148], [149] However, lifestyle changes that produce even modest, sustained weight loss of about 5% of initial body weight, can reduce steatosis,140 liver enzymes150 and health benefits as clinically meaningful reductions in triglycerides, blood glucose, haemoglobin A1c, and the risk of developing type 2 diabetes.
⋅ Drinking coffee reduces HCC risk. The hepatoprotective effects of coffee may be linked not only to caffeine but also to its polyphenolic fraction.....In a US multi-ethnic prospective cohort of 162,022 participants, those who drank 2-3 cups of coffee per day had a 38% risk reduction for HCC compared with non-coffee drinker. Those who drank ≥4 cups per day had a 41% reduction in HCC risk. Furthermore, compared with non-coffee drinkers, participants who consumed 2-3 cups of coffee per day had a 46% risk reduction of death from chronic liver disease and those who drank ≥4 cups per day had a 71% reduction.
⋅ Physical activity is a key determinant of metabolic control and is commonly recommended for people with NAFLD, usually alongside weight loss and dietary change....Physical activity, we have known for some time that everyday physical activity, not exercise, is associated with health.
⋅ Exercise, unlike the usually unstructured and unplanned nature of physical activity, more deliberate physical activity is described as exercise. Exercise is one of the cornerstones of NAFLD and NASH management, although the evidence underpinning this is still in its infancy compared to other conditions (type 2 diabetes for example)....The mechanisms underlying the change in liver fat following exercise in NAFLD reflect changes in energy balance, circulatory lipids and insulin sensitivity.....Exercise has little effect on hepatic insulin sensitivity, but does improve peripheral insulin sensitivity,128 producing a net improvement in insulin action and consequently, reducing hepatic de novo lipogenesis. It should be noted that the direct benefits of exercise on glycaemic control are significant, but modest, even in people with impaired glucose control.118 However, tracer studies also show that exercise has a direct effect on lipid flux, with an increase in very low density lipoproteins clearance contributing to the reduction in liver fat with exercise,129 so not all of the changes in liver fat are attributable to insulin sensitivity alone.
⋅ Although not the liver itself, there is an important reduction in visceral adipose tissue with exercise. Visceral fat directly links with liver inflammation and fibrosis, independent of insulin resistance and hepatic steatosis.130 The precise mechanism of how visceral fat applies its detrimental effects on liver metabolism, fibrotic and inflammatory consequences remain unclear, although influx of fatty acids and synthesis of cytokines and adipokines has been shown to promote liver lipid accumulation, insulin resistance and inflammation
⋅ Experimental studies have shown that diets enriched with omega-3 polyunsaturated fatty acids (PUFA) increase insulin sensitivity,13 reduce intrahepatic triglyceride content and ameliorate steatohepatitis
⋅ Within the PUFAs, there is superiority for the omega-3 PUFAs and its sub-types; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (both abundant in fish oil) over the omega-6 PUFAs. Epidemiological studies implicate a lower consumption of omega-3 PUFA and a higher n-6/n-3 ratio among NAFLD and NASH patients compared to controls.[18], [19]
⋅ weight gain by itself, even only a modest 3-5 kg, predicts the development of NAFLD, regardless of baseline body mass index (BMI)
⋅ Epidemiological studies show convincing evidence that there is an association between added sugars and NAFLD......Fructose consumption is associated with alterations in gut microbiota, increased intestinal permeability, endotoxemia, increased hepatic TNF production and lipid peroxidation, promoting hepatic steatosis and NAFLD.
⋅ Little is known about the association between dietary composition and HCC in humans. Evidence for a potential association is provided from three large prospective studies. In a population-based prospective cohort study of 90,296 Japanese subjects, consuming n-3 PUFA-rich fish and individual types of n-3 PUFAs was inversely associated with HCC.69 In a prospective cohort of 9,221 American participants of the first National Health and Nutrition Examination Survey, high cholesterol intake, but not total fat consumption, was associated with a higher risk of cirrhosis or liver cancer.70 Among 477,206 participants of the European Prospective Investigation into Cancer and Nutrition cohort, the risk of liver cancer was increased by 43% per 50 g/day of total sugar, and was reduced by 30% per 10 g/day of total dietary fibre.71 Accordingly, in a meta-analysis of observational studies the intake of vegetables, but not fruit, was associated with a lower risk of HCC, which decreased by 8% for every 100 g/day increase in vegetable intake.72 Interestingly, in a case-control study the Mediterranean diet pattern, which is based on high consumption of fish, vegetables and fibre with low consumption of sugars, was shown to be associated with lower odds of liver cancer.73
⋅ Sedentary behaviour, also referred to as physical inactivity, holds strong epidemiological, physiological and molecular relationships with the development of over thirty long-term conditions.103 Both TV sitting (a reliable marker of overall sedentary behaviour) and physical activity are associated with cardio-metabolic health when viewed separately[104], [105] or in combination.106 Beyond cardio-metabolic health, ≤3 h of daily sitting is linked to all-cause mortality....Sedentary behaviour is reported to be higher in people predisposed to the metabolic syndrome, excessive adiposity and type 2 diabetes.107 In addition, prospective studies show that a change in TV viewing over 5 years was associated with waist circumference and clustered cardio-metabolic risk score, independent of physical activity.108 Not only is the total duration of sedentary time important for metabolic risk, but also the breaks in sedentary time, independent of total sedentary time. Increased breaks in sedentary times were beneficial for obesity control, glucose and triglyceride metabolism
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Fatty Liver / NASH -
A silent liver disease epidemic - (05/22/17)
CROI/2017:
Changes in Liver Fibrosis and Steatosis in HIV Mono-Infected patients over 24 months - 50% have fatty liver at average age of 46- (03/28/17)
LIVER STEATOSIS AND FIBROSIS IN AT-RISK EUROPEAN HIV-MONOINFECTED PATIENTS - 64% with steatosis among those who had elevated LFTs and/or metabolic syndrome and/or lipodystrophy- (03/28/17)
CROI/2017: FATTY LIVER DISEASE: A GROWING CONCERN- - (04/12/17)
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Treatment of NAFLD with diet, physical activity and exercise
Jnl of Hepatology Oct 2017 - Manuel Romero-G—mez1, Shira Zelber-Sagi2,3, Michael Trenell4
Summary
Lifestyle intervention can be effective when treating non-alcoholic fatty liver diseases (NAFLD) patients. Weight loss decreases cardiovascular and diabetes risk and can also regress liver disease. Weight reductions of ≥10% can induce a near universal non-alcoholic steatohepatitis resolution and fibrosis improvement by at least one stage. However, modest weight loss (>5%) can also produce important benefits on the components of the NAFLD activity score (NAS). Additionally, we need to explore the role of total calories and type of weight loss diet, micro- and macronutrients, evidence-based benefits of physical activity and exercise and finally support these modifications through established behavioural change models and techniques for long-term maintenance of lifestyle modifications.
Following a Mediterranean diet can reduce liver fat even without weight loss and is the most recommended dietary pattern for NAFLD. The Mediterranean diet is characterised by reduced carbohydrate intake, especially sugars and refined carbohydrates (40% of the calories vs. 50-60% in a typical low fat diet), and increased monounsaturated and omega-3 fatty acid intake (40% of the calories as fat vs. up-to 30% in a typical low fat diet). Both TV sitting (a reliable marker of overall sedentary behaviour) and physical activity are associated with cardio-metabolic health, NAFLD and overall mortality. A 'triple hit behavioural phenotype' of: i) sedentary behaviour, ii) low physical activity, and iii) poor diet have been defined. Clinical evidence strongly supports the role of lifestyle modification as a primary therapy for the management of NAFLD and NASH. This should be accompanied by the implementation of strategies to avoid relapse and weight regain.
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a major health problem because of its high prevalence and the associated risk of progression to liver cirrhosis, liver cancer and also, increased cardiovascular and solid neoplasm risk. NAFLD comprises a wide pathological spectrum ranging from simple steatosis to steatohepatitis (NASH) with variable degrees of fibrosis and cirrhosis.1 The strongest predictor of fibrosis progression in NAFLD is the presence of steatohepatitis.2 The risk of detrimental outcomes is increased in patients with significant fibrosis, or steatohepatitis, whilst it is lower in patients with simple steatosis. Liver biopsy remains the gold standard for histological evaluation of the disease. Non-invasive methods combining imaging and biochemical tests are warranted to pre-empt the need for liver biopsies.
The prevalence of NAFLD varies largely from 20% to 30% and increases with age,3 with an annual incidence of around two new cases/100 patients/year. Since NASH is becoming one of the most frequent causes of cirrhosis and liver transplantation worldwide,[4], [5] it is crucial to identify patients at risk of NAFLD progression in order to implement therapeutic interventions that can lead to prevention or reversal of the deleterious consequences of advanced NASH.
Patients with NAFLD are frequently obese and/or have diabetes, and insulin resistance is a key pathogenic trigger. Four phenotypes of patients with NAFLD have been defined: i) obese, ii) type 2 diabetes, iii) metabolic syndrome and iv) lean patients. PNPLA3 is the genetic hallmark of NAFLD. Patients bearing genotype GG were at three times greater risk of NAFLD. This increased risk is more evident in patients without metabolic syndrome.6 Indeed, TM6SF2 mutation has an additive effect on NAFLD risk.7
Role of macro- and micronutrients in NAFLD
Role of energy restriction
Excess caloric consumption leading to obesity and related comorbidities is a leading risk factor for NAFLD.8 Furthermore, weight gain by itself, even only a modest 3-5 kg, predicts the development of NAFLD, regardless of baseline body mass index (BMI).9 Interestingly, not only excess caloric consumption, but also the way food consumption is distributed throughout the day, affects liver fat accumulation. In a 6-week randomised controlled trial (RCT), high fat high sugar, or high sugar hyper-caloric diets were consumed either together with main meals or between them as snacks. Only the latter increased liver fat (measured by magnetic resonance spectrometry [MRS]) and abdominal fat (measured by magnetic resonance imaging [MRI]), suggesting that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis.10 There is a consensus that gradual weight reduction achieved by caloric restriction, with or without increased physical activity,11 leads to an improvement in serum liver enzymes, liver fat, degree of hepatic inflammation and fibrosis.12
Experimental studies have shown that diets enriched with omega-3 polyunsaturated fatty acids (PUFA) increase insulin sensitivity,13 reduce intrahepatic triglyceride content and ameliorate steatohepatitis.[14], [15] In epidemiological studies, the diet of normal weight NASH patients compared to age, gender and BMI matched controls, is richer in saturated fat and cholesterol and poorer in PUFA.[16], [17] Within the PUFAs, there is superiority for the omega-3 PUFAs and its sub-types; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (both abundant in fish oil) over the omega-6 PUFAs. Epidemiological studies implicate a lower consumption of omega-3 PUFA and a higher n-6/n-3 ratio among NAFLD and NASH patients compared to controls.[18], [19]
In fact, overfeeding with PUFA and saturated FAs (SFAs) has distinct effects on liver and visceral fat accumulation in humans. In a 7-week RCT overeating SFAs or omega 6-PUFAs led to a similar weight gain, but the SFAs markedly increased liver fat compared with PUFAs and caused a twofold increase in visceral fat compared to PUFAs.20 Similarly, a 10-week RCT of isocaloric diets demonstrated that intake of omega 6-PUFAs reduced liver fat compared to increased liver fat with the high saturated fat diet.21 A meta-analysis of small or uncontrolled trials, using omega-3 supplements with varying types and dosages indicated a potentially beneficial effect on reducing liver fat.22 In another meta-analysis of 10 RCTs, omega-3 treatment was beneficial in terms of decreasing the amount of liver fat and improved gamma-glutamyl transferase (GGT) levels, but it was not significantly efficient in reducing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.23 Recent RCTs, which also include liver histology analysis, offer further insight into the effects of omega-3 treatment on NASH and fibrosis, but results are conflicting, indicating a beneficial effect for liver fat reduction (for DHA containing supplements, not for EPA alone), but not for improving NASH or fibrosis.[24], [25], [26] Furthermore, in contrast to experimental findings, there was no consistent significant effect on insulin resistance.[25], [26] In summary, consumption of different types of fats have different effects on NAFLD and NASH, therefore, a reduction in total fat intake is not the simple solution.
The traditional Mediterranean diet is characterised by a high intake of olive oil, which is rich in monounsaturated-fat [MUFA], nuts, fruits and legumes, vegetables, and fish and a low intake of red meat, processed meats, and sweets (wine in moderation). In contrast to the low fat diet, which contains up-to 30% fat, 40% of the calories in the Mediterranean diet are derived from fats, mostly MUFA and omega-3 PUFA. MUFA has a favourable effect on lipid profile.[27], [28] Moreover, the Mediterranean diet plays a beneficial role in metabolic profile29 and has been shown to reduce the risk of cardiovascular disease30 and diabetes,31 two outcomes highly relevant in NAFLD patients.
Interestingly, one of the principles of the Mediterranean diet is to minimise processed and high sugar food. A reduction in processed[32], [33], [34] and high fructose food35 may also lead to reduced intake of advanced glycation end products (AGEs). These are a heterogeneous class of non-enzymatic products derived from protein, lipid and nucleic acid glycation,36 produced endogenously but also introduced through the diet. AGEs are related to the aetiology of diabetes and other metabolic alterations.[34], [37], [38] They have been shown to be elevated in NASH patients compared to simple steatosis and controls, and to be positively correlated with insulin resistance and negatively with adiponectin.39 Furthermore, the soluble receptor of AGEs (sRAGE) that prevents the binding of extracellular AGEs to the cell-surface RAGE, thus exerting protective effects,40 was shown to be inversely correlated with the level of liver fat, and more interestingly, sRAGE levels were increased by lifestyle changes.41
It has been suggested in a single-arm trial that adherence to the Mediterranean dietary pattern leads to a significant decrease in liver fat among overweight patients with NAFLD.42 This was supported by two short-term randomised trials in NAFLD patients with or without type 2 diabetes. In both studies, patients were assigned to two isocaloric diets; either a low fat high carbohydrate diet or an 8-week high-MUFA diet in one study and in the other study the low fat high carbohydrate diet or a 6-week Mediterranean diet. Liver fat content decreased more in the MUFA or the Mediterranean diet (about -35%) than in the low fat high carbohydrate diet (about -5%), despite a stable weight in both groups.[43], [44] Importantly, the Mediterranean diet is also characterised by reduced carbohydrate intake (40% of the calories vs. 50-60% in a typical low fat diet), especially reduced sugars and refined carbohydrates, which may partially account for its beneficial effect in NAFLD. Longer-term trials testing the effects of a Mediterranean diet are warranted.
It should be noted that although the Mediterranean diet advocates consumption of wine in moderation, it is unclear whether NAFLD patients should adopt this recommendation. NASH patients with cirrhosis should avoid alcohol, as any regular alcohol consumption puts them at a greater risk of developing hepatocellular carcinoma (HCC).45 However, uncertainty remains regarding moderate alcohol consumption (up-to two drinks per day) in patients without cirrhosis. Several studies have shown a protective association of moderate alcohol consumption with NAFLD[46], [47], [48], [49], [50] and NASH.51 The protective effect may be specific to wine, as it was found in a national cross-sectional survey that modest wine drinking of up-to 10 g of alcohol per day, but not other types of alcoholic beverages, was associated with a lower prevalence of unexplained elevated ALT compared to non-drinking.47
Currently, the Mediterranean diet is the dietary pattern recommended for NAFLD patients by the recent EASL-EASD-EASO Clinical Practice Guidelines (Grade: B1)11 (Fig. 1).
Added sugars
Fructose consumption is associated with alterations in gut microbiota, increased intestinal permeability, endotoxemia, increased hepatic TNF production and lipid peroxidation, promoting hepatic steatosis and NAFLD.
Added sugar refers to refined sugars (sucrose, fructose and high fructose corn syrup) added to sugared sweetened beverages (SSB) and incorporated into food, fruit drinks, and other beverages.52 Epidemiological studies show convincing evidence that there is an association between added sugars and NAFLD. The association is more prominent with SSB.[19], [53], [54], [55] A sucrose or fructose-rich diet increases the hepatic synthesis of triglycerides.[56], [57] Furthermore, in animal studies fructose intake is associated with alterations in intestinal microflora, increased gut permeability, endotoxemia, increased hepatic tumour necrosis factor production, lipid peroxidation and hepatic steatosis.[58], [59] There is a growing body of evidence to support the role of fructose in increased gut permeability and endotoxin in human NAFLD.60 Fructose also promotes uric acid production,61 which may cause oxidative stress and insulin resistance. Indeed, in epidemiological studies, serum uric acid was shown to be associated with the development of cirrhosis62 and NAFLD,63 and had a positive dose-response association with elevated serum ALT levels regardless of BMI.64 In addition, cola soft drinks contain caramel colouring, which is rich in AGEs, may increase insulin resistance, inflammation and exacerbate liver injury, steatohepatitis, and liver fibrosis.[39], [65]
Indeed, the Framingham Heart Study cohort, which included cross-sectional analysis of fat infiltration in the liver by computed tomography in 2,634 people and ALT measurements in 5,908 participants, showed a dose-response association between soft drinks and fatty liver disease, with a 61% increased risk of fatty liver disease in daily consumers of SSB compared to non-consumers. In addition, sugared soft drink consumption was positively associated with ALT levels. In contrast, there was no significant association between diet soda intake and either liver fat or ALT levels.66 Similarly, in a 6-month RCT, one litre per day of regular cola, but not isocaloric semi skimmed milk or aspartame-sweetened diet cola, led to increased liver fat.67 In an observational study, fructose-containing soft drinks were also demonstrated to be associated with more severe fibrosis in NAFLD patients if consumed on a daily basis.68 Taken together, these findings imply that, like alcohol, questions regarding SSB consumption should be part of the patient's medical history assessment.
Role of dietary composition in NASH to HCC transition risk reduction
Drinking coffee reduces HCC risk. The hepatoprotective effects of coffee may be linked not only to caffeine but also to its polyphenolic fraction.
Little is known about the association between dietary composition and HCC in humans. Evidence for a potential association is provided from three large prospective studies. In a population-based prospective cohort study of 90,296 Japanese subjects, consuming n-3 PUFA-rich fish and individual types of n-3 PUFAs was inversely associated with HCC.69 In a prospective cohort of 9,221 American participants of the first National Health and Nutrition Examination Survey, high cholesterol intake, but not total fat consumption, was associated with a higher risk of cirrhosis or liver cancer.70 Among 477,206 participants of the European Prospective Investigation into Cancer and Nutrition cohort, the risk of liver cancer was increased by 43% per 50 g/day of total sugar, and was reduced by 30% per 10 g/day of total dietary fibre.71 Accordingly, in a meta-analysis of observational studies the intake of vegetables, but not fruit, was associated with a lower risk of HCC, which decreased by 8% for every 100 g/day increase in vegetable intake.72Interestingly, in a case-control study the Mediterranean diet pattern, which is based on high consumption of fish, vegetables and fibre with low consumption of sugars, was shown to be associated with lower odds of liver cancer.73
Coffee drinking can also reduce the risk of HCC. The hepatoprotective effects of coffee may be linked not only to caffeine, but also to its polyphenolic fraction.[74], [75] According to animal studies, coffee exerts its effects by reducing hepatic fat accumulation, systemic and liver oxidative stress, liver inflammation, and expression and concentrations of proteins and cytokines related to inflammation.74 Furthermore, it was demonstrated that chlorogenic acid, a main coffee polyphenol, inhibits hepatic stellate cells activation in vitro.76
In epidemiological studies, coffee consumption is associated with a lower risk of metabolic syndrome,77 and caffeinated and decaffeinated coffee is associated with reduced diabetes risk in a dose-response manner.78 Epidemiological studies in NAFLD patients indicate an inverse association between coffee consumption and liver fibrosis.[79], [80], [81], [82] However, with regard to steatosis the results are conflicting and mostly indicate a lack of association[79], [80], [82], [83], [84] (Table 1). Epidemiological studies, including prospective cohorts, repeatedly suggested a protective effect against HCC.[85], [86] In a US multi-ethnic prospective cohort of 162,022 participants, those who drank 2-3 cups of coffee per day had a 38% risk reduction for HCC compared with non-coffee drinker. Those who drank ≥4 cups per day had a 41% reduction in HCC risk. Furthermore, compared with non-coffee drinkers, participants who consumed 2-3 cups of coffee per day had a 46% risk reduction of death from chronic liver disease and those who drank ≥4 cups per day had a 71% reduction. The inverse associations were significant regardless of the participants' ethnicity, sex, BMI, smoking status, alcohol intake or diabetes status.85
Although the association between diet and liver cancer seems to be important, the results of these observational studies should be confirmed in additional prospective studies specific for NAFLD patients, controlling carefully for other dietary and lifestyle-related potential confounders.
Role of micronutrients
In spite of the evidence supporting the association of oxidative stress with NASH and the usefulness of antioxidants in animal models, the efficacy of antioxidant therapy in humans has not been shown or properly tested,87 with the exception of vitamin E in a high dose supplement form.88 A study in 3,471 subjects tested the cross-sectional association between ultrasound diagnosed NAFLD and dietary vitamin C intake. It found a significant inverse, energy-adjusted association among men and normal weight subgroups.89 Supporting this finding, another cross-sectional study also showed a significant positive association between low vitamin C intake and NAFLD in the male population.90 In contrast, other smaller studies did not find such an association.[91], [92] In a large cross-sectional population-based study in Hong Kong using MRS-diagnosed NAFLD, an inverse association was seen between the intake of vitamin C, vegetables, legumes and fruits and NAFLD prevalence. In this context, the high Dietary Quality Index, created from the joint consumption of these foods, indicated a reduced likelihood of NAFLD, regardless of BMI and other risk factors.93
Choline is an essential component of cell membranes and is required for the synthesis of phospholipids. In a cross-sectional analysis, postmenopausal women with deficient choline intake had worse fibrosis.94 Choline is particularly abundant in egg yolks and animal sources of protein.
Vitamin D has several favourable metabolic effects and according to experimental data it acts as an anti-inflammatory and anti-fibrotic agent.[95], [96]Emerging evidence suggests that vitamin D deficiency may play a role in the pathogenesis of human NAFLD. In support of that, a meta-analysis of observational studies demonstrated that compared to controls, NAFLD patients were more likely to be vitamin D deficient.97 However, a study carefully adjusting for adiposity (evaluated by dual energy X-ray absorptiometry) suggests that there is no relationship between vitamin D levels and insulin resistance, the amount of liver fat (by MRS and liver biopsy), or the severity of NASH.98 In contrast, in a large study using the NASH CRN cohort, vitamin D deficiency was, independently of BMI and metabolic syndrome, associated with histologic features of NAFLD; definitive NASH, increased lobular inflammation, more ballooning and the presence of fibrosis, but not with grade of steatosis or insulin resistance.99 Therefore, the role of vitamin D in human NAFLD is still unclear. Deficient nutritional intake of vitamin D is very common, intake in Europe from food alone is on average 190 IU/day for men and 130 IU/day for women, the lowest in Spain (44 IU/day, in women) and the highest in Finland (330 IU/day, in men),100 whereas the Dietary Reference Intakes for adults is 600 IU/day. However, there is no clear evidence from RCTs that a high dose vitamin D supplement benefits NAFLD in terms of hepatic steatosis, liver enzymes or insulin resistance.[101], [102]
Physical activity in NAFLD
Our body is programmed to move. As such, it is not surprising that physical movement, or lack of, plays an important role in the development and management of NAFLD and NASH.
Sedentary behaviour and physical activity are not just the reciprocal of each other. Increases in sedentary time could play a potential role in the development of, or predisposition towards NAFLD, independent of physical activity.
a) Sedentary behaviour, also referred to as physical inactivity, holds strong epidemiological, physiological and molecular relationships with the development of over thirty long-term conditions.103 Both TV sitting (a reliable marker of overall sedentary behaviour) and physical activity are associated with cardio-metabolic health when viewed separately[104], [105] or in combination.106 Beyond cardio-metabolic health, ≤3 h of daily sitting is linked to all-cause mortality (RR 1.30; 95% CI, 1.06-1.56).104 Increasing sedentary behaviour is becoming a growing problem in the general population, and low levels of physical activity are compounded by an increase in physical inactivity.
Sedentary behaviour is reported to be higher in people predisposed to the metabolic syndrome, excessive adiposity and type 2 diabetes.107 In addition, prospective studies show that a change in TV viewing over 5 years was associated with waist circumference and clustered cardio-metabolic risk score, independent of physical activity.108 Not only is the total duration of sedentary time important for metabolic risk, but also the breaks in sedentary time, independent of total sedentary time. Increased breaks in sedentary times were beneficial for obesity control, glucose and triglyceride metabolism.109 Consequently, increases in sedentary time could play a potential role in the development of, or predisposition towards NAFLD, independent of physical activity/exercise, and need to be considered when introducing lifestyle interventions. Targeting a reversal of sedentary behaviour may also provide an additional therapeutic avenue to complement physical activity and exercise guidelines. There is limited but promising evidence from prospective cohort studies identifying sedentary behaviour as an independent risk factor for NAFLD.110 At this point it is important to highlight that physical activity and sedentary behaviour have independent effects on cardio-metabolic health. Microarray studies exploring the molecular effects of sedentary behaviour and exercise show that they downregulate and upregulate different pathways,111 demonstrating that they are not just the reciprocal of each other. The confusion comes as they tend to be interrelated behaviourally; those who sit most also tend to move least. Worse still, sitting is also associated with more snacking and an unhealthy diet.112 Combined, these create a 'triple hit behavioural phenotype' of: i) sedentary behaviour, ii) low physical activity, and iii) poor diet.
b) Physical activity, we have known for some time that everyday physical activity, not exercise, is associated with health. In a seminal report in 1953 Professor Jerry Morris113 reported that London (UK) bus drivers, who spend most of their day sitting, were three times as likely to have a coronary heart disease than bus conductors, who spend most of the day physically active collecting tickets on double-decker buses. Cross-sectional studies suggest that people with NAFLD have lower levels of physical activity than those without,[114], [115], [116] and are also more prone to fatigue.117 However, activity levels in people with NAFLD have only been measured and described using physical activity questionnaires. Importantly, questionnaires have significant limitations and are subject to recall and social desirability bias, and are inaccurate in determining frequency, duration and intensity of physical activity.[118], [119] A poor association between objective and subjective reports highlight the importance of objectively assessing physical activity in clinical practice. Physical activity is a key determinant of metabolic control and is commonly recommended for people with NAFLD, usually alongside weight loss and dietary change. Even though physical activity and exercise are recommended as part of the treatment for NAFLD, there have been no large-scale studies with adequate statistical power to guide healthcare practitioners in prescribing exercise programmes, or for generating physical activity guidelines for the management of these patients. Evidence for the benefit of physical activity comes from prospective studies showing that individuals who maintain a physically active lifestyle are less likely to develop insulin resistance, impaired glucose tolerance, or type 2 diabetes.[118], [119] To date, no prospective studies have reported the effect of reducing sedentary behaviour or increasing physical activity on NAFLD incidence or severity. However, given the weight of evidence, sedentary behaviour should be explored in NAFLD management, albeit as an adjunct to diet and exercise.
c) Exercise, unlike the usually unstructured and unplanned nature of physical activity, more deliberate physical activity is described as exercise. Exercise is one of the cornerstones of NAFLD and NASH management, although the evidence underpinning this is still in its infancy compared to other conditions (type 2 diabetes for example). This is likely the product of studies combining diet and exercise interventions until recently. Indeed, in 2012 two independent systematic reviews in the Journal of Hepatology could only identify a maximum of six studies that had undertaken RCT to explore the effects of exercise on liver fat in people with NAFLD.[120], [121] A more recent systematic review in 2017 was able to identify 24 exercise studies, showing the rapid increase in work in this area.122 These reviews reveal that exercise, without weight loss, produced a 20-30% relative reduction in intrahepatic lipid.
Different forms of exercise (aerobic exercise, resistance exercise, or high intensity intermittent exercise) appear to have similar effects on liver fat.[120], [121], [122] More vigorous aerobic exercise does not hold additional benefit for liver fat compared with aerobic exercise.[123], [124] However, it should be noted that all exercise trials are still small and have a wide range of variability. The studies to date have been mainly relatively short, lasting in the majority between 8 and 12 weeks. Longer-term studies are starting to be published and reveal that if patients continue to exercise for 12 months the benefits remain.125 However, if patients do not continue to exercise, the benefits are lost.126 As with many other conditions, if you do not use it, you lose it. Moreover, further studies should take into account genetic background of the patients and its influence on response to physical activity. Indeed, PNPLA3 seems to influence response to lifestyle intervention. Patients bearing unfavourable genotype GG did respond better than patients with genotype CC or CG.127
The mechanisms underlying the change in liver fat following exercise in NAFLD reflect changes in energy balance, circulatory lipids and insulin sensitivity. Much of the early work looking at exercise in NAFLD has been debated, as exercise was either accompanied by dietary changes, or diet induced weight loss - leaving the question of whether there is an exercise only effect unanswered. More recently, better controlled studies are able to not only demonstrate that there is an exercise only effect on liver fat, but also begin to explore the underlying mechanisms. Exercise has little effect on hepatic insulin sensitivity, but does improve peripheral insulin sensitivity,128 producing a net improvement in insulin action and consequently, reducing hepatic de novo lipogenesis. It should be noted that the direct benefits of exercise on glycaemic control are significant, but modest, even in people with impaired glucose control.118 However, tracer studies also show that exercise has a direct effect on lipid flux, with an increase in very low density lipoproteins clearance contributing to the reduction in liver fat with exercise,129 so not all of the changes in liver fat are attributable to insulin sensitivity alone.
Although not the liver itself, there is an important reduction in visceral adipose tissue with exercise. Visceral fat directly links with liver inflammation and fibrosis, independent of insulin resistance and hepatic steatosis.130 The precise mechanism of how visceral fat applies its detrimental effects on liver metabolism, fibrotic and inflammatory consequences remain unclear, although influx of fatty acids and synthesis of cytokines and adipokines has been shown to promote liver lipid accumulation, insulin resistance and inflammation.130 There is much that is not known in the field of exercise and NAFLD, including; the effect of exercise on inflammation (a key mediator in the progression of NAFLD), effect on gut microbiota, and appetite for a start. However, given that people with NAFLD are at nearly double the risk of developing cardiovascular disease than those without,131 the beneficial effects of exercise on cardiovascular function132 should be explored further. Indeed, it is possible that the major benefits for exercise in NAFLD are not in the liver, but in improving cardiovascular function. A schematic representation of the mediators of response to exercise in NAFLD can be seen in Fig. 2.
Data reporting the effects of exercise in people with NASH are limited. To date, only a few studies have reported the effects of exercise on NASH. One presents promising effects on liver lipid, but not on circulating markers of inflammation or fibrosis and a non-significant reduction in circulatory apoptosis marker,133 while another presents a significant reduction in apoptosis marker.134 The one study with liver histology, showed little effect on biopsy measures of liver disease in a small number of patients.135
Diet, sedentary behaviour, physical activity and exercise
Although exercise has a significant and clinically meaningful effect on liver lipid (20-30% relative reduction), its effects are modest in comparison to weight reduction, which can produce >80% reduction in liver fat.120 This is important as, clinically, supporting people to manage their weight through diet approaches will produce greater changes in liver fat than exercise alone. However, completely disassociating exercise and diet may not be beneficial as data suggests that cardiorespiratory fitness is a determinant of response to dietary intervention in NAFLD, with those with a greater cardiorespiratory fitness having a greater response to dietary intervention.136 This creates a difficult paradox where those with the lowest cardiorespiratory fitness, who find exercise most difficult, also have the lowest response to diet-induced lifestyle interventions. Additionally, high levels of physical activity (i.e., 200-300 min/week) are crucial for weight loss maintenance,137 and since physical activity has an independent effect in NAFLD treatment, it provides another treatment option for those who have difficulties in weight loss.
Weight loss as the first endpoint treating NASH
Losing weight decreases cardiovascular and diabetes risk and also regresses liver disease.
The primary approach to treat NAFLD focuses on the control of the underlying risk factors like diabetes, hyperlipidaemia, obesity and other comorbidities. Lifestyle changes through diet and physical activity modifications are well-established therapeutic strategies for conditions such as diabetes and cardiovascular disease.[138], [139] To date, only a few studies have evaluated the impact of lifestyle modification on NAFLD (summarised in Table 2). Marked differences in the study design including various forms of lifestyle intervention with different diets and physical activity regimens, absence of standardised endpoints, diverse phenotypes of NAFLD, different following times together with a relatively small number of patients included in these earlier trials have led to inconclusive recommendations. Recent studies have reported that a comprehensive lifestyle modification based on reduced energy intake and increased physical activity during 6-12 months induces improvement in liver enzymes (AST/ALT and GGT levels) and metabolic (fasting glucose and insulin sensitivity) parameters, improved intrahepatic triacylglycerol concentrations (assessed by proton magnetic resonance spectroscopy[140], [141]), and reduced steatosis and necroinflammation, including ballooning and fibrosis detected in paired liver biopsies.[142], [143] Moreover, weight loss can also have a favourable impact on abdominal obesity,[144], [145] cardiovascular disease146 and extrahepatic malignancies.147 Most studies conclude that at least 7-10% of weight loss is required to induce an improvement in NAFLD activity score (NAS) and its components (steatosis, lobular inflammation and ballooning).[148], [149] However, lifestyle changes that produce even modest, sustained weight loss of about 5% of initial body weight, can reduce steatosis,140 liver enzymes150 and health benefits as clinically meaningful reductions in triglycerides, blood glucose, haemoglobin A1c, and the risk of developing type 2 diabetes.137
Promrat et al. conducted a small-randomised controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behaviour modification, on histological parameters of NASH. The primary outcome measure was the change in NAS after 48 weeks of intervention. The lifestyle intervention group had significant improvements in histology at 48 weeks, with 67% improving their NAS. There was improvement in hepatic steatosis, lobular inflammation, and ballooning in the intervention group; but results showed no improvement in fibrosis in either group.148 In another study on the effect of lifestyle changes in patients with NASH, those who lost 10% or more of total body weight exhibited significantly higher rates of fibrosis regression (63% vs. 9%).151
A prospective study by Vilar et al.12 evaluated the impact on histological features of NASH in a large cohort of patients of a program of lifestyle changes through a hypocaloric diet combined with exercise. They followed these patients during routine clinical practice for 12 months. The study examined the relationship between the degree of weight reduction and the improvements in overall histological parameters. It reported that a dose-response relationship is evident among weight loss percentage and overall histological changes, with the greatest reduction observed in those with the greatest weight loss. Weight reductions of ≥10% are required for inducing NASH resolution (reaching 90% of patients who achieved this weight reduction) or improving fibrosis by at least one stage (81%). However, more modest weight losses (7-10%) produce important benefits on NAS (88%) and its components (steatosis, 100%; lobular inflammation, 100%; and ballooning, 90% of patients who achieved this weight reduction) (Fig. 3). In a post-hoc analysis of this study, patients with weight loss between 7 and 10% and "unfavourable" risk factors such as female sex, presence of diabetes, a BMI of >35 or many ballooned cells at baseline had lower rates of NASH resolution. However, higher rates of NASH resolution were seen in subjects with more significant weight losses (≥10%) irrespective of the presence of "unfavourable" risk factors,152 suggesting that a weight reduction >10% is required in the high risk group of patients.
Accordingly, the EASL-EASD-EASO Clinical Practice Guidelines recommend that in overweight/obese NAFLD patients, a 7-10% weight loss is the target of most lifestyle interventions, and results in an improvement of liver enzymes and histology (Grade B1).11
The impact of weight loss on histological improvement depends on the degree of weight reduction irrespective of the method used to reach it. Lifestyle intervention including hypocaloric diet and exercise, weight loss-induced by drugs like orlistat or weight loss after bariatric surgery seem to have the same positive impact on NASH resolution and fibrosis regression. For example, low carbohydrate diet may seem more effective in reducing liver fat, but only in the short-term.[153], [154] In the long-term, reduction appears to be similar in both diets as long as a 7% weight loss is achieved.155 In a 6-month RCT, both energy restricted diets of either reduced carbohydrate (<90 g carbohydrates and a minimum of 30% fat of total energy intake) or reduced fat (<20% fat of total energy intake) led to similar, significant reductions in intrahepatic lipid content and ALT.156 This equivalence of diets is also supported by a small meta-analysis.149 These findings indicate that the diet of choice should be the one which individuals are able to adhere to for years, as long as it is generally healthy and leads to weight reduction.
NASH resolution rate after lifestyle intervention appears to be reduced in older people, in patients suffering from type 2 diabetes and in patients showing higher histological activity in liver biopsy (NAS ≥5). Moreover, NASH resolution was demonstrated to be strongly related to the normalisation of ALT (≤19 in females or ≤30 in males) and weight loss percentage.152 Taking into account all these five variables, a NASH resolution calculator ([NASHRES] available at http://www.aeeh.es/calculadora-nashres/) has been developed and could be useful in the management of patients undergoing focussed weight loss intervention. In a cohort of 261 patients treated with a lifestyle intervention during 52 weeks (140 in derivation set and 121 in the temporary validation set), the NASHRES calculator showed a high diagnostic accuracy (AUROC 0.96 in the estimation cohort and AUROC 0.95 in the validation cohort). A score lower than 46.15 showed a negative predictive value for NASH resolution of 92%, whereas a result higher than 69.72 showed a positive predictive value of 91%. Indeed, this tool was validated in the LEAN trial comparing liraglutide, a GLP-1 agonist, vs. placebo.157 NASHRES calculator allowed the correct classification of patients with a diagnostic accuracy of 94% to detect lack of NASH resolution. Thus, it is a useful tool to detect futility impact of lifestyle intervention and could help to select patients requiring further therapeutic interventions.158
Behavioural aspects of lifestyle modification
There is no doubt that lifestyle modification and weight loss pose a great challenge to both the patients and caregivers. NAFLD patients may have a low level of readiness for change and motivation to adopt a healthier lifestyle.159 Furthermore, NAFLD diagnosis is not necessarily associated with lower general health perception nor is it associated with higher health care utilisation.160 It has been repeatedly demonstrated that weight loss achieved by diet is highest at 6-months follow-up and thereafter a weight regain occurs, with patients only reaching 3 to 4 kg weight reduction at 2-year follow-up.137Interestingly, even if there is weight regain after diet, there seems to be a long lasting beneficial effect on liver fat and insulin resistance. In a study with 2-year follow-up after six months dietary intervention, improvements in liver fat and insulin resistance were maintained despite regaining of weight, perhaps because the intervention elicited sustained favourable lifestyle changes.161 In support of that, in overweight and obese adults with type 2 diabetes undergoing lifestyle intervention and followed for four years, despite partial weight regain haemoglobin A1c levels remained below pre-intervention levels, and the reduction remained clinically meaningful.162 Nevertheless, in the study by Vilar-Gomez et al.12 just 10% of patients (29/293) reached a 10% weight loss and more than 70% of the cohort (208/293) did not lose 5% of total body weight.
In patients with successful NASH resolution the key point is to prevent weight regain. In the Look AHEAD study, which included 5,145 overweight type 2 diabetes patients,163 long-term lifestyle intervention produced ≥5% weight loss at eight years in 50% of participants. The key factors influencing long-term weight loss were intensity of physical activity and percentage of weight loss during the first year. The 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults provides practical recommendations for weight reduction; high intensity (i.e., ≥14 sessions in six months) comprehensive weight loss interventions, and for weight loss maintenance; a long-term (≥1 year) comprehensive program that provides regular contact (monthly or more frequently).137
The role of the multidisciplinary approach and behavioural therapy in the lifestyle treatment of NASH
The 5 A's model (ask, advise, assess, assist, and arrange) may be useful as a tool to assist clinicians advising NAFLD patients to modify their behaviour, assessing their interest in doing so, assisting in their efforts to change, and arranging appropriate follow-up.
One approach to improve the self-management in NAFLD patients may be by implementing a "multidisciplinary team approach" in which patients will be followed by physicians, dieticians, psychologists and physical activity supervisors.164 Unfortunately, in many cases a full multidisciplinary team is not available for the patient due to limited resources. Either way, the active support of the physicians is much needed, since the physician's advice is a catalyst for lifestyle change,165 and several studies indicate that physician's advice to lose weight has positive effects on the probability of keeping the diet and exercise recommendations166 and on the patients' motivation for weight loss.167 Furthermore, general practitioners and hepatologists treating NAFLD patients should provide information and refer the patients to appropriate resources about NAFLD implications and treatment and have training in behavioural therapy. Similarly to the treatment approach in other chronic diseases, healthcare providers need to discuss with their patients the broader picture of NAFLD complications; liver cancer, increased risk of diabetes, cardiovascular disease, with the message that risk reduction is possible.168 In a recent cross-sectional study among 146 patients with NAFLD, a better nutritional behaviour was associated with higher patient's perceptions of understanding what NAFLD is, believing in treatment effectiveness and a higher self-efficacy.169 The 5 A's model (ask, advise, assess, assist, and arrange) may be useful as a tool to assist clinicians advising patients with NAFLD to modify their behaviour, assessing their interest in doing so, assisting in their efforts to change, and arranging appropriate follow-up meetings.170
A practical guide for behavioural therapy in the lifestyle treatment of NASH
NAFLD patients rarely receive support to encourage meaningful and sustainable changes to diet and physical activity behaviour. Given the strength of evidence demonstrating that lifestyle changes are effective, knowledge of the clinical care team will not be a limitation. The lack of effective use of lifestyle interventions is most likely due to the lack of training given to clinical care teams with the aim of delivering effective behaviour change interventions (i.e., use of behaviour change and brief motivational techniques). Behaviour change typically involves three stages, described in Fig. 4.
Summary & conclusions
Lifestyle change, including dietary habits and physical activity, are and should be the first line of treatment in NAFLD and NASH. Weight reduction is the most established treatment for both NAFLD and NASH, with a clear dose-response association. Generally, any form of healthy diet (low fat or low carbohydrates or Mediterranean diet), which will lead to caloric reduction and is acceptable by the patient, should be encouraged. For those who find caloric restriction difficult, changing dietary composition without necessarily reducing caloric intake may offer a more feasible alternative, although the benefit to liver health is not as marked as weight reduction. The importance of weight loss is highlighted in people with NASH, where weight loss >7% is associated with a clinically meaningful regression of disease status. Exercise produces significant but modest changes in liver fat (vs. weight loss). However, given the strong cardiovascular benefits of exercise, the optimal placement for exercise is likely as an adjunct to dietary manipulation, whether in NAFLD or NASH. Combined, this evidence strongly supports the role of lifestyle as a primary therapy for the management of NAFLD and NASH. The question is no longer whether lifestyle is an effective clinical therapy; the question is now how do we implement lifestyle as a therapy in everyday clinical care.
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