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Review
Treatment of NAFLD with diet, physical activity and exercise
1,⇑ 2,3 4
Manuel Romero-Gómez , Shira Zelber-Sagi , Michael Trenell
Summary Keywords: Mediterranean diet;
Steatosis; Steatohepatitis;
Lifestyle intervention can be effective when treating non-alcoholic fatty liver diseases (NAFLD) Fibrosis; Physical activity;
patients. Weight loss decreases cardiovascular and diabetes risk and can also regress liver dis- Exercise; Weight loss; Behaviour
intervention.
ease. Weight reductions of P10% can induce a near universal non-alcoholic steatohepatitis
resolution and fibrosis improvement by at least one stage. However, modest weight loss Received 1 March 2017; received in
([5%) can also produce important benefits on the components of the NAFLD activity score revised form 9 May 2017; accepted
15 May 2017
(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 tech-
niques for long-term maintenance of lifestyle modifications.
Following a Mediterranean diet can reduce liver fat even without weight loss and is the most
recommendeddietary 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.
2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights
reserved.
Introduction
1
Non-alcoholic fatty liver disease (NAFLD) is a major incidence of around two new cases/100 patients/ Mac.Ro UCM IC Digestive Diseases
health problem because of its high prevalence and year. Since NASH is becoming one of the most fre- and Ciberehd, University Hospital
the associated risk of progression to liver cirrhosis, quent causes of cirrhosis and liver transplantation Virgen del Rocio, Institute of Bio-
4,5 medicine of Seville, University of
liver cancer and also, increased cardiovascular and worldwide, it is crucial to identify patients at risk Seville, Sevilla, Spain;
2
solid neoplasm risk. NAFLD comprises a wide of NAFLD progression in order to implement thera- Department Gastroenterology, Tel-
pathological spectrum ranging from simple steato- peutic interventions that can lead to prevention or Aviv Medical Center, Tel-Aviv,
sis to steatohepatitis (NASH) with variable degrees reversal of the deleterious consequences of Israel; w
3
1 School of Public Health, Faculty of
of fibrosis and cirrhosis. The strongest predictor of advanced NASH. Social Welfare and Health Sciences, vie
fibrosis progression in NAFLD is the presence of Patients with NAFLD are frequently obese and/or e
University of Haifa, Haifa, Israel; R
2 4
steatohepatitis. The risk of detrimental outcomes have diabetes, and insulin resistance is a key patho- NIHR Innovation Observatory,
is increased in patients with significant fibrosis, or genic trigger. Four phenotypes of patients with Newcastle University, Newcastle,
steatohepatitis, whilst it is lower in patients with NAFLD have been defined: i) obese, ii) type 2 dia- UK
simple steatosis. Liver biopsy remains the gold betes, iii) metabolic syndrome and iv) lean patients. ⇑ Corresponding author. Address:
standard for histological evaluation of the disease. PNPLA3 is the genetic hallmark of NAFLD. Patients Inter-Centres Mac.Ro UCM Diges-
Non-invasive methods combining imaging and bio- bearing genotype GG were at three times greater tive Diseases, Virgen del Rocío
chemical tests are warranted to pre-empt the need risk of NAFLD. This increased risk is more evident University Hospital, Avenida
6 Manuel Siurot s/n, 41013 Sevilla,
for liver biopsies. in patients without metabolic syndrome. Indeed, Spain.
The prevalence of NAFLD varies largely from TM6SF2 mutation has an additive effect on NAFLD E-mail address: mromerogome-
3 7 z@us.es (M. Romero-Gómez).
20%to30%andincreaseswithage, withanannual risk.
Journal of Hepatology 2017 vol. 67 j 829–846
Review
Role of macro- and micronutrients in NAFLD another meta-analysis of 10 RCTs, omega-3 treat-
ment was beneficial in terms of decreasing the
Role of energy restriction amount of liver fat and improved gamma-glutamyl
transferase (GGT) levels, but it was not significantly
Excess caloric consumption leading to obesity and efficient in reducing alanine aminotransferase (ALT)
23
related comorbidities is a leading risk factor for and aspartate aminotransferase (AST) levels.
8
NAFLD. Furthermore, weight gain by itself, even RecentRCTs,whichalsoincludeliverhistologyanal-
only a modest 3–5kg, predicts the development ysis, offer further insight into the effects of omega-3
of NAFLD, regardless of baseline body mass index treatment on NASH and fibrosis, but results are con-
9
(BMI). Interestingly, not only excess caloric con- flicting, indicating a beneficial effect for liver fat
sumption, but also the way food consumption is reduction (for DHA containing supplements, not
distributed throughout the day, affects liver fat for EPA alone), but not for improving NASH or fibro-
accumulation. In a 6-week randomised controlled sis.24–26 Furthermore, in contrast to experimental
trial (RCT), high fat high sugar, or high sugar findings, there was no consistent significant effect
25,26
hyper-caloric diets were consumed either together oninsulin resistance. In summary, consumption
with main meals or between them as snacks. Only of different types of fats have different effects on
thelatterincreasedliverfat(measuredbymagnetic NAFLD and NASH, therefore, a reduction in total
resonance spectrometry [MRS]) and abdominal fat fat intake is not the simple solution.
(measured by magnetic resonance imaging [MRI]), The traditional Mediterranean diet is charac-
suggesting that snacking, a common feature in the terised by a high intake of olive oil, which is rich
Western diet, independently contributes to hepatic in monounsaturated-fat [MUFA], nuts, fruits and
10
steatosis. There is a consensus that gradual legumes, vegetables, and fish and a low intake of
weight reduction achieved by caloric restriction, red meat, processed meats, and sweets (wine in
11
with or without increased physical activity, leads moderation). In contrast to the low fat diet, which
to an improvement in serum liver enzymes, liver contains up-to 30% fat, 40% of the calories in the
12 Mediterranean diet are derived from fats, mostly
fat, degree of hepatic inflammation and fibrosis.
MUFA and omega-3 PUFA. MUFA has a favourable
27,28
Role of dietary composition effect on lipid profile. Moreover, the Mediter-
ranean diet plays a beneficial role in metabolic
29
Fat type and the Mediterranean dietary pattern profile and has been shown to reduce the risk of
Key point 30 31
cardiovascular disease and diabetes, two out-
The Mediterranean diet can Experimental studies have shown that diets comes highly relevant in NAFLD patients.
reduceliverfat evenwithout enriched with omega-3 polyunsaturated fatty acids Interestingly, one of the principles of the
weight loss and is the most (PUFA) increase insulin sensitivity,13 reduce intra- Mediterranean diet is to minimise processed and
recommended dietary pat- 32–34
hepatic triglyceride content and ameliorate steato- high sugar food. A reduction in processed and
tern in NAFLD. 14,15 35
hepatitis. In epidemiological studies, the diet of highfructose food mayalsoleadtoreducedintake
normal weight NASH patients compared to age, of advanced glycation end products (AGEs). These
gender and BMI matched controls, is richer in satu- are a heterogeneous class of non-enzymatic prod-
16,17 ucts derived from protein, lipid and nucleic acid gly-
rated fat and cholesterol and poorer in PUFA.
36
Within the PUFAs, there is superiority for the cation, produced endogenously but also
omega-3 PUFAs and its sub-types; eicosapen- introduced through the diet. AGEs are related to
taenoic acid (EPA) and docosahexaenoic acid the aetiology of diabetes and other metabolic alter-
34,37,38
(DHA) (both abundant in fish oil) over the omega- ations. They have been shown to be elevated
6 PUFAs. Epidemiological studies implicate a lower in NASH patients compared to simple steatosis and
w consumption of omega-3 PUFA and a higher n-6/n- controls, and to be positively correlated with insulin
39
vie 3ratio amongNAFLDandNASHpatientscompared resistance and negatively with adiponectin. Fur-
e 18,19 thermore, the soluble receptor of AGEs (sRAGE) that
R to controls.
In fact, overfeeding with PUFA and saturated prevents the binding of extracellular AGEs to the
40
FAs (SFAs) has distinct effects on liver and visceral cell-surface RAGE, thus exerting protective effects,
fat accumulation in humans. In a 7-week RCT was shown to be inversely correlated with the level
overeating SFAs or omega 6-PUFAs led to a similar of liver fat, and more interestingly, sRAGE levels
41
weight gain, but the SFAs markedly increased liver were increased by lifestyle changes.
fat compared with PUFAs and caused a twofold It has been suggested in a single-arm trial that
20 adherence to the Mediterranean dietary pattern
increase in visceral fat compared to PUFAs. Simi-
larly, a 10-week RCT of isocaloric diets demon- leads to a significant decrease in liver fat among
42
strated that intake of omega 6-PUFAs reduced overweight patients with NAFLD. This was sup-
liver fat compared to increased liver fat with the ported by two short-term randomised trials in
21 NAFLD patients with or without type 2 diabetes. In
high saturated fat diet. A meta-analysis of small
or uncontrolled trials, using omega-3 supplements both studies, patients were assigned to two isocalo-
with varying types and dosages indicated a poten- ric diets; either a low fat high carbohydrate diet or
22 an 8-week high-MUFA diet in one study and in the
tially beneficial effect on reducing liver fat. In
830 Journal of Hepatology 2017 vol. 67 j 829–846
JOURNALOFHEPATOLOGY
64
other study the low fat high carbohydrate diet or a less of BMI. In addition, cola soft drinks contain
6-week Mediterranean diet. Liver fat content caramel colouring, which is rich in AGEs, may
decreased more in the MUFA or the Mediterranean increase insulin resistance, inflammation and exac-
diet (about 35%) than in the low fat high carbohy- erbate liver injury, steatohepatitis, and liver
39,65
drate diet (about 5%), despite a stable weight in fibrosis.
43,44
both groups. Importantly, the Mediterranean Indeed, the Framingham Heart Study cohort,
diet is also characterised by reduced carbohydrate which included cross-sectional analysis of fat infil-
intake (40% of the calories vs. 50–60% in a typical tration in the liver by computed tomography in
low fat diet), especially reduced sugars and refined 2,634peopleandALTmeasurementsin5,908partic-
carbohydrates, which may partially account for its ipants, showedadose-responseassociationbetween
beneficial effect in NAFLD. Longer-term trials test- soft drinks and fatty liver disease, with a 61%
ing the effects of a Mediterranean diet are increased risk of fatty liver disease in daily con-
warranted. sumersofSSBcomparedtonon-consumers.Inaddi-
It should be noted that although the Mediter- tion, sugared soft drink consumption was positively
ranean diet advocates consumption of wine in associated with ALT levels. In contrast, there was no
moderation, it is unclear whether NAFLD patients significant association between diet soda intake and
66
should adopt this recommendation. NASH patients either liver fat or ALT levels. Similarly, in a 6-
with cirrhosis should avoid alcohol, as any regular month RCT, one litre per day of regular cola, but
alcohol consumption puts them at a greater risk not isocaloric semi skimmed milk or aspartame-
45 67
of developing hepatocellular carcinoma (HCC). sweetened diet cola, led to increased liver fat. In
However, uncertainty remains regarding moderate an observational study, fructose-containing soft
alcohol consumption (up-to two drinks per day) drinkswerealsodemonstratedtobeassociatedwith
in patients without cirrhosis. Several studies have more severe fibrosis in NAFLD patients if consumed
68
shownaprotective association of moderate alcohol on a daily basis. Taken together, these findings
46–50 51
consumption with NAFLD and NASH. The imply that, like alcohol, questions regarding SSB
protective effect may be specific to wine, as it consumptionshouldbepartofthepatient’smedical
was found in a national cross-sectional survey that history assessment.
modest wine drinking of up-to 10g of alcohol per
day, but not other types of alcoholic beverages, Role of dietary composition in NASH to HCC transition
was associated with a lower prevalence of unex- risk reduction
47
plained elevated ALT compared to non-drinking.
Currently, the Mediterranean diet is the dietary Little is known about the association between diet-
pattern recommended for NAFLD patients by the ary composition and HCC in humans. Evidence for a
recent EASL–EASD–EASO Clinical Practice Guideli- potential association is provided from three large
11
nes (Grade: B1) (Fig. 1). prospective studies. In a population-based prospec-
tive cohort study of 90,296 Japanese subjects, con-
Added sugars suming n-3 PUFA-rich fish and individual types of
69
n-3 PUFAs was inversely associated with HCC. In
Added sugar refers to refined sugars (sucrose, a prospective cohort of 9,221 American participants
fructose and high fructose corn syrup) added to of the first National Health and Nutrition Examina-
sugared sweetened beverages (SSB) and incorpo- tion Survey, high cholesterol intake, but not total Key point
52
rated into food, fruit drinks, and other beverages. fat consumption, was associated with a higher risk
70
Epidemiological studies show convincing evidence of cirrhosis or liver cancer. Among477,206partic- Fructose consumption is
that there is an association between added sugars ipants of the European Prospective Investigation associated with alterations
and NAFLD. The association is more prominent into Cancer and Nutrition cohort, the risk of liver in gut microbiota, increased w
19,53–55 intestinal permeability,
with SSB. A sucrose or fructose-rich diet cancer was increased by 43% per 50g/day of total endotoxemia,increasedhep- vie
56,57 e
increases the hepatic synthesis of triglycerides. sugar, and was reduced by 30% per 10 g/day of total atic TNF production and R
71
Furthermore, in animal studies fructose intake is dietary fibre. Accordingly, in a meta-analysis of lipid peroxidation, promot-
associated with alterations in intestinal microflora, observational studies the intake of vegetables, but ing hepatic steatosis and
increasedgutpermeability,endotoxemia,increased not fruit, was associated with a lower risk of HCC, NAFLD.
hepatic tumour necrosis factor production, lipid which decreased by 8% for every 100g/day increase
58,59 72
peroxidation and hepatic steatosis. There is a in vegetable intake. Interestingly, in a case-control
growing body of evidence to support the role of study the Mediterranean diet pattern, which is
fructose in increased gut permeability and endo- based on high consumption of fish, vegetables and Key point
60
toxin in human NAFLD. Fructose also promotes fibre with low consumption of sugars, was shown
61 73
uric acid production, which may cause oxidative to be associated with lower odds of liver cancer. Drinking coffee reduces HCC
stress and insulin resistance. Indeed, in epidemio- Coffee drinking can also reduce the risk of HCC. risk. The hepatoprotective
logical studies, serum uric acid was shown to be Thehepatoprotective effects of coffee may be linked effects of coffee may be
62 linked not only to caffeine
associated with the development of cirrhosis notonlytocaffeine,butalsotoitspolyphenolicfrac- but also to its polyphenolic
63 74,75
and NAFLD, and had a positive dose-response tion. According to animal studies, coffee exerts fraction.
association with elevated serum ALT levels regard- its effects by reducing hepatic fat accumulation, sys-
Journal of Hepatology 2017 vol. 67 j 829–846 831
Review
Healthy liver Fatty liver NASH/Fibrosis Liver cancer
Western diet Western diet Western diet
X?
Hypocaloric or isocaloric - Mediterranean diet 7-10% Weight reduction Mediterranean diet
by energy deficit of 500-750 kcal/day through • High fibres
Aerobic or resistance excercise either diet: • High fish
(Clinical trials) • low fat • High vegetables
• low carb • Low cholesterol
• Mediterranean • Low sugar
(Clinical trials)
Drinks
Dietary composition modification • Coffee 2-3 cups/day
Reduced fructose • No alcohol in cirrhotics
Mediterranean diet (Observational studies)
(Observational studies)
Fig. 1. A summary of the nutritional treatment options (based on clinical trials or observational studies) through the course of NAFLD. Remission of steatosis can
occur with weight reduction achieved by several types of diet or with isocaloric Mediterranean diet (which induces metabolic and anti-inflammatory benefits), as indicated
by clinical trials. For remission of NASH or fibrosis, there is no evidence from clinical trials for a benefit of merely improving dietary composition, while there is evidence
that at least 7% weight reduction is needed. For prevention of progression to liver cancer, the evidence regarding certain foods and nutrients is derived only from large
observational studies and needs further confirmation.
temicandliveroxidativestress, liver inflammation, patients, controlling carefully for other dietary and
and expression and concentrations of proteins and lifestyle-related potential confounders.
74
cytokines related to inflammation. Furthermore,
it was demonstrated that chlorogenic acid, a main Role of micronutrients
coffee polyphenol, inhibits hepatic stellate cells
activation in vitro.76 In spite of the evidence supporting the association
In epidemiological studies, coffee consumption of oxidative stress with NASH and the usefulness
is associated with a lower risk of metabolic syn- of antioxidants in animal models, the efficacy of
77
drome, and caffeinated and decaffeinated coffee antioxidant therapy in humans has not been shown
is associated with reduced diabetes risk in a dose- 87
or properly tested, withtheexceptionofvitaminE
78 88
response manner. Epidemiological studies in in a high dose supplement form. A study in 3,471
NAFLD patients indicate an inverse association subjects tested the cross-sectional association
79–82
between coffee consumption and liver fibrosis. between ultrasound diagnosed NAFLD and dietary
However, with regard to steatosis the results are vitamin C intake. It found a significant inverse,
conflicting and mostly indicate a lack of associa- energy-adjustedassociationamongmenandnormal
79,80,82–84 89
tion (Table 1). Epidemiological studies, weight subgroups. Supporting this finding,
including prospective cohorts, repeatedly sug- another cross-sectional study also showed a signifi-
85,86
gested a protective effect against HCC. In a US cant positive association between low vitamin C
multi-ethnic prospective cohort of 162,022 partici- 90
intake and NAFLD in the male population. In con-
w pants, those who drank 2-3 cups of coffee per day trast, other smaller studies did not find such an
vie had a 38% risk reduction for HCC compared with association.91,92 In a large cross-sectional
e non-coffee drinker. Those who drank P4 cups per population-based study in Hong Kong using MRS-
R day had a 41% reduction in HCC risk. Furthermore,
diagnosed NAFLD, an inverse association was seen
compared with non-coffee drinkers, participants between the intake of vitamin C, vegetables,
who consumed 2-3 cups of coffee per day had a legumes and fruits and NAFLD prevalence. In this
46% risk reduction of death from chronic liver dis- context, the high Dietary Quality Index, created
ease and those who drank P4 cups per day had a fromthejointconsumptionofthesefoods,indicated
71% reduction. The inverse associations were sig- a reduced likelihood of NAFLD, regardless of BMI
nificant regardless of the participants’ ethnicity, 93
and other risk factors.
sex, BMI, smoking status, alcohol intake or diabetes Choline is an essential component of cell mem-
85
status. branes and is required for the synthesis of phospho-
Although the association between diet and liver lipids. In a cross-sectional analysis, postmenopausal
cancer seems to be important, the results of these women with deficient choline intake had worse
observational studies should be confirmed in addi- 94
fibrosis. Choline is particularly abundant in egg
tional prospective studies specific for NAFLD yolks and animal sources of protein.
832 Journal of Hepatology 2017 vol. 67 j 829–846
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