Download The Role of Diet and Nutrient Composition in Nonalcoholic Fatty

RESEARCH
Review
The Role of Diet and Nutrient Composition in
Nonalcoholic Fatty Liver Disease
Erin Marie McCarthy, MS, RD, LDN; Mary E. Rinella, MD
ARTICLE INFORMATION
ABSTRACT
Article history:
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the
developed world. NAFLD is tightly linked to insulin resistance and considered to be the hepatic
manifestation of the metabolic syndrome. The cornerstone of any treatment regimen for patients
with NAFLD is lifestyle modification focused on weight loss, exercise, and improving insulin sensitivity. Here we review the literature and discuss the role of diet and nutrient composition in the
management of NAFLD. Because there are currently no specific dietary guidelines for NAFLD, this
review proposes a dietary framework for patients with NAFLD based on the available evidence and
extrapolates from dietary guidelines aimed at reducing insulin resistance and cardiovascular risk.
J Acad Nutr Diet. 2012;112:401-409.
Accepted 30 September 2011
Keywords:
Nutrition
Obesity
NAFLD/NASH
Fatty liver
Copyright © 2012 by the Academy of Nutrition
and Dietetics.
2212-2672/$36.00
doi: 10.1016/j.jada.2011.10.007
N
ONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE
most common cause of chronic liver disease in the
developed world (1). NAFLD is a significant health
problem and affects 70 million adults in the United
States (⬃30% of the adult population). NAFLD
encompasses a spectrum of liver disease that ranges from simple
steatosis to nonalcoholic steatohepatitis (NASH), its progressive
subtype. An estimated 20% of patients with NAFLD have NASH,
which can progress to cirrhosis necessitating liver transplantation. NAFLD in both forms represents the hepatic manifestation of
the metabolic syndrome that also includes dyslipidemia, central
obesity, hypertension, and insulin resistance (IR) (2). Most patients with fatty liver have excess body weight. Although promising pharmacologic therapies are emerging, sustained weight
loss is the most effective treatment for NAFLD and should be the
foundation of any treatment plan.
A thorough discussion of the pathophysiology of NAFLD is
beyond the scope of this review; however, how obesity and
dietary composition affects hepatic fat accumulation and inflammation will be briefly discussed. Obesity itself represents a
chronic, inflammatory condition resulting from the failure of
the normal homeostatic regulation of energy intake, storage,
and use (3,4). In the setting of obesity, particularly central obesity, there is an expansion of active visceral adipose tissue. This
adipose tissue compartment becomes infiltrated by inflammatory cells that lead to a milieu in which proinflammatory cytokines such as tumor necrosis factor ␣ and interleukin-6 increase while adiponectin, which counteracts the effects of
tumor necrosis factor ␣, decreases (1). This leads to hepatic
steatosis and a state of heightened IR and increased oxidative
injury. Weight loss can change the activity of adipose tissue
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© 2012 by the Academy of Nutrition and Dietetics.
and reverse many of these consequences as can, potentially,
dietary macronutrient content (see the Figure). In the setting of
excessive nutrient intake, diets rich in fat or carbohydrate can
decrease insulin sensitivity and increase serum free fatty acid
levels, leading to hepatic steatosis. A critical review of diets for
the metabolic syndrome and popular diets as they might relate
to NAFLD is discussed elsewhere (5). This review discusses the
existing data on the effects of diet-induced weight loss and
dietary composition and proposes a rational dietary approach
that promotes slow and controlled weight loss designed to improve insulin sensitivity and reduce cardiovascular risk in patients with NAFLD.
METHODS
Articles featured in this review were identified through an electronic database search using PubMed with dates ranging from
1990 through 2011. Randomized controlled trials, case control
studies, and observational studies of adult patients were included. The search terms used for this review included: fatty liver
disease, fatty liver nutrition, NASH nutrition, NASH diet, fructose NAFLD, saturated fat liver, carbohydrate metabolic syndrome, insulin
resistance and diet, antioxidants, and bariatric surgery.
Effects of Weight Loss on NAFLD
Although the liver is not meant to store fat, excess energy and
unmatched energy expenditure can result in the accumulation of
fat in the liver. Weight management, dietary macronutrient composition, physical activity, and behavior therapy all play a critical
role in successful weight loss.
Patients with NAFLD have been shown to have higher energy
intake when compared with healthy controls (6). Long-term wellcontrolled dietary intervention studies are limited; however, the
preponderance of the evidence suggests that it is effective in improving liver disease related to NAFLD because it improves insulin
sensitivity, hypertension, and dyslipidemia. Several studies show
that diet-induced weight loss reduces liver enzymes and hepatic
steatosis, with less consistent effects on other components of liver
histology (7-9). In patients with NASH, some studies have shown
that a 1,400 kcal/day diet and weight loss of ⬃3.5 kg improve
histology on liver biopsy and liver enzyme levels (10). In the largJOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS
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Figure. Adipose tissue undergoes significant transformation during weight gain that is characterized by adipocyte hypertrophy
and infiltration by macrophages. These changes lead to an increased rate of adipocyte apoptosis and the secretion of a host of
proinflammatory cytokines from both adipocytes and macrophages. This chronic inflammatory state then promotes insulin
resistance. Hepatic steatosis develops as a result of increased adipose tissue lipolysis and an adipocytokine profile that promotes
insulin resistance, lipogenesis, and impairs fatty acid oxidation and export. Weight loss can reverse this process and thereby restore
insulin sensitivity and reduce hepatic fat accumulation and inflammation.
est randomized controlled trial of lifestyle intervention in NASH,
patients were randomized 2:1 to a combination of diet, exercise,
and behavior modification (lifestyle intervention group) or a control group, with a goal of 7% to 10% weight reduction (11). The
primary outcome measure was an improvement in the NAFLD
activity score after 48 weeks of treatment. Subjects in the lifestyle
intervention group (n⫽21) were assigned an energy goal based on
their starting weight (1,000 to 1,200 kcal/day if baseline weight
⬍200 lb or 1,200 to 1,500 kcal/day if baseline weight ⬎200 lb) and
were instructed to consume a 25% fat diet. Participants in the
control group (n⫽10) attended group sessions providing basic
education about NASH and principles of healthy eating and physical activity. The lifestyle intervention group had an average
weight loss of 9.3% of their weight compared with only 0.2% in the
control arm (P⫽0.005). Furthermore, after treatment, NAFLD activity score was lower in the lifestyle intervention group compared with the control group (P⫽0.05). Those who lost ⱖ7% of
their body weight had significant improvements in steatosis
(P⬍0.001), lobular inflammation (P⫽0.03), and NAFLD activity
score (P⬍0.001).
Although weight loss is the most effective treatment for NAFLD,
excessive energy restrictions and sudden weight loss may worsen
liver injury (12). In fact, rapid weight loss (⬎2.5 lb/week) as seen
in antiquated bariatric procedures such as the jejunoileal bypass
often worsened steatohepatitis or resulted in cirrhosis and liver
failure (13,14). In patients with NAFLD, particularly those with
advanced liver disease, slow and controlled weight loss over time
is the goal. Short-term and pilot studies have shown that a 25
kcal/kg/day diet or a reduction of ⬃200 kcal/day produces significant decreases in aspartate aminotransferase, alanine aminotransferase (ALT), fasting glucose, body mass index, and the degree of hepatic steatosis (9,15). Modest weight loss, ⬍2 lb (1 kg)
per week, is associated with a decrease in the incidence of the
metabolic syndrome and improvement in the histologic features
of NASH in ⬎80% of cases (16). As little as 5% weight loss can have
beneficial effects on NAFLD, although an initial 10% weight loss is
typically recommended and supported by the National Heart,
Lung, and Blood Institute–National Institute of Diabetes and Digestive and Kidney Diseases clinical guidelines (17). To avoid
rapid weight fluctuations, the recommended rate of weight loss is
1 to 2 lb/week (17).
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Influence of Dietary Macronutrients
Aside from the possibility of achieving weight loss through caloric
restriction as a treatment of NAFLD, dietary composition can directly influence the development of NAFLD. Various types of diets
(either low in carbohydrates or low in fats) are equally effective
for long-term weight reduction (18). However, there is evidence
that manipulation of either micronutrient or macronutrient content can affect hypertension, levels of inflammation, serum lipids,
and IR independent of weight loss (19-21). This is illustrated by
the differences in recommended macronutrient content by various societies (Table 1). Animal data and observational studies
suggest that a diet high in carbohydrates worsens liver injury
related to NAFLD. Although no prospective study has compared
the effects of popular fad diets on patients with NAFLD, this is
thoroughly reviewed elsewhere (5).
Carbohydrate
Extrapolating from the diabetes literature and available data on
NAFLD, the percentage of carbohydrate in the diet and the Glycemic Index (GI) value of the carbohydrates is likely to have an
important influence on NAFLD (22). Diets enriched in carbohydrate lead to increased circulating insulin concentrations, which
contribute to elevated fasting triglyceride concentrations even
under isocaloric conditions (23,24). A low-fat, high-carbohydrate
diet promotes the development of fatty liver via increased de
novo fatty acid synthesis (25). In patients with the metabolic syndrome and NAFLD, a diet containing more carbohydrate and less
fat has been associated with greater histologic severity (26). In
one study, patients consuming ⬎54% of energy from carbohydrates compared with those consuming ⬍35% had a 6.5-fold increased risk of hepatic inflammation (27). Ryan and colleagues
(28) randomized patients to hypocaloric diets containing either
60% carbohydrate/25% fat or 40% carbohydrate/45% fat (15% protein in both) of equal energy deficit (750 kcal/day) for 16 weeks.
Patients receiving the lower carbohydrate diet had lower ALT
concentrations compared with those given a high-carbohydrate/
low-fat diet, despite equal weight loss. This suggests that a hypocaloric, lower carbohydrate diet may be beneficial to patients
with NAFLD, independent of weight loss (28). In another study
(29), patients with NAFLD following an energy-restricted (1,200
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Table 1. Diets for a healthy lifestyle,a as recommended by authoritative groups in the United States
Group
Component
American Heart Association
Academy of Nutrition
and Dietetics
US Department of Agriculture
Fruits
4 servings
2-4 servings
1.5-2 c
Vegetables
3-4 servings
3-5 servings
2-3 c
Whole grains
6 servings
6 servings
6 oz grains
Lean meat
3-6 oz (cooked)
2-3 servings
5.5-6.5 oz
Low-fat dairy
2-3 servings
2-3 servings
3c
Fat/oils
2 servings
Avoid trans & saturated 5-6 tsp
3 oz whole grains
Nuts, seeds
3-4 servings/wk
Sweets
0 servings
Cut back on snacks
Include
Weight Loss
2500 kcal/d
No fad diets
1 lb/wk
Count kilocalories
150-200 kcal/d
Discretionary energy
Physical activity 2 h 30 min/wk moderate-intensity cardio Exercise regularly
ⱖ2 d/wk resistance training
Energy balance
Nutrient-dense foods
ⱖ30 min/d moderate-intensity
60 min/d prevent weight gain
60-90 min/d maintenance weight loss
a
All dietary recommendations represent servings per day based on a 1,600 kcal/d diet.
to 1,500 kcal/day) diet were compared with patients with NAFLD
following a carbohydrate-restricted (⬍20 g/day) diet. Both
groups had similar weight loss. Weight loss resulted in a reduction in hepatic fat by magnetic resonance spectroscopy; however,
patients following the low carbohydrate diet had a more dramatic
reduction in hepatic triglyceride level (55%) compared with the
control group (28%) (P⫽0.008) (29).
Simple Carbohydrates. Consumption of simple carbohydrates has
increased during the past few decades and the role of fructose and
sucrose (which is 50% fructose) in metabolic disorders has been reviewed extensively (30,31). Dietary fructose consumption in industrialized countries has increased in parallel with the increase in NAFLD, obesity, and diabetes and some studies have suggested a direct
association (32,33). The increased consumption of high fructose corn
syrup, primarily in the form of soft drinks, is linked with complications of the metabolic syndrome and an increase in liver enzymes
(34,35). Unlike glucose, fructose stimulates de novo fatty acid synthesis directly and promotes weight gain. Interestingly, unlike glucose, fructose does not stimulate insulin or leptin secretion, effectively bypassing normal satiety signals that are integral to the
regulation of food intake and body weight. Moreover, a recent study
compared 16 healthy men who received a high-energy, high-fructose diet to eight subjects following an isocaloric diet for 7 days.
Those receiving fructose had an increase in hepatic fat deposition
and decreased hepatic insulin sensitivity (36). Thus, ingestion of
sweetened beverages with fructose or sucrose may lead to changes
in long-term energy balance in the central nervous system that favor
increased energy consumption and weight gain. Furthermore, fructose consumption may be proinflammatory and activate cellular
stress pathways such as the unfolded protein response directly (37).
shown to decrease total cholesterol levels (38,39). Although there
are no studies in human beings examining the effects of GI specifically in patients with NAFLD, the effects of the GI on other
comorbidities associated with NAFLD suggest that GI may be an
important factor to consider when giving dietary recommendations to patients with NAFLD (22). A low-GI diet alone does not
improve hepatic insulin sensitivity but in conjunction with exercise it does reduce post-prandial hyperinsulinemia (40). A randomized controlled trial by Fraser and colleagues (41) found that
ALT levels decreased by 35% in patients following a low-carbohydrate/low-GI diet when compared with those following a highcarbohydrate/high-GI diet (P⬍0.05). Given the available evidence
it is reasonable to favor the incorporation of lower GI foods into a
diet for patients with NAFLD. However, the GI is a gross measurement whose direct influence on NAFLD remains unknown.
Fat
Increased fat intake has been linked to insulin resistance and impaired postprandial lipid metabolism. Western diets contain more
saturated fat, vegetable oil rich in n-6 polyunsaturated fatty acid
(PUFA), and less n-3 PUFA. Patients with NASH ingest a higher percentage of their energy from fat (37%) and this may be an independent nutritional risk factor for the development or progression of
NAFLD (odds ratio [OR]⫽2.51) (42,43). In a study by Yamamoto and
colleagues (15) the reduction of fat consumption from 27% to 19% for 6
months decreased aspartate aminotransferase and ALT from 68 IU/L
and 104 IU/L to 33 IU/L and 42 IU/L, respectively. Although few studies
on fat intake exist on which to base recommendations for NAFLD, evidence supports the benefits of a Mediterranean diet for patients with
the metabolic syndrome, through improving insulin sensitivity and reducing cardiovascular risk, both of which would be beneficial to patients with NAFLD (44-46).
GI
Low-GI foods, also called slow release carbohydrates exert a second meal effect whereby the glycemic response to the subsequent
meal is enhanced. Furthermore, such foods (eg, oats) have been
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Saturated/Trans-Fatty Acids. Saturated fatty acids (SFA) have adverse effects on lipid and glucose homeostasis, which in turn worsen
the progression of metabolic syndrome and possibly NAFLD (47).
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Two studies in patients with fatty liver further support this association, and have shown that NAFLD patients consume more SFA while
consuming less PUFA, fiber, and antioxidants (33,48). However,
whereas diets containing ⬍10% SFA are likely to be beneficial, extreme reductions in SFA may have deleterious effects on plasma lipid
levels. In a double blind randomized controlled trials of two reduced-fat diets (30% fat with 9% SFA or 25% fat with 6% SFA) compared with a control (38% fat with 14% SFA) in healthy men, both
reduced-fat diets reduced low-density lipoprotein cholesterol levels. Interestingly, high-density lipoprotein cholesterol levels also decreased and triglyceride levels increased after the 6-week intervention. This effect was most pronounced in insulin resistant or
overweight subjects in whom low-density lipoprotein cholesterol
level benefits were less pronounced and unfavorable changes in
high-density lipoprotein cholesterol and triglyceride were more
prominent (49). This suggests that although reduced SFA intake
(⬍10%) might be beneficial to patients with NAFLD, intake of ⬍6%
may have counterproductive effects on plasma lipid levels. Although
no studies in human beings have made a direct link between NAFLD
and diets high in SFA, experimental evidence in rodents demonstrates that high dietary SFA consumption worsens IR, NAFLD, and
cardiovascular disease in rats (50-52).
Monounsaturated Fat. Compared with high-carbohydrate diets,
diets high in monounsaturated fat (MUFA) may be preferable if they
are not coupled with increased energy intake or contain higher
quantities of cholesterol. An increase in MUFA intake, especially as a
replacement for SFA, may offset the proinflammatory effects of SFA
and decrease IR and hepatic steatosis. Epidemiologic studies have
shown anti-inflammatory and cardiovascular benefits of a Mediterranean-style diet rich in MUFA (46,53). There appears to be a direct beneficial role of olive oil (73% MUFA) in improving plasma lipid levels in
the treatment of the metabolic syndrome (54). An olive oil-rich diet
decreases the accumulation of triglycerides in the liver as well as improves postprandial triglyceride level and glucose response in subjects
with IR (55). Incorporating MUFA into Western dietary patterns, particularly at the expense of SFA, may reduce the risk of metabolic syndrome
and NAFLD/NASH.
PUFA. PUFAs of the n-3 and n-6 series are essential fatty acids that
must be provided by the diet. Fish oils, rich in eicosapentaenoic
and docosahexaenoic acids, are the most biologically active n-3
PUFAs and exhibit protective effects. They promote oxidation of
fatty acids via peroxisome proliferator-activated receptor-␣ activation and downregulate fatty acid synthesis (56,57). In insulin
resistant animal models, the consumption of a diet high in n-3
PUFA has favorable effects on the regulation of plasma lipid levels,
cardiovascular disease, immune function, and insulin (58). Three
recent clinical trials in human beings support these findings by
showing that n-3 PUFA administration (1.0 to 2.7 g/day for 6 to 12
months) to patients with NAFLD improved hepatic steatosis, inflammation, and fibrosis (59-61). Capanni (59) and Spadaro (60)
both demonstrated that triglyceride level decreased an average of
25 to 37 mg/dL (0.28 to 0.39 mmol/L) when supplemented with 1
g PUFA/day for 6 and 12 months, respectively. Furthermore, other
studies have shown that increased n-3 PUFA consumption improves dyslipidemia related to the metabolic syndrome and cardiovascular disease (62,63). Supplementation with n-3 PUFA decreases plasma triglyceride levels by 25% and by 50% in
individuals with normolipemia and hypertrigliceridemia, respectively (2,3). Specifically, because the dyslipidemia of NAFLD is
characterized by high triglyceride level and low high-density lipoprotein cholesterol level, n-3 PUFA supplementation is likely to
be beneficial. Alpha-linoleic acid, found in walnuts, may also be of
benefit by reducing triglyceride levels and raising high-density
lipoprotein cholesterol level (64). Low levels of circulating n-3
PUFA are associated with higher de novo lipogenesis (ie, increasing intrahepatic saturated fat content), increased hepatic uptake
of circulating free fatty acids and decreased fatty acid oxidation,
all of which can worsen hepatic steatosis (65). The available data
suggest that decreased intake of n-3 fatty acids could have an
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adverse effect on NAFLD and its associated comorbidities. Therefore, higher consumption of fish rich in n-3 PUFAs or walnuts may
reduce the risk for NAFLD or improve the dyslipidemia that characteristically accompanies it (33).
Protein
Very few clinical studies have examined the effect of protein consumption in subjects with metabolic syndrome or NAFLD. Protein
intake, expressed as the percentage of energy from protein, has generally not been reported to be altered in NAFLD, although ZelberSagi and colleagues (33) found significantly higher meat protein
consumption in NAFLD after adjustment for age, sex, body mass index, and total energy intake. Animal data suggest that soy protein
may reduce hepatic lipogenesis and improve insulin sensitivity
(48,66). In human beings, there is only one study suggesting that the
short-term consumption of soy protein as part of a low-energy diet
may provide an additional benefit for weight reduction in subjects
with obesity (67). Currently, conclusive evidence is lacking to make a
definitive statement regarding the effect of dietary protein on NAFLD. Protein is well represented in the American diet, thus deficiency
is unlikely. Excess protein intake can have untoward effects on renal
function in susceptible individuals (68,69).
Promoting Sustained Weight Loss
Maintenance of weight loss is one of the biggest challenges of dietary
interventions. Although the data are incomplete, most evidence suggests that the vast majority of people who lose weight regain it during the subsequent months or years (70,71). Several variables have
been related to weight loss maintenance such as increased moderateintensity physical activity 60 min/day, eating breakfast daily, increases
in emotional support, and less sugar-sweetened soft drink consumption (70,72). Also, improved weight loss maintenance is associated with
creating long-term goals, taking personal responsibility for weight
management, and self-monitoring (73). Obesity surgery provides the
most effective therapy for sustained weight loss (74). The effects of bariatric surgery on NAFLD are encouraging and are reviewed extensively
elsewhere (74,75). For weight maintenance, meal replacements in
combination with regular physical activity can be used to get patients
back on track if they start to regain weight (75,76). To date, it remains
largely unknown how effective weight loss maintenance interventions
are in clinical or community practice settings.
Understanding Barriers to Maintaining Weight Loss. Maintenance of weight loss can be difficult to achieve due to physical,
economic, or other barriers in patients’ lives. In patients with advanced liver disease, it is particularly important to achieve slow
and sustained weight loss because large fluctuations in weight
can exacerbate liver injury and result in liver dysfunction. Patients with NAFLD often have other medical conditions such as
diabetes, heart disease, or immobility. Furthermore, economic
limitations, work schedules, or limited access to good quality food
can make maintaining healthy eating habits difficult. It is important to keep these limitations in mind when designing a weight
loss plan for patients. Sustainable changes in lifestyle that naturally result in weight loss over time should be the goal, rather than
weight loss itself through any specific dietary intervention.
Behavior Modification. Dietary modification is most successful
when accompanied by behavioral modification. Only a behavioral
approach may give patients the practical instruments to achieve
their dietary and exercise goals, incorporate them into their lifestyle,
and maintain the results for a prolonged period. Cognitive-behavior
treatment should be provided to patients at risk of advanced liver
disease (77). Increased effectiveness is associated with increased
contact frequency and using self-regulatory behavior change techniques (eg, goal setting and self-monitoring). Moscatiello and colleagues (78) examined NAFLD subjects and compared a cognitivebehavior treatment program to a prescriptive diet group. The
cognitive-behavior treatment program consisted of 13 weekly sessions, 120 minutes each supported by the LEARN program for weight
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Table 2. The effects of nutrient supplements on nonalcoholic fatty liver disease
Supplement Study
Vitamins
Type
Sanyal and colleagues, RCTb
2010 (87)
n⫽84
Liver histology Liver enzymes
resulta
resulta
Duration Dose
96 wk
800 IU vitamin E daily vs 2*
placebo
2
Standard diet/exercise
recommendations
Foster and colleagues, RCT
2011 (91)
N⫽1,005;
nonalcoholic
fatty liver
disease
n⫽80
3.6 y
Sanyal and colleagues, Pilot study; RCT
2004 (89)
n⫽20
6 mo
1,000 IU vitamin E, 1,000 2*
mg vitamin C
Atorvastatin
Vitamin E 400 IU daily
2**
2
c
NHLBI guidelines for
diet
Kugelmas and
colleagues, 2003
(90)
Pilot study
n⫽16
6 wk
Harrison and
colleagues, 2003
(92)
RCT
n⫽45
6 mo
2**
800 IU vitamin E daily
Step 1 AHA diet ⫹
exercise
d
Vitamin E 1,000 IU ⫹
vitamin C 1,000 mg
2 fibrosis
...
Or placebo daily
Low-fat diet (30 g/d)
20 g daily or placebo
2**
NAe
6 mo
NA
NA
2
Observational
n⫽5,944
6y
NA
NA
2
Control trial
n⫽42
4 mo
NA
2
Betaine
Abdelmalek and
colleagues, 2009
(97)
RCT
n⫽35
Caffeine
Modi and colleagues,
2010 (107)
Observational
n⫽177
Ruhl and Everhart,
2005 (109)
Loguercio and
colleagues, 2005
(100)
Probiotics
12 mo
NHANES IIIf
Probiotic VSL #3g
a
2⫽Decreased/improved.
RCT⫽randomized controlled trial.
c
NHLBI⫽National Heart, Lung, and Blood Institute.
d
AHA⫽American Heart Association.
e
NA⫽not applicable.
f
NHANES III⫽Third National Health and Nutrition Examination Survey.
g
VSL Pharmaceuticals, Inc. ©2011 Sigma-Tau Pharmaceuticals, Inc.
*P⬍0.001.
**P⬍0.05.
b
control. At 2 years, cognitive-behavior treatment was associated
with increased weight loss (OR⫽2.56), normalization of liver enzymes (OR⫽3.57), and a higher probability of maintaining weight
loss. Evidence for long-term effectiveness for weight loss and dietary
interventions emphasizes the role of cognitive-behavior treatment
in the treatment of NAFLD (79).
Physical Activity. Exercise, in the absence of weight loss, improves skeletal muscle insulin sensitivity, which may improve IR
in patients with NAFLD (80,81). On average, subjects who increased moderate-vigorous physical activity to a level of 150 minMarch 2012 Volume 112 Number 3
utes/week or more have the greatest improvements in liver enzymes independent of weight loss (82,83). There are clear
benefits of exercise on NAFLD (84,85); however, a thorough discussion is beyond the scope of this review. Incorporating physical
activity has many benefits and should be part of any healthy lifestyle.
Nutrient and Antioxidant Treatments
Oxidative injury is a well-accepted cause of liver injury in NASH.
Vitamin E is the best-studied antioxidant for the treatment of
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Table 3. Proposed lifestyle modification guidelines for
persons with nonalcoholic fatty liver disease/nonalcoholic
steatohepatitis
Modification
Guideline
Weight loss
Initial goal: 5-10% body weight
lost over 1 y
Long-term goal: ideal body weight
Maintenance of weight loss
Energy intake
1,200-1,500 kcal/d
Total fat intake
⬍35% of total energy
Monounsaturated
fatty acid intake
Up to 25%
Polyunsaturated
fatty acid intake
Increase n-3 fatty acids
Saturated fatty
acid intake
⬍7% of total energy
Carbohydrate
intake
ⱖ50% whole grain; avoid highfructose corn syrup
Protein intake
Lean animal- or vegetable-based
protein
Antioxidant intake
Vitamin E 800 IU/d
Fish oil 1 g/d (eicosapentaenoic ⫹
docosahexaenoic acids)
Physical activity
ⱖ150 min/wk at moderatevigorous intensity
Cardiovascular 5 times/wk
Resistance training ⱖ2 times/wk
NAFLD. Many small studies have addressed the efficacy of various
nutrient and antioxidant therapies, many of which are discussed
below. Table 2 summarizes the largest studies of antioxidants in
patients with NAFLD. The available evidence for other antioxidants
requires further study before any conclusions can be drawn.
Vitamin E. Patients with NASH have been shown to have lower
intakes of the antioxidant vitamin E (48). Vitamin E supplementation suppresses lipid peroxidation and oxidative stress, which
improves inflammation and fibrosis in patients with NASH (86).
Several studies have shown significant improvements in hepatic
steatosis with 800 and 1,000 IU/day (87-90). In the largest randomized controlled trial to date, Sanyal and colleagues (87) evaluated the effectiveness of vitamin E in 247 patients with NASH.
After 96 weeks of treatment, vitamin E (800 IU/day) improved
liver histology compared to placebo (87). Despite not improving
insulin resistance, vitamin E met the primary endpoint of improving the NAFLD activity score. Others have looked at the combination of vitamins C and E (91). Harrison and colleagues (92) randomized 45 patients with NASH to 1,000 mg vitamin C and 1,000
IU vitamin E or placebo daily for 6 months. Fibrosis improved to a
significant degree in those treated with vitamins C and E. There
were no improvements in inflammation/necrosis scores or ALT
levels with vitamin E and C supplementation. Although the risk is
believed to be low, certain high-dosage (ⱖ400 IU/day) trials have
shown an increase in all-cause mortality and clinicians should be
mindful of this when considering supplementation with vitamin
E (93).
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Betaine. Betaine (trimethylglycine) is a precursor of S-adenosyl
methionine, a hepatoprotective factor. Therapeutic effects of betaine on NAFLD have been reported in both clinical and experimental studies (94,95). Betaine may improve in adipose tissue
function, which could have beneficial effects on the development
of NAFLD (96). However, clinical data have not shown dramatic
effects. In the only randomized placebo-controlled study of betaine (20 g daily) in 55 patients with NASH, betaine had no affect
on liver enzymes or histology when compared with placebo (97).
Therefore, although mechanistically one could foresee a benefit in
NASH, larger clinical studies may be needed to show a benefit.
Probiotics. Probiotics are live microbial food supplements or
components of bacteria and may have beneficial effects on human
health. Emerging data suggest that modifications of the gut microbiota may play a role in the development of NAFLD and progression to NASH (98). No randomized clinical trials have been
done on probiotics and NAFLD. Preliminary data from two pilot
nonrandomized studies suggested that probiotics may improve
liver chemistry tests and may decrease markers of lipid peroxidation (99,100).
Other Nutrients that May have Hepatoprotective Effects.
Ginger (Zingiber officinale) has medicinal properties that could be
beneficial to patients with NAFLD. Small, mostly animal, studies
suggest it has antioxidant properties and can improve insulin sensitivity and reduce hepatic fat content (101). Genistein, a soy isoflavone, has been shown to improve insulin sensitivity in insulin
resistant animal models and improved oxidative stress in animals
with NASH (102-104). Studies in human beings have not been
published and, thus, nutritional supplementation with genistein
cannot be recommended. Animal data and several observational
studies in human beings suggest that caffeine may have a hepatoprotective role (105-109). The mechanisms by which caffeine—
specifically coffee, as suggested by some—protect the liver are not
well understood.
CONCLUSIONS
NAFLD leads to substantial morbidity and mortality in the
United States and other developed countries. Although pharmachologic therapies are lacking, sustained and gradual
weight loss is the most effective treatment for NAFLD. Early
identification and treatment could prevent the development of
cirrhosis, cardiovascular disease, and diabetes mellitus in this
population. Lifestyle modification through diet and exercise
must be the cornerstone of any treatment plan for patients
with NAFLD (see Table 3). Long-term, moderate weight loss
through the reduction of energy intake and regular physical
exercise is recommended for patients with NAFLD. The influence of the macronutrient composition of the diet is important
and can help reduce hepatic fat and inflammation.
The role of weight loss in the treatment of fatty liver is well
established. Based on data from cardiovascular or diabetes trials and limited studies in patients with NAFLD, a diet that is
lower in carbohydrates and saturated fat and higher in lean
protein, fiber, and n-3 PUFA is likely to be beneficial. Vitamin E
supplementation reduces liver enzymes and improves liver
histology in patients with NASH but without diabetes; however, sufficient evidence for other antioxidants or nutritional
supplements is lacking. Therefore, well-designed dietary intervention trials are needed to create definitive evidence-based
dietary guidelines for patients with NAFLD.
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AUTHOR INFORMATION
E. M. McCarthy is a registered dietitian, Northwestern Faculty Foundation, Chicago, IL. M. E. Rinella is an associate professor of medicine,
Department of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital,
Chicago, IL.
Address correspondence to: Mary E. Rinella, MD, Department of Gastroenterology and Hepatology, Northwestern University Feinberg School
of Medicine, Northwestern Memorial Hospital, 303 E Chicago Ave, Searle 10-563, Chicago, IL 60611. E-mail: [email protected]
STATEMENT OF POTENTIAL CONFLICT OF INTEREST:
No potential conflict of interest was reported by the authors.
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