Nash Nutrition

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https://doi.org/10.3350/cmh.2020.0067
Review Clinical and Molecular Hepatology 2020;26:383-400
Evidence-based clinical advice for nutrition and dietary

weight loss strategies for the management of NAFLD
and NASH
Theresa J. Hydes1, Sujan Ravi1, Rohit Loomba2, and Meagan E. Gray1
1
Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL; 2Division of Gastroenterology,
University of California, San Diego, La Jolla, CA, USA
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and affects
approximately one third of adults in the United States. The disease is becoming a global epidemic as a result of the rising
rates of obesity and metabolic disease. Emerging data suggest weight loss of ≥10% overall body weight is beneficial in
resolving steatosis and reversing fibrosis. Prospective trials comparing various diets are limited by lack of sufficient power
as well as pre- and post-treatment histopathology, and therefore no specific diet is recommended at this time. In this
narrative review we examine the pathophysiology behind specific macronutrient components that can either promote
or reverse NAFLD to help inform more specific dietary recommendations. Overall, the data supports reducing saturated
fat, refined carbohydrates, and red and processed meats in the diet, and increasing the consumption of plant-based
foods. Diets that incorporate these recommendations include plant-based diets such as the Dietary Approaches to Stop
Hypertension, Mediterranean, vegetarian, and vegan diets. (Clin Mol Hepatol 2020;26:383-400)
Keywords: Diet, Vegetarian; Diet, Healthy; Nonalcoholic fatty liver disease; Diet
INTRODUCTION trum of disorders ranging from simple steatosis to steatohepatitis.

NAFLD is the most common cause of chronic liver disease world-
Nonalcoholic fatty liver disease (NAFLD) encompasses a spec- wide, affecting approximately 25% of the adult population in the
Abbreviations: Corresponding author : Meagan E. Gray

ALT, alanine aminotransferase; BCAA, branched chain amino acids; BMI, Division of Gastroenterology and Hepatology, University of Alabama at
body mass index; CHO, carbohydrates; DASH, Dietary Approaches to Stop Birmingham, BDB 395A, 1720 2nd Ave. S., Birmingham, AL 35294-0012,
Hypertension; DNL, de novo lipogenesis; EASL, European Association for the USA
Study of the Liver; FFAs, free fatty acids; FGF21, fibroblast growth factor 21; FLI, Tel: +1-205-975-9698, Fax: +1-205-975-9777
fatty liver index; HCC, hepatocellular carcinoma; HOMA-IR, Homeostatic Model
E-mail: [email protected]
Assessment of Insulin Resistance; IF, intermittent fasting; IHLC, intrahepatic lipid
content; LDL, low-density lipoprotein; mTOR, mammalian target of rapamycin; https://orcid.org/0000-0001-7556-8985
MUFA, monounsaturated fatty acids; NAFLD, nonalcoholic fatty liver disease;
NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; NutriRECS,
Nutritional Recommendations; PPAR, peroxisome proliferator-activated
receptor; PUFAs, polyunsaturated fatty acids; RCT, randomized controlled trial;
SFAs, saturated fatty acids; SREBP-1c, sterol regulatory element-binding protein-
1c; SSBs, sugar-sweetened beverages; T2DM, type 2 diabetes mellitus; TMA,
trimethylamine; TMAO, trimethylamine N-oxide; US, United States; VAT, visceral
adipose tissue; VLDL, very low-density lipoprotein
Editor: Won Kim, Seoul National University College of Medicine, Korea Received : Arp. 6, 2020 / Revised : May 8, 2020 / Accepted : May 19, 2020
Copyright © 2020 by Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Volume_26 Number_4 October 2020
United States (US) and globally.1 Approximately 25% of patients (EASL) recommend exclusion of NAFLD-promoting components
with NAFLD have nonalcoholic steatohepatitis (NASH), which is (processed food, high fructose foods and beverages) in addition
associated with a 20% risk of progression to cirrhosis.2 It is esti- to a macronutrient composition in line with a Mediterranean diet,
mated that NAFLD affects 40–70% of patients with type 2 diabe- this recommendation is only supported by evidence graded as
tes mellitus (T2DM),2-4 67% of adults with a body mass index “moderate” in quality.14 Here we review the pathophysiology be-
(BMI) between 25 and 30 kg/m2, and up to 91% of adults with a hind how the quality of proteins, carbohydrates (CHOs), and fats
BMI >30 kg/m.5-9 can promote or reverse NAFLD, the available data on specific di-
The diagnosis of NAFLD requires >5% hepatic steatosis with ets, and discuss ongoing knowledge gaps for future research.
lack of secondary cause for hepatic fat accumulation. Steatosis re-
sults from a surplus of free fatty acids (FFAs) either from excessive
lipolysis (60%), de novo lipogenesis (DNL, 25%), dietary FFA ENERGY AND CALORIC RESTRICTION
(15%), diminished export by very low-density lipoprotein (VLDL),
or impaired beta-oxidation (Fig. 1).10 Excess FFAs are stored as Observational studies
triglycerides in the hepatocytes. In NAFLD, peripheral lipolysis is
resistant to suppression by insulin, further increasing serum FFA The diabetes, obesity and NAFLD epidemics are products of a
levels.11 Lipotoxicity, along with oxidative stress and a pro-inflam- significant rise in net population energy intake, resulting from en-
matory environment, lead to NASH.12 ergy-dense foods and a sedentary lifestyle. A high-calorie diet is
Due to lack of approved pharmacologic therapy, current treat- fundamentally linked to obesity and is the initial trigger point for
ment recommendations for NASH are for weight loss of ≥10% to- NAFLD through adipose tissue expansion, increased inflammation
tal body weight, which is associated with resolution of steatohep- and mitochondrial dysfunction. It is often imbalanced with high
atitis and fibrosis regression.13-15 Prospective trials comparing quantities of saturated fatty acids (SFAs), refined CHOs, sugar-
various diets are limited by lack of sufficient power as well as pre- sweetened beverages (SSBs) and alcohol excess. Understanding
and post-treatment histopathology.13 As a result, the American the individual impact of these factors is therefore a challenge for
Association for the Study of Liver Disease has not made any spe- clinical trial design, and limits our understanding of the role of
cific dietary recommendation for NAFLD at this time. While guide- specific macronutrients outside the context of excess energy intake.
lines from the European Association for the Study of the Liver In terms of observational studies, a cohort study of 55 patients
Lipolysis (60%) De nove Dietary FFAs

Lipotoxicity
TG → FFAs + glycerol lipogenesis (25%) (15%)
Oxidative stress
SREBP-1c Inflammatory cytokines
Insulin resistant ChREBP
adipose tissue
Excess Steatosis NASH
FFAx Insulin resistance
NAFLD:
↑ import from adipose tissue
↓ export by VLDL Beta-oxidation
Stored at
Impaired beta-oxidation of FFAs
triglycerides
Export as VLDL-
cholesterol
Figure 1. The pathogenesis of NAFLD. TG, triglycerides; FFAs, free fatty acids; SREBP-1c, sterol regulatory element-binding protein-1c; ChREBP, carbohy-
drate response element-binding protein; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; VLDL, very low density lipopro-
tein.
384 https://doi.org/10.3350/cmh.2020.0067 http://www.e-cmh.org

Theresa J. Hydes, et al.
Evidence-based nutritional advice for NAFLD
with NAFLD and 88 healthy controls observed that NAFLD pa- striction. A meta-analysis of therapeutic options for NAFLD,
tients consumed more calories overall (2,739 vs. 2,173 kcal), how- including lifestyle interventions, reported that weight loss of ≥7%
ever the macronutrient composition (fat, CHO, fructose) was (achieved by <50% of patients even with intensive multi-disciplin-
largely comparable between groups.16 Given this, energy restric- ary support) led to improved histological disease activity deter-
tion, and thereby weight loss, plays a crucial role in the treatment mined by NAS, although there was no impact on fibrosis.25
of these patients. The largest prospective trial to date in this field While guidelines currently recommend continuous energy re-
followed 293 patients with biopsy-proven NASH for 52 weeks. striction along with physical activity,26 there is increasing popular
Patients were advised to follow a low fat, hypocaloric diet which interest in intermittent fasting (IF), i.e., a low calorie period lasting
contained 750 kcal/day less than their daily energy needs, in addi- less that 24 hours followed by a normal period of feeding. Evi-
tion to walking 200 minutes per week.15 Overall 19% had fibrosis dence suggests that intermittent energy restriction results in
regression, 47% had reduction in NAFLD activity score (NAS) on equivalent weight loss compared to continuous energy restriction
histology and 25% achieved complete resolution of steatohepati- in the short-term, with a lack of long-term data.27 Several RCTs
tis. The highest rates of fibrosis regression, NAS reduction and have looked at the effectiveness of IF in the setting of NAFLD. An
NASH resolution occurred in patients achieving ≥10% weight 8 weeks modified alternate-day calorie restriction was found to
loss, however benefits were also seen for weight loss of ≥5%. Us- lead to reductions in BMI, liver enzymes, liver steatosis and liver
ing nutritional counselling, a small study of 15 patients with biop- stiffness (based on shear wave elastography) compared to no in-
sy-proven NASH and a BMI >25 found histologic improvement to tervention with adherence rates of 75–83%.28 A larger trial com-
be associated with greater weight reduction.17 After 1 year of cal- paring alternate-day and time-restricted feeding with a control
orie restriction (mean reduction of 195 kcal/day), nine patients group for 12 weeks revealed that both diets led to significant
had histologic improvement and six had stable NAS. Histological short-term reductions in weight and improvements in dyslipidae-
improvement was associated with greater changes in weight re- mia, although no changes were seen for fasting levels of insulin or
duction. liver stiffness.29
Pathophysiology Clinical advice
A high-caloric diet leads to adipose tissue expansion, one of the Calorie restriction with a 500–1,000 kcal daily deficit is an ex-
sentinel events in the pathogenesis of NAFLD. Visceral adipose tremely effective lifestyle intervention for both the prevention of
tissue (VAT) is particularly biological active. Excess accumulation NAFLD and histological improvement in patients with established
of VAT increases the production of FFAs through reduced insulin disease. The goal of calorie reduction should be to achieve ≥10%
sensitivity, leading to increased fatty acid influx into the liver, DNL overall body weight loss.
and insulin resistance. Hypertrophy and hyperplasia of adipocytes
results in hypoxemia and adipocyte dysfunction.18 This exacer-
bates insulin resistance and dyslipidemia, and creates a pro-in- PROTEIN
flammatory environment within the adipose tissue. The secretion
of adipokines (adiponectin, resistin, leptin, visfatin) and pro-in- Observational studies
flammatory cytokines (interleukins and tissue necrosis factor α)
from VAT induce a state of systemic low-grade chronic inflamma- The consumption of animal protein, specifically red and pro-
tion which can promote the onset of NAFLD and NASH.18-20 cessed meat, is associated with higher all-cause, cardiovascular
and cancer-related mortality compared to plant protein.30-41 In a
Randomized controlled trial data large US cohort, red and processed meats were associated with
nine causes of death, with the strongest correlation being for
The findings from key randomized controlled trials (RCT) in this mortality from chronic liver disease.34 High animal protein intake
field involving lifestyle intervention for NAFLD and NASH are sum- is also associated with NAFLD in overweight Caucasians indepen-
marized in Table 1.21-24 Weight loss is consistently identified as be- dent of sociodemographic, lifestyle and metabolic traits.42 Animal
ing central to the metabolic benefits that result from calorie re- protein is positively associated with high fatty liver index (FLI)
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Table 1. Summary of randomized controlled trial data examining the influence of hypocaloric diets on hepatic steatosis
Study Participant Intervention Result
23
Ueno et al. (1997) Obese adults Randomized to receive the following The low calorie diet was associated with reductions
(BMI >25 kg/m2; n=25) for 3 months: 1) hypocaloric diet in weight, aminotransferases, albumin,
(ideal weight ×25 kcal/kg; 50% cholesterol and fasting glucose, in addition to
carbohydrate, 30% fat) combined histologically determined levels of steatosis.
with physical activity; 2) no Improvements seen for other histological
intervention parameters did not reach statistical significance.
Kirk et al.24 (2009) Obese adults (mean Randomized to receive the following IHTG content and insulin-mediated glucose uptake
BMI, 36.5±0.8 kg/m2; for 11 weeks: 1) high carbohydrate were similar in both dietary groups after 7%
n=22) 1,000 kcal daily energy deficit diet; weight loss, i.e., calorie restriction and weight loss
2) low carbohydrate 1,000 kcal daily more important than macronutrient composition
energy deficit diet for these parameters.
Harrison et Obese adults Randomized to receive the following Weight loss (6.0% vs. 8.3%, P=NS), reductions
al.155 (2009) (BMI ≥27 kg/m2) with for 36 weeks: 1) 1,400 kcal/day + in aminotransferases, hepatic steatosis,
biopsy-proven NASH vitamin E 800 IU daily; 2) 1,400 necroinflammation, ballooning, and NAS were
(n=50) kcal/day + vitamin E 800 IU daily + similar between groups. Overall cohort stratified
Orlistat 120 mg three times daily according to weight loss: loss ≥5% body weight
vs. <5% led to improved insulin sensitivity
(P=0.001) and steatosis (P=0.015); loss ≥ 9% body
weight vs. <9% also led to improved ballooning
(P=0.04), inflammation (P=0.045) and NAS
(P=0.009).
Lazo et al.21 (2010) Overweight adults Ancillary study linked to the “Look Lifestyle intervention group vs. controls: lost on
(BMI ≥25 kg/m2) AHEAD” RCT. Participants had 12 average 8.3% of their body weight vs. 0.03%
with T2DM who months of either: 1) intensive lifestyle (P<0.001), had significant improvements in HbA1c
underwent proton intervention: moderate calorie (-0.7% vs. -0.2%, P=0.04) and a greater decrease
magnetic resonance restriction (1,200–1,500 kcal/day in hepatic steatosis (-50.8% vs. -22.8%, P=0.04).
spectroscopy of the for individuals weighing <114 kg, Individuals who lost ≥10% of their body weight
liver (n=96) 1,500–1,800 kcal/day for those >114 achieved a 79.5% reduction in steatosis vs. 13.7%
kg; <30% calories from fat and <10% for those with little weight change (±1%).
from SFAs) and increased physical NAFLD incidence was significantly lower in the
activity; 2) general education lifestyle intervention group compared to controls.
Promrat et al.22 (2010) Obese adults (BMI Randomized 2:1 to receive the Lifestyle intervention group vs controls: lost on
25–40 kg/m2) with following for 48 weeks: 1) intensive average 9.3% of their body weight vs. 0.2%
biopsy-proven NASH lifestyle intervention: moderate (P=0.003), had significant improvements in their
(n=31) hypocaloric diet (1,000–1,200 NAS (72% vs. 30%, P=0.03).
kcal/day if baseline weight <200 % weight reduction correlated significantly with
lb or 1,200–1,500/day if >200 lb), improvement in NAS (r=0.497, P=0.007).
with restrictions on fat intake, in Individuals achieving ≥7% weight loss experienced
combination with physical activity; significant improvements in steatosis, lobular
2) general education inflammation, ballooning and NAS vs individuals
who lost <7%.
Lin et al.156 (2009) Obese (BMI >30 kg/m2) Randomized to receive the following The percentage change in body weight for the
Taiwanese adults for 12 weeks: 1) very low calorie diet groups was -9.1% (VLCD-450) and -9.0% (VLCD-
(n=132) 450 kcal/day (VLCD-450); 2) very low 800) (P=NS). The improvement rate of NAFLD
calorie diet 800 kcal/day (VLCD-800) as determined by ultrasound was 41.5% in the
Both groups had 2 weeks run in of VLCD-450 group and 50.0% in the VLCD-800
1,200 kcal/day group. No serious adverse events were reported
in either group.
BMI, body mass index; IHTG, intrahepatic triglyceride; NASH, nonalcoholic steatohepatitis; NS, not significant; NAS, NASH histological activity score; T2DM,
type 2 diabetes mellitus; AHEAD, Action for Health in Diabetes; RCT, randomized controlled trial; SFAs, saturated fatty acids; HbA1c, haemoglobin A1C; NAFLD,
nonalcoholic fatty liver disease; VLCD, very low calorie diet.

scores, whereas plant protein is inversely related.43 In a cross-sec- and methionine and choline-deficient diets, can also induce
tional study, patients with NAFLD ate 27% more animal protein NAFLD in the animal model as a result of their ability to promote
compared to controls (P <0.001), with 46% of those in the highest lipid dysregulation and oxidative stress.56,57 Red and processed
quartile of consumption having NAFLD, compared with only 17% meats also contain high levels of phosphatidylcholine and L-carni-
in the lowest quartile (P =0.001).44 A follow-up study showed a tine, which are metabolized to trimethylamine (TMA) by gut mi-
significant association between total (P =0.028), red and/or pro- crobiota (Fig. 2). TMA is oxidized in the liver by hepatic flavin-
cessed meat (P =0.031) consumption with NAFLD and insulin re- containing monooxygenases to form trimethylamine oxide
sistance even after adjustment for BMI, physical activity, alcohol, (TMAO), which is then released into the circulation. TMAO pro-
energy, SFA and cholesterol intake.45 motes atherosclerosis via the up-regulation of multiple macro-
phage scavenger receptors,58,59 and high TMAO levels correlate
Pathophysiology with increased incidence of major cardiovascular events.60 It is hy-
pothesized TMAO may promote NAFLD by altering the synthesis
Red and processed meats likely lead to NAFLD, insulin resis- and transport of bile acids, decreasing the overall bile acid pool
tance and T2DM as a result of their high content of SFAs, choles- and reversing the direction of cholesterol transport and glucose
terol, heme-iron, nitrates and nitrites, preservatives, advanced- and energy homeostasis.61 Indeed, plasma TMAO levels correlate
glycation end-products and branched chain amino acids with the presence and severity of biopsy proven NAFLD in a large
(BCAAs).46 BCAAs, found in higher concentrations in animal pro- Chinese adult population.61 Individuals eating a vegan diet have
tein, lead to impaired insulin sensitivity by recruiting mammalian an altered intestinal microbiota composition compared to omni-
target of rapamycin (mTOR) and assembling mTOR complex 1 in vores, with reduced capacity to produce TMAO.62
combination with insulin (Fig. 2).47 mTOR complex 1 induces sterol
regulatory element-binding protein-1c (SREBP-1c) leading to Randomized controlled trial data
DNL.48,49 Diets low in methionine (found predominantly in meat,
fish and dairy products), can prevent the development of insulin It is therefore hypothesized that a vegetarian diet would be su-
resistance in animal models via activation of fibroblast growth perior to an omnivorous diet in reversing NAFLD and metabolic
factor 21 (FGF21), which inhibits SREBP-1, suppressing DNL while parameters.63 This was not borne out, however, in a small ran-
activating hepatic FFA oxidation;50-55 although it should be noted domized prospective study comparing the influence of a 6-week
that in addition to methionine-rich diets, methionine-deficient isocaloric high-protein diet using either plant or animal protein on
Animal protein (red and processed meats)
Saturated fat Cholesterol

Phosphatidylcholine, L-carnitine
Branched chain amino acids Nitrates & intrites
Heme-iron Preservatives Gut microbiota
Advanced glycation end-products TMA
Liver: hepatic flavin-
containing monooxygenases
Insulin
mTOR → mTOR complex 1 (+ insulin) resistance TMAO
FGF21 activation
SREBP-1
(diet low in methionine, i.e., low meat, fish, dairy)
Activate hepatic FFA oxidation

? Altered synthesis & transport of bile acids
Hepatic steatosis (reverse direction of cholesterol transport &
De novo hepatic lipogenesis
glucose homeostasis)
Figure 2. Potential mechanisms linking the consumption of animal protein with the development of NAFLD. TMA, trimethylamine; mTOR, mammalian
target of rapamycin; TMAO, trimethylamine oxide; SREBP-1, sterol regulatory element-binding transcription factor 1c; FGF21, fibroblast growth factor 21;
FFA, free fatty acid; NAFLD, nonalcoholic fatty liver disease.

liver fat and lipogenic indices in patients with T2DM and NAFLD. also been shown to be significantly higher in obese children with
While the high animal protein diet led to large postprandial in- NAFLD compared to those without.69 CHO intake has also been
creases in BCAA and methionine compared to the plant protein shown to increase in parallel to the degree of liver fat detected by
group, both groups experienced significant improvements in ultrasonography.69
FGF21, reductions in liver fat and down-regulation of lipolysis.64 No studies thus far directly compares the impact of refined ver-
The results may have been similar due to small sample size and sus unrefined CHOs on NAFLD, however there are several studies
significant weight loss in both groups. Furthermore, the type of evaluating refined CHOs alone. In two small studies, consumption
animal protein consumed (red, processed, lean) was not de- of dietary fructose has been shown to be significantly higher
scribed. among NAFLD patients compared to controls.70,71 SSBs, a surro-
gate for free sugars, have been associated with NAFLD in an Is-
Clinical advice raeli population based study independent of age, gender, BMI
and total caloric intake.44,72 In the Framingham Heart Study co-
While large, prospective, RCTs are lacking to determine the im- hort, higher consumption of SSBs incrementally increased the
pact of animal protein on the progression of NAFLD, it is reason- odds ratio for NAFLD across quartiles of consumption, even after
able to advise patients with NAFLD to reduce their intake of red adjustment for BMI, energy intake, dietary fiber, fat, protein and
and processed meats in light of their increased cardiovascular risk. diet soda.72 SSB consumption was also positively associated with
ALT levels in this group. After controlling for dietary composition
and physical activity, SSB consumption has been shown to be an
CHOS independent variable to predict NAFLD with sensitivity of 100%,
specificity 76%, positive predictive value 57% and negative pre-
Observational studies dictive of 100%.73
The data on histologic impact of CHO consumption is limited.
Studies examining the association between CHOs and NAFLD When comparing nutrient intake of 28 patients with biopsy-prov-
are heterogeneous due to lack of differentiation between refined en NASH to 18 with simple steatosis, those with NASH had higher
and unrefined CHOs. Low-diets have been associated with higher intake of CHOs, specifically simple CHOs.74 In a bariatric surgery
all-cause and cardiovascular mortality despite their benefits on cohort, higher CHO intake was significantly associated with in-
initial weight loss, presumably due to reduced intake of unrefined flammation, but not fibrosis, on liver biopsy.7 In older adults with
CHOs (which are high in fiber, antioxidants, minerals, and vita- NAFLD, higher daily fructose consumption has been associated
mins), and increased consumption of animal protein, cholesterol with fibrosis, hepatic inflammation and hepatocyte ballooning.75
and SFAs.65 In a small study evaluating intestinal permeability, pa-
tients with NAFLD were found to have significantly higher intake Pathophysiology
of protein and CHOs, specifically mono- and disaccharides, com-
pared to controls.66 Protein and CHO intake correlated to higher CHOs induce DNL by activating the CHO responsive transcrip-
alanine aminotransferase (ALT) levels in this group. High CHO in- tion factor, CHO response element binding protein (Fig. 1).76 Fruc-
take (>70% of overall energy intake) has also been associated tose is metabolized predominantly in the liver where it is convert-
with higher aminotransferases and presence of the metabolic syn- ed into glyceraldehyde-3-phosphate, which can be used for
drome in a large Korean cohort, which persisted after adjustment gluconeogenesis or acetyl-CoA production.77 The latter can be ox-
for overall energy intake and BMI.67 The opposite was found in a idized, or used for lipogenesis. Diets high in fructose contribute to
Portugal cohort comparing the diets of 45 patients with NASH to NAFLD by increasing DNL and reducing fatty acid oxidation.78-81
856 controls, where lower CHO consumption was seen in patients Fructose can also activate fatty acid synthase and stearoyl-CoA-
with NASH, although this was accompanied by other differences desaturase-1,82 sensitizing the liver towards inflammation, which
in dietary composition.68 A European cohort of 55 NAFLD patients may promote the development of NASH.83 Although data are
and 88 controls found no significant differences in the relative in- lacking, unrefined CHOs are likely to be protective against NAFLD
take of CHOs or fructose, although patients with NAFLD con- as a result of their low glycemic index, high fiber content, and role
sumed more calories overall.16 In children, total CHO intake has in increasing production of short-chain fatty acids in the gut.84

Randomized controlled trial data weight changes.93 After overfeeding overweight adults with 1,000
kcal/day of candy or SSBs for 3 weeks, body weight increased by
Several RCTs have been performed to evaluate the effects of a 2% accompanied by 27% increase in IHLC.94 IHLC returned to
low CHO diet (<50% of daily calories) on NAFLD. In attempt to baseline once baseline weight was achieved over the following
consolidate the data, a meta-analysis of 10 RCTs was performed, 6 months. Whole, unrefined CHOs are protective against cardio-
however significant heterogeneity was encountered.85 The overall vascular disease, T2DM, colorectal and breast cancer,95 and are
conclusion was that a low CHO diet could reduce intrahepatic lip- associated with decreased all-cause mortality,96 however data in
id content (IHLC) by over 10%, however significant weight loss NAFLD is lacking.
across all intervention groups limited the ability to isolate the ef-
fects of a low CHO diet alone. Two of the trials evaluated a keto- Clinical advice
genic diet (8% CHO in one, <20 g CHO per day in the other) over
2 and 24 weeks, respectively.86,87 Despite weight loss in both, Clinicians should advise reduction in refined CHOs, specifically
there was no significant reduction in ALT, however the 2 weeks fructose, in patients with NAFLD.
study did show reduction in liver fat content. When low (<60 g/day)
and high CHO (>180 g/day) diets were compared over an 11
weeks calorie restriction intervention, reduction in IHLC was com- FIBER
parable between both groups after 7% weight loss.24 Further-
more, a direct comparison of hypocaloric diets (30% energy re- Observational studies
stricted) either low in CHO (and high in fat), or low in fat in 170
overweight individuals for 6 months, revealed comparable de- High fiber consumption is associated with a 15–30% decrease
creases in body weight, visceral fat and IHLC.88 A meta-analysis of in all-cause and cardiovascular-related mortality, lower risk of
13 trials with a total of 260 participants reported an association heart disease, stroke, T2DM and gastro-intestinal cancer.95 Epide-
between a high fructose diet and NAFLD incidence and severity.89 miological studies suggest there may be an association between
Only seven of these trials were isocaloric however, and in these a low fiber diet and the development of NAFLD. In a study of
studies fructose had no significant effect on IHLC or ALT.89 Unfor- 45 patients with NASH and over 800 controls, more than one-
tunately the majority of studies were small, of short duration and third of patients with NASH consumed lower than the recom-
marred by confounding factors. Similarly a subsequent meta-anal- mended requirements of fiber, although this did not reach statisti-
ysis of 21 interventional studies found only low levels of evidence cal significance compared to the controls unless the consumption
that a high fructose diet was associated with increased liver fat of soluble fiber was considered in isolation (in this case nearly
content and transaminases as studies were significantly con- 90% of patients consumed less than 10 g/day).68 Similarly, in an
founded by excess energy intake.90 observational study of 55 NAFLD patients and 88 controls, NAFLD
In adolescent boys, those on a limited free sugar diet (<5% dai- patients were found to consume less fiber.16 These findings were
ly calories) for 8 weeks experienced a significant decrease in he- supported by a case-control study from Iran (NAFLD, n=159; con-
patic steatosis and aminotransferases compared to those with no trols, n=158),97 however both studies are limited by differing mac-
dietary intervention, though weight loss was greater in the inter- ronutrient composition compared to controls. Fiber consumption
vention cohort.91 Focusing specifically on fructose reduction (by has also been shown to be significantly lower in obese children
50%), a small pilot study showed reduction in IHLC and amino- with moderate and severe hepatic steatosis, compared to obese
transferases over 6 months.92 Results are difficult to interpret giv- children without NAFLD.69 In a small uncontrolled pilot study, liver
en lack of control group as well as significant reduction in weight, enzymes normalized in 75% of NAFLD patients eating 10 g/day of
SFA and sucrose intake. Over-feeding studies further highlight the soluble fiber for 3 months.98 This study is limited not only by lack
association between SSB and NAFLD. When randomized to 1 L of a control group, but also reduction in BMI, waist circumference,
daily of sugar sweetened soda, skim milk, diet soda, or water for insulin resistance index and cholesterol levels in two thirds of patients.
6 months, those consuming the sugar sweetened soda had signif-
icant increases in IHLC, visceral fat, and skeletal muscle fat, com-
pared to no changes in the other groups, despite no significant

Pathophysiology trial, seven patients with NASH received 16 g/day of oligofructose

(a prebiotic fiber), or placebo for 8 weeks. Oligofructose led to a
The majority of studies looking at the benefits of fiber on car- significant reduction in insulin levels, as well as ALT and aspartate
diovascular risk factors have focused on soluble fiber. Soluble fi- aminotransferase after 4 and 8 weeks, respectively, independent
ber is thought to be protective against NAFLD by reducing serum of a significant effect on plasma lipids.103
low-density lipoprotein (LDL)-cholesterol levels.99 The mechanism
for this is unclear, although it has been proposed that soluble fi- Clinical advice
ber may bind to bile acids or cholesterol during the formation of
micelles, lowering the cholesterol concentration in hepatocytes, Increasing fiber intake by increasing intake of fruits, vegetables,
leading to up-regulation of LDL receptors and clearance of LDL- whole grains and legumes, should be encouraged in patients with
cholesterol.100 Soluble fiber can also slow the rate at which CHOs NAFLD.
are absorbed into the circulation reducing post-prandial hypergly-
cemia, i.e., high fiber foods have a low glycemic index leading to
improved glucose tolerance.101 FATS
Randomized controlled trial data Observational studies
RCTs studying the effect of fiber intake in isolation on NAFLD There is a strong degree of concordance between observational
are lacking, as this usually forms part of a wider dietary interven- studies to show that a higher intake of SFAs,68,69,74,97,104 and a low-
tion. In one study, 70 obese individuals with features of the meta- er intake of polyunsaturated fatty acids (PUFAs),69,74,104 is associat-
bolic syndrome were randomized to two energy-restricted diets ed with NAFLD and NASH. In a cohort of 25 patients with NASH
for 6 months.102 Participants who consumed higher levels of fiber and 25 BMI matched controls, 7-day alimentary records revealed
from fruit experienced improvements in their FLI, hepatic steatosis that patients with NASH consumed significantly higher propor-
index, NAFLD liver fat score and liver enzymes, supporting the tions of SFAs and a lower percentage of PUFAs, although differ-
consumption of fiber in the context of energy restriction for pa- ences were also seen between their intake of cholesterol, fiber
tients with NAFLD. In a small, randomized double-blind crossover and anti-oxidant vitamins.104 The ratio of PUFAs to SFAs was also
Saturated fatty acids

Adipose
tissue PPARγ coactivator-1β Hepatocyte
SREBP-1c apoptosis
Unsaturated Unsaturated
↑ Lipolysis De novo lipogenesis
fatty acids fatty acids
Inflammatory cells
Oxidative stress
Excess FFAs
Triglycerides
VLDL-cholesterol Beta-oxidation
Regulated by PPARα
& SREBP-1c
Steatosis
Steatohepatitis
Insulin resistance
Figure 3. Mechanisms via which saturated and unsaturated fatty acids influence the pathogenesis of NAFLD. PPAR, peroxisome proliferator-activated
receptor; FFAs, free fatty acids; VLDL, very low density lipoprotein; SREBP-1c, sterol regulatory element-binding protein-1c; NAFLD, nonalcoholic fatty
liver disease.

lower in patients with NASH and NAFLD compared to the general sis by increasing lipolysis as well as DNL, which occurs through
population in a Japanese cohort.74 These findings were replicated the promotion of the transcription of peroxisome proliferator-acti-
in pediatric cohort in which SFA intake correlated proportionally vated receptor (PPAR) γ coactivator-1β and SREBP-1c (Fig. 3).105
to the degree of hepatic steatosis.69 Furthermore, omega-3 fatty SFAs also promote lipotoxicity through ceramides and diacylglyc-
acid consumption was lower in pediatric NAFLD patients and this, erides,106 and can induce hepatocyte apoptosis and increase oxi-
along with insulin resistance, remained the most significant factor dative stress, which may encourage progression towards NASH.107
following multiple regression analysis. Cortez-Pinto et al.68 also Conversely, monounsaturated fatty acids (MUFAs) activate tran-
reported higher total fat consumption in NASH patients compared scription factors PPARγ and PPARα, promoting safe fatty acid
to controls, including higher consumption of omega-6 fatty acids, storage in adipose tissue and lipid detoxification via fatty acid oxi-
which differs from other studies. This study may have been con- dation, respectively.108 PUFAs increase the transcription of PPARα,
founded by differences in CHO and fiber consumption between increasing lipid metabolism and mitochondrial oxidation, thereby
groups. reducing hepatic FFA concentrations.109,110 They also inhibit SREBP-
1c, reducing fatty acid synthesis.111,112 Omega-3 fatty acids lower
Pathophysiology the hepatic triglyceride content by suppressing hepatic VLDL apo-
lipoprotein B-100,113 and inhibit inflammatory cells involved in
SFAs exert their effects on the liver through the promotion of NASH.114
insulin resistance and oxidative stress. They induce hepatic steato-
Table 2. Summary of randomized controlled trial data examining the influence of diets high in saturated fatty acids and poly- and mono-unsaturated
fatty acids on hepatic steatosis
Study Participant Intervention Result
119
Bozzetto et al. (2012) Adults with T2DM (n=45) 8 weeks diet, either: 1) high- An isocaloric diet high in MUFA led to a
carbohydrate/high-fiber/low-glycemic reduction in liver fat, independent of weight
index diet; 2) high-MUFA diet; 3) high- loss and exercise compared to patients
carbohydrate/high-fiber/low-glycemic consuming a high-carbohydrate, high-fiber,
index diet plus physical activity; and low-glycaemic index diet
4) high-MUFA diet plus physical activity
Bjermo et al.117 (2012) Obese adults (sagittal 10 weeks isocaloric diet high in omega A modest increase in weight was seen,
abdominal diameter 6 PUFAs or SFAs (butter); no other however this did not differ between groups.
>25 cm, or waist changes to macronutrients The SFA group had significant increases
circumference >88 cm in liver fat (assessed using MRI), serum
[women] or >102 cm triglycerides, total and LDL cholesterol and
[men]; n=67) insulin resistance compared to the group
receiving PUFAs, in which all these markers
improved.
Rosqvist et al.116 (2014) Young, normal weight 750 extra kcal/day for 7 weeks from The SFA group had greater increases in liver
adults (n=39) muffins high in SFAs vs. muffins high in fat (P=0.033) and a 2-fold increase in VAT
PUFAs (P=0.035). The PUFA group had a 3-fold
increase in lean tissue (P=0.015).
Errazuriz et al.118 (2017) Adults with pre-diabetes 12 week isocaloric weight-maintaining Only the MUFA group demonstrated a
(n=43) diets: 1) high MUFAs (olive oil), 2) fiber- significant decrease in liver fat fraction as
rich, and 3) standard US food determined by MRI (P<0.0003), in addition
to improvements in hepatic and total insulin
sensitivity.
Luukkonen et al.115 Overweight adults (mean 1,000 extra kcal/day for 3 weeks from Overeating 1,000 kcal/day of SFAs increased
(2018) BMI, 31±1 kg/m2; n=38) either SFAs/unsaturated fat/simple IHTG more than unsaturated fats (55% vs.
sugars 15%, P<0.05).
T2DM, type 2 diabetes mellitus; MUFA, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; SFAs, saturated fatty acids; MRI, magnetic resonance
imaging; LDL, low-density lipoprotein; VAT, visceral adipose tissue; US, United States; BMI, body mass index; IHTG, intrahepatic triglyceride.

Randomized controlled trial data low-glycemic, low energy-dense diet characterized by high intake
of fruits and vegetables, whole grains, and low fat dairy products,
The beneficial effects of PUFAs and MUFAs, and metabolically with limited SFAs. An RCT comparing patients with NAFLD eating
harmful effects of SFAs, are shown in Table 2.115-119 Two meta- the DASH diet versus a control diet for 8 weeks (both of which
analyses have examined the effects of omega-3 supplementation contained 52–55% CHOs, 16–18% protein, 30% fat and approxi-
on NAFLD.120,121 The number of eligible studies analysed were nine mately 1,900 kcal/day), showed that the DASH group had signifi-
and 10, respectively (335 individuals and 577 individuals with cantly greater reduction in aminotransferases and metabolic
NAFLD). Both reported that omega-3 supplementation was bene- markers, including serum triglycerides, total cholesterol, VLDL
ficial in reducing liver fat (predominantly quantified using ultra- cholesterol, high sensitivity c-reactive protein, insulin and Homeo-
sound), but did not impact liver biochemistry. The analyses, how- static Model Assessment of Insulin Resistance (HOMA-IR).123 The
ever, were limited by poor quality study design and heterogeneity. data are confounded by greater weight loss in patients following
It was not possible to comment on an optimal dose. In terms of the DASH diet, however the high fiber and antioxidant content,
histology, a trial comparing the effect of a diet high in PUFAs vs. and low saturated fat and refined CHOs content, is likely to be
placebo for 1 year in individuals with NASH revealed no signifi- beneficial for NAFLD.
cant difference in NAS (≥2 point reduction) despite a greater re- Soy is also thought to be helpful in NAFLD by inhibiting SREBP-
duction in liver fat in the treatment group, although participant 1c and activating PPARα, reducing lipid deposition and increasing
numbers were small (n=34).122 antioxidant capacity. A three-arm RCT comparing patients eating
a low calorie diet to a low-CHO, low calorie diet to a low-CHO,
Clinical advice low calorie, soy-containing diet, reported that individuals eating
the soy-containing diet had significantly greater improvements in
Clinicians should advise patients with NAFLD to replace dietary liver tests and serum insulin levels.124
SFAs with PUFAs or MUFAs. While RCT data is sparse, research suggests that the Mediterra-
nean diet (rich in plant-based foods, legumes and unsaturated
fats) should prove ideal for patients with NAFLD as a result of its
DIETS effectiveness as a form of primary prevention for components of
the metabolic syndrome, and ability to reduce insulin resistance,
The Dietary Approaches to Stop Hypertension (DASH) diet is a liver fat and inflammation.125 An ad libitum Mediterranean diet
Table 3. Suggested research priorities

Nutrient of interest Research question
Protein 1. Does plant-based protein offer any benefit over lean animal protein (i.e., chicken/fish) in the prevention of NAFLD,
cirrhosis, HCC, or liver-related mortality?
2. What is the impact of red and processed meat, lean meat, and plant protein on the histologic features of NASH?
Carbohydrate 1. Does a diet high in whole grains offer any protection against NAFLD and progression to cirrhosis, HCC, or liver-related
mortality?
2. What is the impact of refined versus unrefined carbohydrates on the histologic features of NASH?
3. What is the impact of a diet low in free sugars on the histologic features of NASH?
Fiber 1. Are high fiber diets protective from developing NAFLD, cirrhosis, HCC, or liver-related mortality?
2. Can increasing fiber in the diet reduce hepatic steatosis and improve histologic features of NASH, with or without
weight loss?
3. Is there a difference in the impact of insoluble and soluble fiber on reversing NAFLD?
Fat 1. Can diets high in unsaturated fat prevent fibrosis progression or even reverse fibrosis?
2. What is the impact of saturated versus unsaturated fat on the histologic features of NASH?
Diets 1. Can a plant-based diet reverse histologic features of NASH without weight loss?
2. Can any of these diets lead to fibrosis reversal without weight loss?
3. Are these diets sustainable in this population long term?
NAFLD, nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis.

compared to a low-fat diet showed similar reductions in hepatic dence that patients drinking excessively (≥2 drinks/day for
steatosis over 12 weeks with similar weight loss in both groups. women and ≥3 drinks/day for men) with NAFLD are at signifi-
The Mediterranean group alone, however, saw improvements in cantly increased risk of developing advanced liver fibrosis and this
cholesterol, triglycerides and hemoglobin A1C.126 Furthermore, should therefore be discouraged.137 Even mild to moderate drink-
obese individuals with diabetes asked to follow a modified Medi- ing (<210 g/week) has been found to increase the risk of steato-
terranean diet for 12 months were found to display lower levels of hepatitis, fibrosis, decompensated liver disease, mortality and liv-
ALT compared to participants allocated to the American Diabetes er cancer among individuals with obesity and diabetes,138-144
Association diet and a low glycaemic index diet.127 The Mediterra- although there is some disagreement among studies.135,145,146 Ab-
nean diet is now recommended by EASL for the management of stinence has been advocated for patients with NASH cirrhosis in
NAFLD.14 order to reduce the risk for decompensation and hepatocellular
carcinoma (HCC).147
Clinical advice
Clinical advice
For patients with NAFLD we recommend diets high in whole,
unprocessed foods, fiber, and unsaturated fats, with limited quan- Coffee consumption is protective against the development of
tities of red and processed meats, refined CHOs and saturated fat. NAFLD and disease progression. Moderate to heavy alcohol con-
Example diets include the Mediterranean diet, DASH diet, and sumption should be avoided in the presence of obesity, NAFLD,
other plant-based diets. and other metabolic risk factors. Abstinence is advised for pa-
tients with advanced fibrosis.
BEVERAGES
LIMITATIONS OF CURRENT DATA
Two large systematic reviews have shown that coffee leads to a
relative risk reduction of cirrhosis and liver-related mortality sec- One of the biggest challenges encountered when studying di-
ondary to all causes.128,129 In terms of NAFLD, two meta-analysis etary determinants of diseases is the confounding effects of other
have demonstrated that coffee can reduce the incidence of dietary components and lifestyle factors. This may not be easily
NAFLD, in addition to decreasing the risk of liver fibrosis among handled by multivariable analyses alone and can lead to errone-
patients with established NAFLD.130,131 A non-linearity curve rela- ous conclusions. These issues were recently demonstrated in a se-
tionship between coffee consumption and the development of ries of meta-analyses which concluded that red or processed meat
NAFLD is described, with more than 3 cups per day reducing the may only lead to small differences in the risk of all-cause mortali-
incidence of NAFLD significantly.130 Several constituents found ty, cardiometabolic outcomes and cancer incidence;148-151 in con-
within coffee have been postulated as being mechanistic due to trast to the established medical opinion and public beliefs. Three
their favourable effects on glucose metabolism.132 For example, of the reviews were reliant on observational studies for which
chlorogenic acid inhibits glucose-6-phosphate hydrolysis, leading many received low GRADE scores in terms of evidence quality.
to a reduction in gluconeogenesis and glycogenolysis, and can in- The authors identified fundamental issues inherent to the design
hibit glucose absorption from the gut.133 of many nutritional studies including a lack of a clear hypothesis,
Concomitant alcohol consumption is frequently encountered in selective reporting of results, reliance on self-reported food con-
patients with NAFLD. Previous meta-analyses have shown no as- sumption, lack of controls and failure to address confounders.152,153
sociation between alcohol intake (up to 80 g/day) and hepatic A review of RCT data comparing diets with differing amounts of
steatosis,134 and a protective effect for individuals drinking up to red meat consumed for at least 6 months was similarly afflicted
40 g/day,135 however these studies were largely heterogenous, by poor quality evidence and discordant results.150 These results
retrospective and subject to selection bias. A cross-sectional study were used to inform guidelines published by the Nutritional Rec-
concluded that steatosis is present in nearly 95% of obese per- ommendations (NutriRECS) Consortium, which are the first to
sons who drink more than 60 g of alcohol per day, however obe- suggest there is no need for adults to reduce their consumption of
sity plays the over-arching role.136 There is, however, strong evi- red and processed meat,154 and have received widespread public

criticism. It is vital that we are able to provide the public with ac- ticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-
curate information about their dietary choices and maintain the Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed,
integrity of evidence-based medicine. There therefore needs to be Gemphire, Gilead, Glympse bio, GNI, GRI Bio, Intercept, Ionis,
radical reform in terms of how these studies are undertaken. Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals,
Small, poorly design observational studies are perhaps damaging Novartis, Novo Nordisk, Pfizer, Prometheus, Sanofi, Siemens, and
to these field; instead investment is required in high quality large Viking Therapeutics. In addition, his institution has received grant
RCTs looking at long term outcomes, in addition to the collection support from Allergan, Boehringer-Ingelheim, Bristol-Myers
of longitudinal data on markers of early disease. We have summa- Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics,
rized these research priorities in Table 3. Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail,
Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuti-
cals, NuSirt, Pfizer, pH Pharma, Prometheus, and Siemens. He is
CONCLUSION also co-founder of Liponexus, Inc.
This review has highlighted a significant lack of high quality Conflicts of Interest
RCT data in this field, offering a number of research opportunities The authors have no conflicts to disclose.
for the future. Although well intentioned, diets focusing specifi-
cally on reducing CHO or fat intake miss out on the benefits of
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Evidence-based clinical advice for nutrition and dietary

INTRODUCTION trum of disorders ranging from simple steatosis to steatohepatitis.

Abbreviations: Corresponding author : Meagan E. Gray

Copyright © 2020 by Korean Association for the Study of the Liver

Lipolysis (60%) De nove Dietary FFAs

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Pathophysiology Clinical advice

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Animal protein (red and processed meats)

Saturated fat Cholesterol

Activate hepatic FFA oxidation

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Pathophysiology trial, seven patients with NASH received 16 g/day of oligofructose

Randomized controlled trial data Observational studies

Saturated fatty acids

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Table 3. Suggested research priorities

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subjects. Hepatology 2011;53:1504-1514. jects under energy restriction. Nutrients 2017;9:667.

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Diabetes 2014;63:2356-2368. diseases: a systematic review. Liver Int 2014;34:495-504.

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