Anatomy disccuss7

 

More people are becoming interested in detox diets and organ health. As a health educator, one of your roles is differentiating evidence versus popular media and marketing. In this discussion, we will explore evidence that supports the role of nutrition in liver health to add to your ability to differentiate nutrition science from media.

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Initial post:  

Start by reading the article titled,

Impact of nutritional changes on nonalcoholic fatty liver disease

.

Focus on the general concepts, as opposed to understanding every word. After completing the reading, answer the following question for your initial post: “What evidence-based general nutrition recommendations would you share with patients interested in liver health?”

Use the assigned article, with appropriate APA citations, to support your position with at least 5-6 sentences to support your case. 

 

Reference(s)

Perdomo, C. M., Frühbeck, G., & Escalada, J. (2019). Impact of nutritional changes on nonalcoholic fatty liver disease. Nutrients, 11(3). https://doi.org/10.3390/nu11030677

nutrients

Review

Impact of Nutritional Changes on Nonalcoholic Fatty
Liver Disease

Carolina M. Perdomo 1 , Gema Frühbeck 1,2 and Javier Escalada 1,2,*
1 Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain;

cperdomo@unav.es (C.M.P.); gfruhbeck@unav.es (G.F.)
2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), ISCIII, 28029 Madrid, Spain
* Correspondence: fescalada@unav.es; Tel.: +34-948-255-400

Received: 28 February 2019; Accepted: 16 March 2019; Published: 21 March 2019
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Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major global health threat due to its growing
incidence and prevalence. It is becoming the leading cause of liver disease in addition to its strong
association with cardio-metabolic disease. Therefore, its prevention and treatment are of strong public
interest. Therapeutic approaches emphasize lifestyle modifications including physical activity and
the adoption of healthy eating habits that intend to mainly control body weight and cardio-metabolic
risk factors associated with the metabolic syndrome. Lifestyle interventions may be reinforced by
pharmacological treatment in advanced stages, though there is still no registered drug for the specific
treatment of NAFLD. The purpose of this review is to assess the evidence available regarding the
impact of dietary recommendations against NAFLD, highlighting the effect of macronutrient diet
composition and dietary patterns in the management of NAFLD.

Keywords: NAFLD; NASH; diet; macronutrients

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) results from hepatic fat accumulation (>5% of liver
weight), which is not due to excess alcohol consumption, autoimmune, infectious or other established
liver diseases [1,2]. NAFLD can exist as pure steatosis, steatosis with mild lobular inflammation,
non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. In addition to the degree of
fibrosis, in the liver biopsy NASH is classified as mild fibrosis (F0–F1), significant fibrosis (≥F2),
advanced fibrosis (≥F3, bridging) and cirrhosis (F4). No accurate data exist on the incidence of
NAFLD [3]. The worldwide prevalence of NAFLD ranges between 8–45%. In North America and
Europe, it is estimated to range from 25–34% and, in Asia, between 15–20%. The highest prevalence is
described in the Middle East and South America. However, in certain subpopulations (i.e., obesity,
type 2 diabetes [T2D]) the estimated prevalence of NAFLD is significantly higher, ranging from
43–92%. When compared to the general population, patients with NAFLD have higher mortality from
both liver and non-liver-related causes. They are at increased risk for cardiovascular diseases [4],
T2D and chronic kidney disease [2]. NAFLD is currently ranked as the second most common cause
of liver transplantation and is predicted to become the first in Western countries [3]. Additionally,
NAFLD is the second most common cause of hepatocellular carcinoma. Therefore, NAFLD is a major
global health threat; its prevention and treatment represent a mounting challenge in health services.
Therapeutic approaches focus on lifestyle modification [5]. Diet and exercise interventions remain as
the first line of therapy, aiming mainly at controlling body weight and cardio-metabolic risk factors
related to metabolic syndrome. In the early stages of NAFLD, a healthy diet and weight loss of at least
7% might be sufficient [4]. In more advanced stages, high genetic risk or, in the presence of diabetes,
intensified lifestyle intervention reinforced by pharmacological treatment might be necessary, though

Nutrients 2019, 11, 677; doi:10.3390/nu11030677 www.mdpi.com/journal/nutrients

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Nutrients 2019, 11, 677 2 of 25

there is still no registered drug for the treatment of NAFLD. This review assesses the evidence available
for dietary recommendations against NAFLD.

We searched for original articles and reviews published between 1 January 2000 and
31 December 2018, focusing on NAFLD dietary treatment in PubMed and MEDLINE using the
following search terms (or combination of terms): “NAFLD”, “NASH”, “fatty liver”, “macronutrient”,
“dietary”, “recommendations”, “composition”, “life-style intervention”, “Mediterranean diet”.
Only full-text articles written in English were included. More weight was given to studies with
a high level of evidence from either randomized controlled trials, prospective case-control studies,
meta-analyses or systematic reviews. Articles in journals with explicit policies governing conflicts of
interest and stringent peer-review processes were favored. Data from larger replicated studies with
longer periods of observation when possible were systematically chosen to be presented. Reference
lists of retrieved articles were used to obtain additional references.

2. Pathophysiology

The major established risk factors for NAFLD include obesity, insulin resistance and
dyslipidemia [5]. Genetic modifiers are associated with the increased progression to NASH and
cirrhosis, however, some of them are associated with apparent protection from cardiovascular
diseases [4]. The best-characterized genetic association is with PNPLA3 [6] encoding I148M (regulator
of the mobilization of triglycerides from lipid droplets) and with TM6SF2 [1,3,4] encoding E167K
(regulator of very low-density lipoprotein (VLDL) secretion).

Dietary lipids (15%), lipolysis of adipose tissue (60–80%) and de novo lipogenesis (5%) contribute
to the pool of lipids stored in the liver [7]. Adipose tissue lipolysis is regulated by the actions
of insulin on adipocytes [2,8]. De novo lipogenesis is the process in which hepatocytes convert
excess carbohydrates, especially fructose, into fatty acids [2], it is strictly regulated by nuclear
receptor and cytoplasmic transcription factors including the liver X receptor (intervening in hepatic
fatty acid synthesis), the farnesoid X receptor (interfering in VLDL assembly) and the peroxisome
proliferator-activated receptors [PPARs] family [7]. PPAR-α regulates free fatty acids oxidation, PPAR-γ
has an anti-inflammatory function, and PPAR-δ suppresses hepatic lipogenesis and reduces the hepatic
expression of pro-inflammatory genes.

Lipid removal is mediated by both mitochondrial fatty acid β-oxidation and re-esterification
to form triglyceride [7]. Triglycerides can be exported into the blood as VLDL or may be stored in
lipid droplets. Lipid droplet triglycerides may undergo lipolysis to release fatty acids back into the
hepatocyte free fatty acid pool. In order to understand the different nutritional advice for the treatment
of NAFLD, it is necessary to comprehend that insulin resistance in adipose tissue contributes to fat
accumulation and NASH through dysregulated lipolysis, resulting in the excessive delivery of fatty
acids to the liver.

A ‘two-hit’ hypothesis to explain NAFLD development has been proposed. The ‘first hit’ is
steatosis, the accumulation of fat in hepatocytes because of excessive triglycerides due to an imbalance
in the lipid metabolism [7,9]. Steatosis is a consequence of insulin resistance [5,10,11]. Insulin
resistance leads to hepatic triglyceride accumulation due to the increase of lipolysis in the peripheral
adipose tissue resulting in higher levels of circulating non-esterified fatty acids, which are taken
up by the liver and esterified into triglycerides. Impaired insulin signaling results in compensatory
hyperinsulinemia [5]. Hyperinsulinemia decreases glycogen synthesis, which increases the hepatic
fatty acid uptake, alters triglycerides transportation, and inhibits liver β-oxidation. In addition,
glucose can be taken up by the liver through an insulin-independent transporter and be converted
to pyruvate (a precursor of acetyl-CoA and malonyl-CoA) which can be transformed into fatty
acids through de novo lipogenesis [5,10]. All of these alterations increase the pro-inflammatory
cytokine activity leading to oxidative stress-mediated lipotoxicity, impaired hepatocyte apoptosis,
inflammasome activation and mitochondrial dysfunction, contributing to fatty acid accumulation,
hepatocellular injury, inflammation and the progressive accumulation of excess extracellular matrix [2].

Nutrients 2019, 11, 677 3 of 25

Oxidative stress, triggered by pro-inflammatory cytokines (such as tumor necrosis factor-alpha
[TNF-α], interleukin-6 and interleukin-8) or the reduction of anti-inflammatory cytokines (adiponectin),
is considered the ‘second hit’ of NAFLD’s pathogenesis [11]. This may further exacerbate insulin
resistance and hepatocyte injury induced by genetic or environmental susceptibilities.

A ‘three-hit’ hypothesis has been proposed as a result of inadequate hepatocyte regeneration and
apoptosis [9]. However, all of these hypotheses might be outdated because free fatty acid accumulation
alone is sufficient to induce liver damage [2]. It is not even certain whether NASH is always preceded
by steatosis. The variable progression of NAFLD has led to the description of a ‘multiple-hit’ hypothesis
suggesting that multiple events act in parallel (including lipotoxicity, proinflammatory cytokines,
increased oxidative stress, mitochondrial dysfunction, genetic or environmental susceptibilities) [9,11].
Consequently, in NAFLD, a modest weight reduction through diet and exercise leads to an
improvement in the substrate overload and insulin sensitivity [12]. Figure 1 summarizes the liver
effects of the different macronutrients present in the diet composition (discussed ahead).

Lipotoxicity, increased oxidative stress,
mitochondrial dysfunction, genetic or
environmental susceptibilities

Fat accumulation and
NAFLD progression

Insulin Resistance:
Hyperinsulinemia

Vegetable proteins
Prebiotic fiber intake
Probiotics

MUFA and Omega-3 PUFAs

Simple sugars (fructose)

Saturated and trans fats
Animal proteins

De novo lipogenesis

Hepatic fatty acids uptake

Antioxidant/anti-inflammatory properties (activation
of PPARs): reinstatement of insulin sensitivity

Hepatic lipid oxidation

Figure 1. The effects of diverse macronutrients on non-alcoholic fatty liver disease pathophysiology.
An unhealthy dietary pattern including saturated fats, trans fats, simple sugars and animal protein
(red and processed meat) results in an increased total and visceral fat mass, insulin resistance,
increased hepatic de novo lipogenesis and gut dysbiosis. Under these conditions and acting
parallel, fat accumulates in the liver causing lipotoxicity, increased oxidative stress and mitochondrial
dysfunction adding genetic or environmental predisposition for hepatic lipid accumulation (‘multiple
hit hypothesis´). Red arrow: unfavorable/harmful effect; Green arrow: favorable/beneficial effect.
NAFLD: non-alcoholic fatty liver disease; PPAR: peroxisome proliferator-activated receptors.

3. Lifestyle Intervention

A 2011 systematic review (23 trials) [13] assessed the effect of diet and physical activity on NAFLD.
Lifestyle modifications leading to weight reduction and/or increased physical activity consistently
showed reductions in liver fat, aminotransferase concentrations and improved insulin sensitivity.
The strongest correlation was seen with a weight reduction of >7%. A reduction in inflammation
was evidenced in five trials that included histopathology. However, only one study revealed a
significant fibrosis reduction. A recent network meta-analysis (19 studies) [12] confirmed that in
NAFLD, exercise plus a dietary intervention is the most effective treatment. Dietary intervention may
be more effective in improving aminotransferases, although exercise showed superiority in improving
insulin sensitivity and in reducing body mass index (BMI). Look AHEAD (Action for Health in

Nutrients 2019, 11, 677 4 of 25

Diabetes) [14] is a multicenter clinical trial including 5145 overweight adults with T2D. Steatosis
reduction was evidenced after a 12-month intensive lifestyle intervention, achieving a weight loss of at
least 7%. A recent randomized controlled trial (n = 154) [15] reaffirmed that lifestyle intervention with
a weight reduction in a dose-dependent manner effectively leads to NAFLD remission in non-obese
and obese patients. However, weight loss and maintenance is a difficult task. There is an urgent need
to simplify dietary recommendations for NAFLD patients.

4. Diet Composition Focusing on Macronutrients

Independently of energy intake, the macronutrient composition of a diet is associated with
NAFLD/NASH development [16]. Different epidemiological studies have identified macronutrients
with a harmful or beneficial effect on the liver (Table 1). Since 2003, Musso et al. [17] identified that
dietary habits may directly promote NASH by modulating hepatic triglyceride accumulation and
antioxidant activity and, indirectly, by affecting insulin sensitivity and the postprandial triglyceride
metabolism. They examined 25 NASH patients vs. 25 healthy controls. Compared to controls,
patients with NASH had a significantly higher saturated fat intake and a smaller amount of
polyunsaturated fatty acid (PUFAs), fiber, vitamin C and vitamin E consumption. Similarly, in 2006,
Cortez-Pinto et al. [18] compared the dietary composition in 45 NASH patients vs. 856 healthy controls.
NASH patients had a significantly higher total fat and omega-6 PUFAs consumption and a lower fiber
intake. In 2014, a cross-sectional Korean study in 348 patients (169 NAFLD patients vs. 179 healthy
controls) [19] found an inverse association between NAFLD risk and vitamin C, vitamin K, folate,
omega-3 PUFAs, and nuts and seeds consumption. In 2016, Wehmeyer et al. [20] examined 55 NAFLD
patients vs. 88 healthy controls. NALFD patients had a higher energy intake with a significantly
higher glucose and protein consumption and a lower fiber and mineral consumption per 1000 kcal.
However, no significant differences regarding carbohydrates, fructose and fat per 1000 kcal energy
intake were appreciated. Recently, the macronutrient composition was analyzed in NAFLD patients
between 61–79 years of age from the Rotterdam study [21]. A total of 3882 participants were included
(NAFLD patients = 1337). The total protein intake was associated with NAFLD in overweight patients
even after adjusting for sociodemographic and lifestyle covariates. However, after the adjustment for
metabolic covariates, only animal proteins remained associated. Monosaccharides, disaccharides and
fiber were not associated with NAFLD.

Table 1. The summary of dietary indications for the treatment of non-alcoholic fatty liver
disease (NAFLD).

RECOMMENDED

Whole grains Probiotics a

MUFAs Resveratrol a

Omega-3 PUFAs Coffee a

Vegetable protein Taurine a

Prebiotic fiber Choline a

TO BE AVOIDED

Simple sugars (fructose)
Saturated and trans fats

Animal protein (red and processed meat)

MUFAs: monounsaturated fats; PUFAs: polyunsaturated fatty acids. a Insufficient evidence available.

Overall, by being independent of weight loss and energy intake, a healthy diet is effective
in reducing liver fat content and, therefore, protecting one from cardio-metabolic morbidity and
mortality [4]. Contemporary dietary recommendations for NAFLD treatment include caloric restriction
and adherence to the macronutrient composition of the Mediterranean diet (MD) [1]. However, before
recommending a specific dietary pattern, it is necessary to analyze the liver effect of each macronutrient.

Nutrients 2019, 11, 677 5 of 25

4.1. Fats

4.1.1. Saturated Fats

Saturated fats are generally found in animal products (red meat, cream, butter and whole milk
dairy products), some vegetable products (coconut oil, palm oil and palm kernel oil) and prepared
foods (desserts and sausages) [16]. Saturated fat intake is correlated with an impaired glutathione
metabolism towards oxidative stress leading to NAFLD progression. A meta-analysis (8 randomized
trials) [22] including 13,614 patients found a 10% risk reduction of coronary events (myocardial
infarction and/or cardiac death) for every 5% of energy intake conferred by PUFAs after replacing
saturated fats for at least 1 year in the general population. Interestingly, mice fed with saturated
fats vs. regular chow-diet had a PNPLA3 expression in hepatocytes that was 23 times higher [23].
This upregulation was reversed with fasting. In individuals that consume high saturated fat diets,
genetic variations may influence NAFLD susceptibility. Overall, it is reasonable to suggest a saturated
fat intake reduction in the general population.

4.1.2. Monounsaturated Fats

Monounsaturated fatty acids (MUFAs) are found in olive oil, avocados and nuts [24]. Olive oil is
the most representative ingredient in the traditional MD. Olive oil is predominantly constituted by
MUFAs (70–80%) and palmitic acid (up to 20%). Higher grades of olive oil (e.g., extra-virgin and virgin)
contain higher amounts of polyphenols and phytochemicals that are lost when olive oil is refined or
heated. Phenolic compounds in MUFAs have shown antioxidant and anti-inflammatory properties
that may induce an improvement in dyslipidemia and endothelial dysfunction [25]. A decreased
risk of metabolic syndrome and/or cardiovascular disease has been evidenced with a higher MUFAs
consumption [24,25]. Additionally, dietary MUFAs may be protective against age-related cognitive
deterioration, Alzheimer’s disease and cancer [25]. A systematic review (9 trials) [26], including 1547
T2D patients, evaluated the effect of MUFAs in glycemic control. A significant Hb1Ac reduction was
evidenced without fasting plasma glucose or homeostatic model assessment of insulin resistance
(HOMA-IR) improvement.

Regarding NAFLD, in 2006, Cortez-Pinto et al. [18] revealed a higher MUFAs consumption in
patients with NAFLD. Similarly, in 2017, Rietman et al. [27] assessed the dietary intake in 1128 patients
and established an association with the Fatty Liver Index (FLI; derived from BMI, waist circumference,
triglycerides and gamma-glutamyltransferase [GGT]). MUFA consumption and total fat intake were
positively associated with a higher FLI score. In the Rotterdam Cohort [21], MUFA consumption did
not suggest a beneficial effect in NAFLD.

On the other hand, in 2007, Zelber Sagi et al. [28] did not find an association between MUFAs
and NAFLD development. A randomized parallel-group controlled trial (n = 45) [29] in patients with
T2D showed a major liver fat reduction (measured by proton nuclear magnetic resonance spectroscopy
(1H NMR)) following an 8-week isocaloric MUFAs enriched diet vs. a high fiber and low glycemic index
carbohydrate diet, independently of an aerobic training program. Additionally, a recent randomized,
double-blind clinical trial (n = 66 NAFLD patients) [30] evaluated the effect of 20 g/day of olive oil vs.
sunflower oil for 12 weeks. Olive oil improved fatty liver severity (measured by ultrasonography (US)),
triglyceride levels and fat mass independently of correcting cardio-metabolic risk factors. Both MUFAs
and PUFAs might reduce steatosis in NAFLD by PPARs activation, which stimulates free fatty oxidation
and decreases inflammation, insulin resistance and the expression of genes involved in hepatic de
novo lipogenesis [16]. While there is still controversy in some studies, it is prudent to recommend
moderate MUFAs consumption (20 g/day).

4.1.3. Polyunsaturated Fats

Essential PUFAs includes omega-3 PUFAs and omega-6 PUFAs. The latter are mostly found in
vegetable oils (canola and cottonseed), cereal grains (wheat, maize and rice) and nuts [18,31]. Linoleic

Nutrients 2019, 11, 677 6 of 25

acid is the main dietary omega-6 PUFAs. Increased amounts of omega 6-PUFAs are related to a
higher incidence of inflammatory and thrombotic events, including cardiovascular disease, cancer,
inflammatory and autoimmune diseases. An omega-6/omega-3 ratio of 15:1 has been described in
the Western diet [31]. Nevertheless, in a randomized trial (n = 67), lower insulin levels, inflammatory
markers and reduced hepatic steatosis (assessed by magnetic resonance (MRI) or 1H NMR) were
evidenced after a 10-week isocaloric diet supplemented with omega-6 PUFAs vs. saturated fat
supplementation [32].

Omega-3 PUFAs are mostly found in seafood (pilchards, sardines, mackerel, trout, salmon,
herring and tuna, haddock, cod, and crustaceans, shellfish), in certain vegetable oils (flaxseed oil)
and, in lower amounts, in eggs and meat [10]. Marine Omega-3 PUFAs include eicosapentaenoic
acid (EA), docosahexaenoic acid (DHA) and docosapentaenoic acid. Omega-3 PUFAs modulate hepatic
lipid composition and increase anti-inflammatory mediators leading to an improvement of insulin
sensitivity that induces triglyceride redistribution (lipid storage in adipose tissue and the consequent
decrease of triglyceride serum levels) [5,10].

In a cohort of 12,300 patients with multiple cardiovascular risk factors and after a 5-year
follow-up, daily treatment with omega−3 PUFAs did not reduce cardiovascular events or mortality [33].
Yet, a systematic review (23 randomized controlled trials) [34] evaluated the effect of omega-3
PUFA supplementation in 1075 T2D patients with cardiovascular risk factors. Omega-3 PUFA
supplementation (mean dose: 3.5 g/day; mean treatment duration: 8.9 weeks) showed improved
dyslipidemia (triglyceride and VLDL cholesterol serum levels), with no statistically significant effect
on body weight, glycemic control, fasting insulin, total-cholesterol or HDL-cholesterol.

Regarding NAFLD, in 2004, Araya et al. [35] used liquid gas chromatography to analyze liver
and abdominal adipose tissue fatty acids in 19 patients with NAFLD vs. 11 controls; a marked
enhancement in omega-6/omega-3 ratio characterized the liver of NAFLD patients. The first report
about omega-3 PUFAs supplementation in NAFLD patients was performed in 2006 [36]. Forty-two
NAFLD patients received 1 g daily of EA and DHA (in the ratio of 0.9:1.5 respectively) for 12-months
vs. 14 controls. Omega 3-PUFAs supplementation significantly decreased the serum GGT, aspartate
aminotransferase (AST), alanine aminotransferase (ALT), triglycerides serum levels and fasting glucose.
Additionally, the circulating arachidonate and omega-6/omega-3 ratio were reduced in treated patients.
Moreover, US demonstrated the improvement of liver echotexture and the increase of the Doppler
perfusion index after omega-3 supplementation without significant changes in the control group.
A study found a total PUFAs intake below the recommended level and lower hepatic omega-3 and
omega-6 PUFAs in NASH-biopsy-proven patients (n = 38) vs. simple-steatosis-biopsy-proven patients
(n = 18) [37]. Patients with NASH had a higher BMI, central obesity, body fat, insulin resistance,
dyslipidemia and lower physical activity. As suspected, higher liver lipid peroxides with a lower
antioxidant power were evidenced, addressing the higher oxidative stress that leads to the metabolic
abnormalities. Similarly, a Japanese study [38] evidenced a lower PUFAs/saturated fats intake ratio in
biopsy-proven NASH patients (n = 28) vs. simple-steatosis-biopsy-proven patients (n = 18).

In 2008, two studies investigated the effect of calorie-restricted diets with and without PUFA
consumption. Spadaro et al. [39] found a significant improvement in ALT, triglyceride and TNF-α
serum levels, as well as an improvement in the fatty liver measured by US after 2 g/day PUFAs and a
25–30 kcal/kg/day diet in NAFLD patients (n = 20) vs. a control group (n = 20) who followed the same
diet without PUFAs administration. Zhu et al. [40] proved the efficacy of PUFAs supplementation (seal
oil) in NAFLD in a randomized placebo-controlled trial. Seventy-two patients received 2 g of seal oil
three times per day plus dietary recommendations vs. 72 controls. PUFAs from seal oil significantly
improved their total symptom score, fatty liver severity measured by US, ALT and triglycerides serum
levels. In 2012, a meta-analysis (9 studies) [41] of omega-3 PUFAs supplementation including 355
NAFLD patients, suggested an improvement in liver fat and in AST levels, however, substantial
heterogeneity was found and an optimal dose was not clarified.

Nutrients 2019, 11, 677 7 of 25

A reduced liver fat measured by US, improved HOMA-IR and reduced triglycerides serum
levels without weight gain was evidenced after a 6-month treatment with 250 mg/day (n = 20) or
500 mg/day (n = 20) of DHA in children [42]. A similar randomized placebo-controlled trial was
repeated in the adult population from the WELCOME study (Wessex Evaluation of Fatty Liver and
Cardiovascular markers in NAFLD with Omacor therapy) [43]. Sixty patients with NAFLD received
omega-3 PUFAs supplementation (4 g of DHA plus EA) for 15–18 months. Reduced liver fat measured
by 1H NMR could not be significantly evidenced nor could a reduction in the validated liver fibrosis
scores. However, the erythrocyte percentage DHA enrichment using gas chromatography was linearly
associated with the decreased liver fat percentage. Likewise, a phase 2b multicenter, double-blinded,
randomized, placebo-controlled trial found no histological or blood markers improvement in 243
NASH patients receiving 1.8 g/day or 2.7 g/day of EA vs. placebo for 12 months [44]. However,
with 2.7 g of EA, reduced levels of triglyceride were significantly observed.

Flaxseed oil is another source of omega-3 PUFAs. A two-arm randomized clinical trial [45] showed
a significantly higher reduction in body weight, liver enzymes, insulin resistance, hepatic steatosis
and fibrosis scores after 12 weeks with 30 g/day of flaxseed oil plus lifestyle modification (n = 25) vs.
lifestyle modification only (n = 25). However, no histological improvement was seen after a six-month
use of flaxseed oil and fish oil vs. mineral oil in NASH patients despite triglyceride levels significantly
improving in flaxseed oil and fish oil arm [46].

As evidenced, few clinical trials have addressed the potential benefits of omega-3 PUFAs on
NAFLD/NASH. Larger well-designed clinical trials for longer periods are still needed to fully
evaluate the beneficial effects of omega-3 PUFAs in NAFLD. Overall, omega-3 PUFAs is preferable
than other forms of PUFAs, therefore, it is essential to recommend omega-3 PUFAs intake with an
omega-6/omega-3 fatty acid ratio of about 1–2:1 [31].

4.1.4. Trans-Fats

The substantial loss of trans-fats from the liver lipid pool in parallel with NASH improvement
suggests a potential role of trans-fats in the pathogenesis of NAFLD/NASH. Alferink et al. [21]
recently indicated that trans-fats (predominantly from desserts, cream or solid fats) were associated
with higher odds for NAFLD. Due to known trans-fat harmful effects in humans, there is a lack of
human clinical trials evaluating the effect on the liver. In an animal study [47], mice were fed with
a diet high in trans-fats (partially hydrogenated vegetable oil) and fructose corn syrup for 16 weeks.
They developed hyperinsulinemia and severe hepatic necroinflammation. However, when trans-fats
were removed, NASH improved biochemically and histopathologically [48]. Moreover, hepatocellular
carcinoma development was observed in 6 out of 10 mice after a 12-month high dietary trans-fats and
fructose corn syrup intake plus a sedentary lifestyle [49]. Without hesitation, it is necessary to advise
minimizing or avoiding trans-fats consumption.

4.2. Protein

Regarding the protein content in diet, several studies have evidenced a significantly higher protein
intake in patients with NAFLD [18,20,28,50]. However, other studies have found no difference in
protein intake in patients with NAFLD compared to controls [17,51]. Controversies may be explained
by the nature of the protein consumed. Rietman et al. [27] found an inverse association between
vegetable protein and NAFLD assessed by FLI score in a Dutch adult population (n = 1128). Animal
protein, soft drinks and less dietary fiber intake were positively associated with NAFLD.

Bortoletti et al. [52] observed a 20% reduction in intrahepatocellular lipids measured by MR in
sedentary obese women that consumed 60 g/day of whey protein for 4 weeks. An improvement in
plasma lipid profile was also observed, without effects on glucose tolerance or creatinine clearance.
Similarly, soy protein intake improved liver function in mice with NASH [53]. Soy protein has
isoflavones, which have an anti-oxidative ability capable of improving insulin resistance and, therefore,
lowering lipid levels. Amino acid catabolism requires energy, subsequently, a high protein intake might

Nutrients 2019, 11, 677 8 of 25

generate increased hepatic lipid oxidation that could explain the beneficial effect of vegetable protein in
NAFLD [16]. Moreover, experimental animal data suggest that taurine, a non-essential amino acid and
a bile acid conjugate, may reduce hepatic lipid accumulation, inflammation, triglycerides and insulin
serum levels [54]. Taurine supplementation may ameliorate liver injury, henceforward, becoming a
possible treatment for diet-induced NAFLD.

On the contrary, it is well known that high meat intake, especially processed meats, is associated
with impaired insulin sensitivity and, therefore, may increase the risk of T2D [55,56]. The PREDIMED
study [57] has demonstrated in 717 participants (after a year of follow up) that higher red meat
consumption is associated with a significantly higher incidence and prevalence of metabolic syndrome.
Regarding NAFLD, a cross-sectional study (n = 349) [28] determined that NAFLD patients consumed
27% more protein from all types (of high and low-fat meat) including beef, liver, sausage, lamb, chicken
and turkey. Similarly, a nested case-control study [58] was conducted with 200 NAFLD patients
vs. 200 matched by age and gender controls. NAFLD patients had a significantly higher red meat
consumption level. In the Rotterdam cohort [21], NAFLD patients (n = 1337) had a higher protein
intake even after adjustment for sociodemographic, lifestyle and metabolic covariates vs. controls.
As expected, high processed meat consumption is associated with an increased risk of NAFLD due
to its high sodium content and the presence of preservatives, additives, food flavor enhancers [59],
saturated and trans-fats [56,60].

A recent large epidemiological study [61] from six states and two metropolitan areas in the United
States of America (USA) (n = 536,969; aged 50–71; 16-year follow-up) revealed that high red meat intake
was associated with all-cause mortality and specifically with mortality from liver diseases. They also
demonstrated reduced risks after substituting red meats for white meat, particularly unprocessed
white meat. Heme iron and processed meat nitrate/nitrite from processed meat were independently
associated with mortality. Furthermore, a recent Israeli study (n = 357) [62] found that high meat
consumption, specifically red and processed meat consumption were associated with higher odds of
insulin resistance and NAFLD (assessed by US), independently of saturated fat intake, BMI, physical
activity, smoking and alcohol consumption. Additionally, cooking meat at high temperatures for a
long duration (fried, grilled or broiled to a well-done level) was independently associated with insulin
resistance due to higher intake of heterocyclic amines. A recent German prospective study (n = 37) [63]
suggested a beneficial effect of either vegetable or animal protein in T2D. Patients were assigned to
a diet high in vegetable protein (mainly legume protein) or to a diet high in animal protein (rich in
meat and dairy foods) without calorie restriction for 6 weeks. Both diets had the same macronutrient
composition (30% protein, 40% carbohydrates, and 30% fat). After 6 weeks, intrahepatic lipid content
(assessed by MR and 1H NMR), insulin resistance and hepatic necroinflammation markers decreased.
Overall, it seems cautious to limit the consumption of unhealthy meats. Additionally, improved
cooking methods should be recommended as part of NAFLD dietary treatment.

4.3.

Carbohydrates

Several studies have evidenced the detrimental metabolic effects after high consumption of simple
carbohydrates (CHO). Wehmeyer et al. [20] observed a significantly higher glucose intake per 1000 kcal
in patients with NAFLD (n = 55) compared to healthy controls (n = 88). A cross-sectional study
(n = 375 patients) [28] demonstrated that simple CHO consumption (soft drinks) was significantly
higher in NAFLD patients. Similarly, a Japanese study [38] exposed that a diet rich in CHO, particularly
simple CHO, was associated with a higher risk of biopsy-proven NASH (n = 28) vs. biopsy-proven
simple steatosis (n = 18). Volynets et al. [50] identified a higher intake of total carbohydrates,
monosaccharides, disaccharides and protein in NAFLD patients (n = 20) vs. controls (n = 10).
Plasminogen activator inhibitor-1, endotoxin and ALT plasma levels were positively associated with
the total protein and carbohydrate intake.

In contrast, in the Rotterdam study [21], the total carbohydrate, monosaccharide and disaccharide
intake were inversely related to NAFLD prevalence. The authors advert that this study was performed

Nutrients 2019, 11, 677 9 of 25

in an elderly population (61–79 years old) where soft drink consumption was less than 1 drink/day,
therefore, fruits were the main source of monosaccharide and disaccharide intake. Similarly,
Rietman et al. [27] found that monosaccharide and disaccharide intake was inversely associated with
NAFLD, though, soft drink consumption was associated with NAFLD. Dietary fiber is discussed
ahead. Overall, the dietary source of monosaccharides and disaccharides is essential to determine their
effect on NAFLD.

4.3.1. Fructose

The rising incidence of metabolic syndrome coincides with a marked increase in fructose
consumption. In Asian cross-sectional studies, Jia et al. (n = 4365) [64] and Tajima et al. (n = 2444) [65]
reported a positive association between NAFLD risk and high-fructose products (fruit, cakes,
soft drinks and sugary snacks). A cross-sectional study [66] from the NASH Clinical Research Network
(n = 427 NAFLD patients) found that fructose ingestion from soft drinks is associated with more
advanced liver fibrosis on biopsy. Evidence suggested that even a 1-week fructose consumption of
4 g/kg/day or a glucose consumption of 3 g/kg/day may increase the liver fat content measured by
1H NMR or MR [67]. A randomized controlled trial [68] evaluated the effect of high sucrose intake (1 L
of cola/day for 6 months) vs. water, milk or artificially sweetened soft drink in 47 overweight subjects.
An association between sucrose intake and liver fat (measured by 1H NMR) as well as between skeletal
fat and visceral fat (measured by dual-energy X-ray absorptiometry and MR) was found. Additionally,
higher systolic blood pressure, serum triglycerides and total cholesterol were evident in the sucrose
group. In a 4-week double-blind trial (n = 32) [69], no differences were found in the HOMA-IR and
hepatic fat content (measured by 1H NMR) between high fructose intake vs. high glucose intake.
The evidence indicates an energy mediated effect rather than a specific macronutrient effect over
fat accumulation. Still, it seems prudent to advise limiting the refined carbohydrate consumption
particularly from soft drinks and fruit juices.

It is hypothesized that fructose is a strong de novo lipogenesis inducer, probably due to the
direct flow of fructose carbon into the glycolytic pathway, evading phosphofructokinase (a key
regulatory enzyme of glycolysis), and thereby contributing to the synthesis of triglyceride glycerol [16].
Additionally, fructose may activate the lipogenic gene expression and may induce bacterial overgrowth
in the small intestine which increases the endotoxin levels in the portal vein producing inflammation
in NASH.

4.3.2. Dietary Fiber

Poor fiber intake is common in NAFLD [18,20,51,70] and in NASH [17]. The mechanism by
which poor fiber ingestion may influence NAFLD has not yet been completely understood [11,71,72].
Some fibers are prebiotics. Prebiotic fibers are a group of non-digestible carbohydrates found in
garlic, asparagus, leek, chicory root and onions. A prebiotic is a nonviable food component that
confers a health benefit on the host through microbiota modulation. Recently, prebiotic fibers have
been added as ingredients to many common food products such as bread, cereal bars and breakfast
cereals [11]. Fructooligosaccharides are now becoming increasingly popular due to their prebiotic
effect [73]. They promote Bifidobacteria as the dominant species in the large bowel, thus, controlling
harmful bacteria growth.

Prebiotics modulate the human microbiota by reducing luminal pH and thus inhibiting pathogen
growth [11,71,72]. It is known that the translocation of bacteria into the systemic circulation may
lead to systemic inflammation that enhances insulin resistance promoting liver injury [74]. However,
microbial metabolites, including ethanol and other volatile organic compounds (VOC) produced in a
dysbiotic intestinal environment may also have toxic effects on the liver after intestinal absorption [75].
A significantly altered fecal VOC profile and compositional shift in the fecal microbiome is observed in
obese patients with clinically suspected NAFLD.

Nutrients 2019, 11, 677 10 of 25

The modification of intestinal bacterial flora is proposed as a therapeutic approach for the
treatment of NASH [72]. Animal studies provide promising evidence [11]. Dietary fiber, regardless
of fermentability, reduces adiposity and hepatic steatosis in rodents [76]. In humans, a body weight
reduction, glucose and lipid metabolism improvement were proven (n = 48) after 21 g/day of
oligofructose supplementation for 12 weeks vs. placebo [77]. Oligofructose is a form of dietary
fiber found in vegetables. A randomized double-blinded cross-over study [78] assessed the effect
of prebiotic fiber in seven biopsy-proven NASH patients after receiving, for 8 weeks, 16 g/day of
oligofructose vs. placebo. An improvement in the serum aminotransferases and insulin levels was
evidenced. Further research is needed to confirm the potential effects of prebiotic fibers in patients
with NAFLD, though it is safe and reasonable to promote its consumption.

In summary, macronutrient recommendations for the treatment of NAFLD are mostly based on
observational studies and robust research is needed to confirm these findings (Table 2).

Table 2. The macronutrient recommendation for the treatment of NAFLD.

FATS

Type Food Source Evidence Recommendation

Saturated fats

Animal products (red
meat, butter and dairy
products), vegetable oils
(coconut and palm oil) and
processed foods (sausages,
desserts)

A risk reduction of coronary events has been
evidenced after replacing saturated fats by PUFAs
for at least one year [22]

Its consumption is
discouraged

Monounsaturated
fats

Olive oil, avocados, nuts
and nut oils

They have phenolic compounds that are associated
with a lower risk of MS [25]. They have shown a
significant reduction in liver fat [29], serum
triglycerides and fat mass [30]. Additionally, Hb1Ac
improvement has been evidenced in T2D [26]

A moderate
consumption is
recommended

Polyunsaturated
omega-6 fats

Vegetable oils (canola and
cottonseed), cereal grains
(wheat, corn and rice) and
nuts

An excess of omega-6 is related to cardiovascular
disease, cancer, inflammatory and autoimmune
diseases [31]

Its consumption is
discouraged

Polyunsaturated
omega-3 fats

Seafood, certain vegetable
oils (flaxseed oil) and, to a
much lesser extent, eggs
and meat

Improvement of liver enzymes [41,46] and
triglyceride levels [34,44,46] have been evidenced
after omega-3 supplementation. Liver fat reduction
is still controversial [41,46]; the WELCOME study
could not significantly evidence a liver fat reduction
nor a reduction in validated liver fibrosis scores;
however, the erythrocyte percentage DHA
enrichment using gas chromatography was linearly
associated with a decreased liver fat percentage [43]

It is advisable to increase
omega-3 intake
(omega-6/omega-3 ratio
of 1-2/1)

Trans fats
Partially hydrogenated
vegetable oil, desserts,
cream or solid fats

Its consumption is associated with hyperinsulinemia,
liver fat accumulation [21] and severe hepatic
necroinflammation [47,48]. HCC development has
been observed in animal studies [49]

Its consumption is
discouraged

Proteins

Type Food Source Evidence Recommendation

Animal protein
Red meat and processed
meat (sausages)

Its consumption is associated with NAFLD due to its
high sodium content and the presence of
preservatives, additives, saturated fats and trans fats
[21,62]. Cooking meat at high temperatures for a
prolonged period is independently associated with
insulin resistance [62]. Its consumption is associated
with an increase in mortality of all causes and
mortality due to liver diseases [61]

Its consumption is
discouraged. Avoid
specific cooking methods
(fried or grilled well
done)

Plant-based protein
Whole grains, cereals,
seeds, nuts, legumes,
vegetables, soybeans, peas

MD is the pattern of choice in the management of
NAFLD [2]. It is characterized by the high
consumption of plant-based foods.

Its consumption is
recommended

Nutrients 2019, 11, 677 11 of 25

Table 2. Cont.

Carbohydrates
Type Food Source Evidence Recommendation

Simple
carbohydrates

Fructose (soft drinks and
fruit juices) and refined
carbohydrate (sucrose,
honey, syrup)

Its consumption is related to a greater hepatic,
skeletal and visceral fat deposition [68], as well as, to
a higher fibrosis stage [66], due to the de novo
lipogenesis and the excessive growth of bacteria in
the small intestine [16]. HCC development has been
observed in animal studies [49]

Its consumption is
discouraged

Dietary fiber

Non-digestible
carbohydrates found in
garlic, asparagus, leeks,
onions and cereals

Dietary fiber may confer a benefit through the
modulation of the microbiota. They have shown
body weight reduction, decreased serum
aminotransferases and improved glycolipid
metabolism [72]

Its consumption is
recommended

PUFAs: polyunsaturated fats; MS: metabolic syndrome; T2D: type 2 diabetes; WELCOME: Wessex evaluation
of fatty liver and cardiovascular markers in NAFLD with Omacor therapy; DHA: docosahexaenoic acid; HCC:
hepatocellular carcinoma; NAFLD: non-alcoholic fatty liver disease; MD: Mediterranean diet.

4.4. Others

4.4.1. Probiotics

Probiotics are bacteria or yeast of the habitual intestinal flora with the capacity of conferring a
health benefit on the host [9,71]. Gut microbiota have been implicated in different disorders including
metabolic diseases. Bifidobacterium and Lactobacillus strains are the most commonly used bacteria
exhibiting probiotic properties. An increase in Firmicutes and a decrease in Bacteroidetes has been
described in obesity [79].

There has been increasing interest in searching whether people with NAFLD have a dysfunctional
microbiome that may promote the NAFLD progression. Intestinal bacteria may be involved in
NAFLD by enhancing intestinal permeability, the direct activation of inflammatory cytokines via the
release of lipopolysaccharide (LPS), favoring absorption of endotoxins, producing endogenous ethanol,
and affecting dietary choline and bile acid metabolism [9,73].

Probiotics communicate with the host immune system through intestinal cell pattern recognition
receptors [73,80]. Inefficient antigen presentation and the continuous presence of endotoxin might
induce the activation of the innate immune system resulting in chronic subclinical inflammation [9].
In a healthy individual, these bacterial products are rapidly cleared by the hepatic immune system,
but in an injured liver, they can result in the release of reactive oxygen metabolites, proteases and
other degenerative enzymes, which worsen the liver damage [81]. Dysbiosis in the gut microbiota
may prompt the hepatic de novo lipogenesis by increasing the expression of lipogenic enzymes [11].
Moreover, elevated LPS levels have been documented in NAFLD [11,71]. Gut-derived LPS may cross
intestine tight junctions inducing liver injury through Kupffer cell activation thus contributing to
the onset of liver fibrosis [9,73]. Furthermore, gut microbiota could contribute to producing higher
endogenous blood ethanol concentration [9]. Additionally, bile acids are regulators of hepatic lipid
and the glucose metabolism and have a strong bactericidal action due to their effect on the bacterial
cell membrane phospholipids. The bile acids metabolism can be altered by microbiota and fat-rich
diets, contributing to the pathogenesis of NAFLD [9].

Aller et al. [82] investigated the impact of probiotic supplementation in 28 NAFLD adult patients.
The probiotic intervention was comprised of 500 million colonies of Lactobacillus bulgaricus and
Streptococcus thermophiles daily for three months. Therapy was associated with a significant reduction
in liver enzymes vs. placebo. No significant changes in anthropometrics or cardiovascular risk factors
were found between groups. Similarly, a 6-month probiotics trial [83] (Lactobacillus and Bifidobacterium
supplementation) in 10 biopsy-proven NASH patients vs. 10 controls resulted in significantly lower
intrahepatic triglyceride (measured by H1 MRS) and AST levels independently of the BMI, waist
circumference, glucose or lipid levels. A further trial (n = 52 NAFLD patients) [84] receiving the same

Nutrients 2019, 11, 677 12 of 25

supplementation for 6 months denoted a reduction in the ALT, AST, GGT, inflammatory markers and
liver stiffness assessed by transient elastography vs. placebo.

Vajro et al. [85] examined 22 obese children noncompliant with lifestyle interventions who
received either probiotic Lactobacillus rhamnosus strain GG (12 billion CFU/day) vs. placebo
for 8 weeks. A significant decrease in ALT and in antipeptidoglycan-polysaccharide antibodies
irrespective of changes in BMI and visceral fat was observed. In parallel, Malaguarnera et al. [86]
evaluated the effects of Bifidobacterium longum with fructooligosaccharides and lifestyle modification
vs. lifestyle modification alone in 66 patients with biopsy-proven NASH. Probiotic supplementation
and lifestyle modification, when compared to lifestyle modification alone, significantly reduced TNF-α,
CRP (C reactive protein), AST, HOMA-IR, serum endotoxin, steatosis and the NASH activity index.
A 2013 meta-analysis [73] including 4 randomized trials (n = 134) suggested that probiotics can reduce
insulin resistance, liver aminotransferases, total-cholesterol and TNF-α. However, the use of probiotics
was not associated with changes in BMI, glucose and LDL-cholesterol. A review in human randomized
clinical trials [71] evaluated the effects of probiotics and synbiotics on obesity, T2D and NAFLD.
The beneficial effects of some probiotics and synbiotics improved the liver function and metabolic
parameters in patients with NAFLD.

Limited studies have evaluated a probiotic intervention in NAFLD using probiotic food.
A randomized, double-blind, placebo-controlled clinical trial (n = 36 NAFLD patients) [87] showed
that consuming 300 g/day of probiotic yogurt with Lactobacillus acidophilus La5 and Bifidobacterium
lactis Bb12 for eight weeks reduced the hepatic aminotransferases, total and LDL-cholesterol compared
to patients consuming conventional yogurt. Another recent 24-week randomized controlled trial
(n = 102) [88], investigated the effects of synbiotic yogurt (containing 108 colony-forming units of
Bifidobacterium animalis/mL and 1.5 g inulin) on NAFLD. Synbiotic yogurt consumption improved
the hepatic steatosis (assessed by US) and liver enzyme concentrations. A recent meta-analysis [89]
including 1309 patients from 25 studies support the potential use of microbial therapies in the treatment
of NAFLD after demonstrating a significant reduction in BMI, liver enzymes, serum cholesterol and
triglycerides, however, no changes in inflammation have been reported, and whether these effects can
be sustained remains uncertain. Though, in an animal NAFLD/NASH model, probiotics have shown
to prevent liver fibrosis even in the absence of significant changes in inflammatory markers and in the
liver fat [90]. Currently, there is insufficient evidence to recommend its use, but given their good safety
profile (except in immunocompromised patients where a risk of fungemia has been described) and
that the described studies support their benefit, we can safely advise its use in NAFLD. Further trials
with clinically relevant liver related outcomes would be informative.

4.4.2. Coffee

Evidence-based on observational studies report an inverse association between caffeine intake and
NASH [91,92]. Coffee has antioxidant, anti-inflammatory and anti-fibrotic properties that could explain
this finding. In a cross-sectional study (n = 177) [93], liver biopsy was taken at the baseline and coffee
consumption was gathered prospectively for 6 months; a daily coffee consumption (>2 cups/day) was
associated with significantly lower odds of liver fibrosis. Similar results were seen two years later
in a NASH specific cohort (n = 306) [94]. In a further prospective study (n = 5147) [95], the coffee
consumption was recorded at the baseline and after 7 years in NAFLD patients. Those who drank more
coffee (>3/day) had a lower fibrosis score. A 2013 systematic review [92] assessed the liver effects of
coffee, showing that its consumption was associated with improved serum GGT, AST and ALT values
in a dose-dependent manner. Additionally, coffee consumption was inversely related to the severity
of NASH. Moreover, coffee consumption could reduce the risk of developing hepatocellular carcinoma
in a 63,257 person cohort [96]. Individuals who consumed 3 or more cups/day experienced a 44% risk
reduction of developing hepatocellular carcinoma. Prospective studies are needed to confirm these
effects and determine the exact dose capable of inducing histological changes.

Nutrients 2019, 11, 677 13 of 25

4.4.3. Resveratrol

Resveratrol is a dietary antioxidant found in red wine. Nineteen patients were enrolled in a
4-week double-blind randomized study comparing resveratrol (10 mg/day) vs. the placebo [97].
Resveratrol appears to improve insulin sensitivity and oxidative stress. Their effect on a more efficient
insulin signaling via the Akt pathway might be a positive influence against liver steatosis. These
interventions remain of theoretical interest until well-conducted prospective data and larger clinical
trials are available.

4.4.4. Alcohol

A cross-sectional analysis of 251 NAFLD lifetime non-drinkers vs. 331 NAFLD modest
drinkers (≤2 drinks/day) found that modest drinkers had lower odds of having NASH, fibrosis
or ballooning [98]. Similarly, alcohol consumption was analyzed in 77 biopsy-proven NAFLD patients,
some degree of regular alcohol consumption over one’s lifetime vs. the minimal intake appears to
have a protective effect on the histological severity [99]. These findings demonstrate the need for
prospective studies to establish alcohol consumption recommendations in NAFLD.

4.4.5. Choline

Choline is an essential nutrient found in egg yolks and animal protein [9]. Choline is a
phospholipid component of cell membranes that help in assembling VLDL and lipid transport from
the liver. Choline’s dietary requirement is modulated by the estrogen status and by genetic variations
in specific genes of choline and folate metabolism [9,100]. A Choline deficiency might genetically
induce NAFLD by inducing irregular phospholipid synthesis, lipoprotein secretion flaws and oxidative
damage due to mitochondrial dysfunction [16]. Human studies are needed to clarify its therapeutic
effect in NAFLD.

The different studies evaluating the effect of macronutrient composition in patients with NAFLD
are summarized in Table 3.

Table 3. The published systematic reviews, meta-analysis, human clinical trials and cross-sectional
analysis using a liver biopsy to evaluate the effect of macronutrient composition in NAFLD.

SATURATED FATS

Author, Year Study Design n Intervention
Time of

Intervention
Results

Mozaffarian et
al., 2010 [22]

A Systematic Review
and Meta-Analysis
of 8 randomized
controlled trials

13,614 participants

Evaluate studies with
increased PUFA
consumption as a
replacement for SFA and
report the incidence of
myocardial infarction
and/or cardiac death

1–8 years

Consuming PUFAs in place of SFA
reduces the occurrence of coronary
heart disease events by 19%,
corresponding to a 10% reduced
coronary heart disease risk (RR = 0.90,
95% CI = 0.83–0.97) for every 5% energy
increase of PUFAs

MONOUNSATURATED FATS

Schwingshackl
et al., 2011 [26]

A Systematic Review
and Meta-Analysis
of 9 randomized
controlled
intervention trials

1547 patients with
an abnormal
glucose
metabolism and
being overweight
or obese

Evaluate the effects of diets
high in MUFAs vs. diets low
in MUFAs in glycemic
control of T2D

6–48 months

An improvement in Hb1Ac (weighted
mean difference–0.21%, 95% CI −0.40
to −0.02; p = 0.03) was evidenced but
without improvement in fasting plasma
glucose or HOMA-IR. MUFAs
consumption should be recommended
in T2D

POLYUNSATURATED OMEGA-3 FATS

Toshimitsu et al.,
2007 [38]

Applied nutritional
investigation

46 patients (28 with
biopsy-proven
NASH vs. 18 with
simple steatosis)

Dietary habits and nutrients
intake were analyzed
through detailed
questioning by physicians
and dieticians

3 consecutive
days

A higher intake of simple
carbohydrates and lower intake of
protein, PUFAs and zinc

Nutrients 2019, 11, 677 14 of 25

Table 3. Cont.

SATURATED FATS
Author, Year Study Design n Intervention
Time of
Intervention
Results

Hartweg et al.,
2009 [34]

A Systematic Review
of 23 randomized
controlled
intervention trials

1075 T2D patients
with
cardiovascular risk
factors

Effect of omega-3 PUFAs
supplementation on NAFLD
(mean dose: 3.5 g/day;
mean treatment duration:
8.9 weeks)

4 weeks–8
months

Improved triglyceride (lowered by 0.45
mmol/L (95% CI −0.58 to 0.32, p < 0.00001)) and VLDL cholesterol (lowered by −0.07 mmol/L (95% CI −0.13 to 0.00, p = 0.04)). May raise LDL cholesterol (non-significant in subgroups). No statistically significant effect on body weight, glycemic control, fasting insulin, total or HDL-cholesterol

Parker et al.,
2012 [41]

A Systematic Review
and Meta-Analysis
of 9 randomized
controlled
intervention trials

355 patients given
either omega-3
PUFAs or the
control treatment
were included

Effect of omega-3 PUFAs
supplementation on NAFLD
(median dose: 4 g/day
(range: 0.8–13.7 g/day);
median treatment duration:
6 months)

8 weeks–12
months

Improvement in liver fat (−0.97, 95% CI
−0.58 to −1.35, p < 0.001) and in AST levels (−0.97, 95% CI −0.13 to −1.82, p = 0.02), however, substantial heterogeneity was found and an optimal dose was not clarified

Sanyal et al.,
2014 [44]

Phase 2b multicenter,
double-blinded,
randomized,
placebo-controlled
trial

243 patients with
NASH and
NAFLD activity
scores >4 (75
receives placebo,
82 low-dosage EA
(1800 mg/d), 86
high-dosage EA
(2700 mg/d)).

Liver biopsies were
collected 2 weeks after the
last dose. The primary
efficacy endpoint was NAS
<3, without worsening of fibrosis; or a decrease in NAS by >2 without the
worsening of fibrosis

12 months

No significant histological effects or
blood markers improvement. However,
with 2.7 g of EA, reduced levels of
triglyceride were observed (−6.5
mg/dL vs. an increase of 12 mg/dL in
the placebo group; p = 0.03)

Nogueira et al.,
2016 [46]

Randomized
controlled trial

50 patients with
biopsy-proven
NASH (23 received
placebo (mineral
oil), 27 received
omega-3 PUFAs
(flaxseed oil and
fish oil)).

Liver biopsies, plasma
biochemical markers of lipid
metabolism, inflammation,
liver function and plasma
levels of omega-3 PUFAs
were assessed as a marker of
intake at the baseline and
after 6 months of treatment

6 months

No histological improvement was seen
after a six-month use of flaxseed oil and
fish oil despite ALA, EA and
triglycerides levels significantly
improved. NAS improvement was
correlated with increased PUFAs
plasma levels

FRUCTOSE

Abdelmalek et
al., 2010 [66]

Cross-sectional study
427 NAFLD
patients

Block food questionnaire
data were collected within 3
months of a liver biopsy

3 months

Daily fructose ingestion from fruit juice
and soft drinks is associated with lower
steatosis grade and higher fibrosis stage.
In patients >48 years, an association
with hepatic inflammation and
ballooning was found (p < 0.05)

DIETARY FIBER

Daubioul et al.,
2005 [78]

Randomized,
double-blinded,
crossover study

7 patients with
biopsy-proven
NASH

Daily ingestion of 16 g of
oligofructose or
maltodextrin (placebo)

8 weeks
Daily oligofructose ingestion decreases
serum aminotransferases and improves
insulin levels

PROBIOTICS

Malaguarnera et
al., 2011 [86]

Randomized
controlled trial

66 patients with
biopsy-proven
NASH (33 patients
received
Bifidobacterium
longum with
fructooligosaccharides
and lifestyle
modification vs. 33
with lifestyle
modification alone)

Analytic assessment at 0, 6,
12, 18, and 24 weeks. Liver
biopsies were performed at
entry and repeated after 24
weeks of treatment

24 weeks

Bifidobacterium longum with
fructooligosaccharides and lifestyle
modification when compared to
lifestyle modification alone,
significantly reduces TNF-α, CRP,
serum AST levels, HOMA-IR, serum
endotoxin, steatosis, and the NASH
activity index (p ≤ 0.05)

Maet al.,
2013 [73]

Meta-Analysis of 4
randomized
controlled trials

134 patients

Assess the efficacy of
probiotic therapies in
modifying liver function, fat
metabolism and insulin
resistance

8 weeks–6
months

Probiotics can reduce insulin resistance,
liver aminotransferases,
total-cholesterol and TNF-α. However,
the use of probiotics was not associated
with changes in BMI, glucose and
LDL-cholesterol

Loman et al.,
2018 [89]

Systematic Review
and Meta-Analysis
of 25 randomized
controlled trials

1309 patients with
NAFLD

Systemically review and
quantitatively synthesize
evidence on prebiotic,
probiotic, and synbiotic
therapies for NAFLD

1.5–4.3 months

Reduction in BMI (0.37 kg/m2; 95%CI:
0.46 to 0.28; p < 0.001), liver enzymes (ALT, 6.9 U/L (95%CI: 9.4 to 4.3); AST, 4.6 U/L (95%CI: 6.6 to 2.7); GGT, 7.9 U/L (95%CI: 11.4 to 4.4); p < 0.001), serum cholesterol (10.1 mg/dL 95%CI: 13.6 to 6.6; p < 0.001), serum cholesterol LDL-c (4.5 mg/dL; 95%CI: 8.9 to 0.17; p < 0.001) and triglycerides (10.1 mg/dL; 95%CI: 18.0 to 2.3; p < 0.001), however, no changes in inflammation (TNF-α and CRP) were reported

Nutrients 2019, 11, 677 15 of 25

Table 3. Cont.
SATURATED FATS
Author, Year Study Design n Intervention
Time of
Intervention
Results

COFFEE

Saab et al.,
2014 [92]

Systematic review of
case-control or
cross-sectional
studies

2723 NAFLD
patients

Effects of coffee on liver
diseases

Coffee consumption was associated
with improved serum GGT, AST and
ALT values in a dose-dependent
manner. Coffee consumption was
inversely correlated to NASH severity

ALCOHOL

Dunn et al.,
2012 [98]

Cross-sectional
Analysis

582 biopsy-proven
NAFLD patients
(251 lifetime
non-drinkers vs.
331 modest
drinkers (≤2
drinks/day))

Evaluate the association
between modest alcohol
drinking (lifetime drinking
history questionnaire) and
NASH among subjects with
biopsy-proven NAFLD

Modest drinkers had lower odds of
having a diagnosis of NASH (summary
OR 0.56, 95%CI: 0.39–0.84, p = 0.002),
fibrosis (OR 0.56 95%CI: 0.41–0.77) or
ballooning (OR 0.66 95%CI 0.48–0.92)

Kwon et al.,
2013 [99]

Cross-sectional
Analysis

77 biopsy-proven
NAFLD patients

Determine alcohol
consumption effect (lifetime
alcohol consumption
questionnaire) on NAFLD
histological severity

Some degree of regular alcohol
consumption (≥24 gram-years) vs.
minimal intake appears to have a
protective effect on NAFLD histological
severity (OR 0.26, 95%CI: 0.07–0.97, p =
0.04)

PUFAs: polyunsaturated fats; SFA: saturated fats; RR: risk ratio; MUFAs: monounsaturated fats; T2D: type 2 diabetes;
HOMA-IR: homeostatic model assessment of insulin resistance; NAFLD: non-alcoholic fatty liver disease; NASH:
non-alcoholic steatohepatitis; AST: aspartate aminotransferase; NAS: NAFLD activity score; EA: eicosapentaenoic
acid; ALA: alpha-linolenic; TNF-α: alpha tumor necrosis factor; CRP: C reactive protein; BMI: body mass index;
ALT: alanine aminotransferase; GGT: gamma-glutamyl transferase; OR: odds ratio.

5. Dietary Patterns

Dietary patterns are based on regular food consumption and take into account interactions
between diverse nutrients. The Western dietary pattern, which usually combines high saturated fats
and fructose intake, has been implicated in the development of NAFLD [101]. In 2013, 995 adolescents’
dietary patterns were analyzed using factor analysis [102]. The Western dietary pattern was associated
with an increased risk of NAFLD, particularly in obese adolescents. A low-calorie diet is necessary to
accomplish weight loss (<1500 kcal/day) [103]. The most studied protective dietary pattern in NAFLD is the MD [24].

5.1. Mediterranean Diet

Since the 1960s, observations have evidenced lower mortality from cardiovascular disease in
countries of the Mediterranean region vs. Northern European populations or the United States of
America [1,45,104]. The MD is a dietary pattern originally inspired by their traditional lifestyle,
characterized by a high consumption of plant-based foods (whole grains, cereals, seeds, nuts, legumes,
vegetables and fruits), moderate consumption of protein-source foods (fish, seafood, and poultry),
low to moderate red wine consumption, low consumption of meat, milk and dairy products and
usually associated with an optimal physical activity. The MD predominantly contains MUFAs from
olive oil, a greater ratio of omega-3/omega-6 PUFAs, polyphenols, carotenoids and high-fiber foods.

Patients with metabolic syndrome under the MD have shown an improvement in insulin
resistance and inflammatory markers (CRP, IL-6, IL-7 and IL-18) [105]. A 2013 Cochrane systematic
review [106] including 11 randomized trials (n = 52,044) concluded that the MD may modulate
important cardiovascular risk factors (total cholesterol and LDL-cholesterol reduction). In terms of
T2D primary prevention, the PREDIMED randomized controlled trial [107] has demonstrated a relative
risk reduction among subjects with a high cardiovascular risk, treated with MD + extra virgin olive
oil vs. MD + nuts or low-fat diet without energy restrictions. In T2D, a 12-week trial (n = 27) with a
cross-over intervention of MD vs. regular diet favored MD due to the lower HbA1C, saturated and
trans fatty acids plasma levels [108].

Although it is likely that these data may be extrapolated to people with NAFLD, randomized
trials examining the MD histologic liver effect are limited. In NAFLD, MD has shown to reduce

Nutrients 2019, 11, 677 16 of 25

hepatic fat and improve hepatic insulin sensitivity independent of exercise and weight loss [24]. In a
Hong Kong-Chinese population (n = 797), a higher consumption of vegetables, legumes and fruits
was associated with a reduced likelihood of having NAFLD [109]. Trovato et al. [110] evidenced a
significant reduction in liver fat (assessed by US) and HOMA-IR in a single arm MD 6-month trial
(n = 90 overweight, non-diabetic patients). The effect of MD was independent of other lifestyle changes.
Kontogianni et al. [111] (n = 73) found that greater adherence to the MD was significantly correlated
with a lower degree of insulin resistance, ALT and NAFLD severity. Similarly, Aller et al. [112] explored
the potential associations between MD adherence and histological characteristics in 82 patients with
NAFLD. Greater adherence to the MD was associated with a lower likelihood of high-grade steatosis
and the presence of steatohepatitis. Trovato et al. [101] evidenced adherence to MD, HOMA-IR and
BMI as the most independent predictors of fatty liver severity in an observational study involving 532
NAFLD patients vs. 667 healthy controls. The positive effect on liver inflammation and fibrosis has
been tested only in a few observational studies and small population studies. Nevertheless, on 2015,
the European Association for the Study of the Liver (EASL), European Association for the Study of
Diabetes (EASD) and European Association for the Study of Obesity (EASO) recommended the MD
for NAFLD treatment based on this moderate quality evidence [1].

A randomized cross-over trial (12 NAFLD-biopsy-proven patients) [113] reported a reduction in
hepatic steatosis (measured by 1H MRS) and insulin resistance after following the MD, independently
of weight loss. Patients followed the MD during a 6-week crossover to a standard diet (low fat-high
carbohydrate) for the same period of time with a 6-week washout period in between. Recently,
a randomized controlled single-blinded clinical trial (n = 63) [114] investigated the liver effect of
MD vs. a Mediterranean lifestyle (exercising at least 30 min/day, optimal sleep duration and
mid-day rest) vs. controls. A Mediterranean lifestyle along with weight loss was better, showing
significant improvements in ALT levels and liver stiffness. In another recent randomized controlled
trial (n = 48) [115], steatosis (measured by MR) and cardio-metabolic risk factors were analyzed in
patients receiving an MD vs. low-fat diet for 12 weeks. Both diets improve hepatic steatosis to a
similar degree, however, the Framingham risk score, total cholesterol, serum triglyceride, and HbA1c
reduction was higher in the MD group with an additional higher adherence compared to a low-fat diet.

The MD may not be practical in some countries or subpopulations, still, recommending at least
some of its components may also be helpful. The MD was successfully applied to a multiethnic
Australian population demonstrating the possibility of translating key elements of the traditional
MD to populations outside the Mediterranean region [116]. Long-term trials including an optimal
nutritional analysis with liver-related outcomes are needed. Meanwhile, due to its high potential for
long-term sustainability and its capacity to prevent cardiovascular events or related diseases, it seems
prudent to recommend this dietary approach.

5.2. DASH Diet

The “Dietary Approach to Stop Hypertension” (DASH) diet is a dietary pattern similar to the
MD but with an emphasis on the low intake of sodium, total fat, saturated fat, cholesterol and added
sugars. Although this dietary pattern was primarily designed for hypertension, it has recently shown
beneficial effects on NAFLD [117,118], possibly because high blood pressure constitutes a significant
predictor for progressive fibrosis [119]. In 2016, a case-control study [117] in 102 patients with NAFLD
vs. 204 controls found an inverse association between the DASH diet score and the risk of developing
NAFLD. After adjusting for BMI and dyslipidemia, the significance of this relationship disappeared.
In the same year, a randomized controlled trial (n = 60 overweight NAFLD patients) [118] conducted
for 8 weeks demonstrated a significant reduction in body weight, serum triglyceride level, VLDL,
liver enzymes and a concurrent improvement in insulin sensitivity, oxidative stress and inflammation
biomarkers in the DASH diet group vs. controls who received a calorie-restricted diet. A higher
calcium and magnesium intake characterized the DASH diet and may have beneficial effects on
insulin sensitivity by decreasing the oxidative activity and restoring anti-oxidative enzymes [120].

Nutrients 2019, 11, 677 17 of 25

More studies are required to determine the features of the DASH diet that are associated with the
greatest benefits in patients with NAFLD.

5.3. Low Carbohydrate Diet

Low-CHO diets have become a common strategy for weight management and
metabolic-syndrome-related conditions. Low-carbohydrate (60–150 g/day) and very low-carbohydrate
diets (<60 g) are popular diets known for their short-term (less than 2 weeks) weight loss capacity. Some low-carbohydrate diets (e.g., Atkins diet) limit the carbohydrate intake to 20 g/day but allow unrestricted amounts of fat and protein. When the carbohydrate intake is <50 g/day, ketosis will develop from glycogenolysis.

In 2003, a one-year multicenter controlled trial (n = 63 obese patients) [121] randomly
assigned patients to either a low-carbohydrate, high-protein and high-fat diet vs. a low-calorie,
high-carbohydrate and low-fat diet. A greater weight loss at six months was evidenced in the
low-carbohydrate diet, nevertheless, this difference was not significant at 12 months. Furthermore,
the low-carbohydrate diet was associated with a greater improvement in HDL-cholesterol and
triglyceride concentrations. Moreover, five biopsy-proven NAFLD patients went through a six-month
low-CHO ketogenic diet (<20 g/day) that significantly improved histologic steatosis, inflammation and fibrosis [122]. However, these results are inconclusive due to the possibility that this improvement may be due to weight loss.

In 2009, 22 obese patients received a calorie-restricted diet (1100 kcal/day) for 3 months, one group
had a low-CHO content (<50 g/day) and the other group had a high-CHO content (>180 g/day) [123].
The decrease of intrahepatic triglyceride (measured by H1 MRS) was similar in both groups. A similar
study was performed in 2010; 162 obese patients were randomized in a low-fat diet vs. a low-CHO
diet for 3 months, both diets showed an improvement in anthropometric measurements (BMI, weight,
fat mass), cardiovascular risk factors (blood pressure, HOMA-IR, triglyceride, LDL and total cholesterol
levels) and liver enzymes (ALT, AST, GGT) [124]. Later on, a six-month trial [125] of either low-CHO
or low-fat diet in 170 overweight patients showed the same effect on intrahepatic lipid accumulation
(assessed by MR), independent of visceral fat loss and changes in insulin sensitivity. On 2016,
a meta-analysis including twenty clinical trials (n = 1073) [126] supports that both low/moderate fat
(≤30% of daily calorie intake) and moderate CHO (≤45% of daily calorie intake) diets have a similar
beneficial effect on liver function.

Despite the popularity and the weight loss observed with low-carbohydrate, high-protein,
high-fat diet (Atkins), and a poor long-term adherence are perceived. A meta-analysis of five trials
(n = 447) [127] found that low-carbohydrate diets and low-fat diets are both capable of inducing
weight loss for a duration of up to 12 months. However, low-carbohydrate diets are associated with
unfavorable changes in total cholesterol and LDL-Cholesterol. They concluded that in the absence
of cardiovascular morbidity and mortality, such diets currently cannot be recommended for the
prevention of cardiovascular disease. A prospective cohort from the Nurses’ Health Study and Health
Professionals’ Follow-up Study [128] examined the mortality of low-carbohydrate diets during 26 years
of follow-ups. A low-carbohydrate diet based on animal protein and fat was associated with higher
all-cause mortality. Low CHO diet has been associated with electrolyte disturbance, hypotension and
cholelithiasis [103,129]. A very low-carbohydrate diet should not be recommended if they are not
supervised by qualified medical personnel. Thus far, the available evidence supports calorie-restricted
diets independently its CHO amount. Long-term and larger studies comparing low-CHO and low-fat
diets are needed in patients with NAFLD/NASH, and most important, to evaluate long-term safety
and efficacy.

6. Conclusions and Future Perspectives

Lifestyle modifications towards a healthy diet and habitual physical activity are desirable in
NAFLD. A 7–10% weight loss and its sustainability is the goal in NAFLD patients. Reduced calorie

Nutrients 2019, 11, 677 18 of 25

intake, improved macronutrient composition and increased physical activity may act independently to
stop disease progression. Dietary adherence is an important determinant of weight loss sustainability.
Therefore, it is essential to provide high-quality and practical highlights of dietary interventions
for NAFLD. High consumption of CHO, simple sugars, saturated fats, trans fat, animal protein
(red meat), and processed food, and a low fiber intake are associated with NAFLD development.
Dietary recommendations should consider energy restrictions and the macronutrient composition
should be adjusted according to the MD. However, choosing a customized diet with a macronutrient
composition according to an individual’s taste may accomplish better compliance. The CHO intake
should be oriented towards a high preference for whole grains and low glycemic index foods. The fat
intake should aim at a high MUFAs and omega-3 PUFAs consumption. The protein intake should
favor vegetable protein consumption. Prebiotic fiber intake and probiotic enriched yogurt must
be recommended to promote a reduced calorie intake and a favorable microbiota, respectively.
However, the available evidence for dietary interventions is derived mostly from observational studies.
To provide strong evidence for lifestyle interventions in NAFLD patients, longer duration trials of
standardized dietary interventions evaluating the effect on fibrosis are needed. Moreover, regarding
future perspectives, for the nutritional field, it would be important to try to find mechanistic clues.
In this context, more insight into the effect of diverse dietary patterns on adipokines and hepatokines
should be performed. Noteworthy is that leptin [130], fibroblasts growth factors [131], serum amyloid
A [132] and caveoli [133], among others, have been shown to be elevated in obesity and T2D underlying
the characteristic low-grade chronic inflammation and decrease following weight loss.

Author Contributions: All authors contributed to the preparation of this review and approved the text.

Funding: This research received no external funding.

Acknowledgments: All sources of funding of the study should be disclosed. Please clearly indicate grants that
you have received in support of your research work. Clearly state if you received funds for covering the costs to
publish in open access.

Conflicts of Interest: The authors declare no conflict of interest.

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    • Introduction
    • Pathophysiology
    • Lifestyle Intervention

    • Diet Composition Focusing on Macronutrients
    • Fats
      Saturated Fats
      Monounsaturated Fats
      Polyunsaturated Fats
      Trans-Fats
      Protein
      Carbohydrates
      Fructose
      Dietary Fiber
      Others
      Probiotics
      Coffee
      Resveratrol
      Alcohol
      Choline

    • Dietary Patterns
    • Mediterranean Diet
      DASH Diet
      Low Carbohydrate Diet

    • Conclusions and Future Perspectives
    • References

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