2021

REVERSING FATTY LIVER DISEASE

WITH HEALTHY LIFESTYLE

1
Authors: Massimiliano Ruscica, Paola Dongiovanni,
Leen Heyens, Geert Robaeys
 Affiliations of the authors:

Massimiliano Ruscica1
Paola Dongiovanni2
Leen Heyens3-5
Geert Robaeys3,5,6

1
Università degli studi di Milano, Department of Pharmacological and Biomolecular Sciences, Milan, Italy
2
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,
Milan, Italy
3
Hasselt University, Faculty of Health and Life Sciences, Diepenbeek, Belgium
4
Maastricht University, School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht, the
Netherlands
5
Ziekenhuis Oost-Limburg, Department of Gastro-enterology and Hepatology, Genk, Belgium
6
University Hospital KU Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium

Editor:

Stephanie De Vriese7

7
Secretary of Alpro Foundation

This review is fully supported by the Scientific Advisory Committee of the Alpro Foundation:
Harry Aiking (VU University Amsterdam); Anna Arnoldi (University Milano);
Peter Clarys (Vrije Universiteit Brussel); Christine Debeuf (Alpro); Stephanie De Vriese (Alpro);
Helmut Heseker (University Paderborn); Sander Kersten (University Wageningen);
Ian Rowland (University Reading); Cesare Sirtori (University Milano);
and Kurt Widhalm (University Vienna)

Date: June 2021

CONTENT

Introduction .............................................................................................................................................................................. 4
Genetic and environmental factors associated with NAFLD......................................................................................... 6
Primary therapeutic advice: lifestyle changes emphasizing weight reduction........................................................ 7
Mediterranean diet ............................................................................................................................................................................... 9
Role of plant protein .......................................................................................................................................................................... 10
The role of gut microbiome ..............................................................................................................................................................11
Other treatment options .....................................................................................................................................................................11
NAFLD and childhood ........................................................................................................................................................... 12
Conclusion ............................................................................................................................................................................... 12
References ............................................................................................................................................................................... 13
INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is
considered the most frequent cause of liver
disorders with a prevalence above 30% in many
adult populations. 1,2
The highest prevalence is
reported in the Middle East (32%) and South
America (31%), followed by Asia (27%), USA (24%)
and Europe (23%), with the lowest in Africa (14%).
Because of its close association with metabolic
syndrome (MetS), NAFLD is seen in 47.3–63.7% of
people with type 2 diabetes (T2DM) and up to 80%
of people with obesity. However, some people
with a healthy body mass index (BMI) can still
develop NAFLD, often described as non-obese or
lean NAFLD. These patients usually have central
obesity or other metabolic risk factors.3 Patients
with NAFLD have 2.5 times higher incidence of
cardiovascular disease (CVD).

FIGURE 1. THE NATURAL EVOLUTION OF NAFLD OR METABOLIC ASSOCIATED FATTY LIVER DISEASE (MAFLD).

The mechanisms underlying NAFLD pathogenesis are multifactorial. Histologically, NAFLD encompasses a continuum including steatosis
with or without mild inflammation (NAFL), NASH with/without fibrosis, cirrhosis, and hepatocellular carcinoma. Equally, environment, gut
microbiota, genetics, and epigenetics influence the disease onset and progression. The first step in NAFLD development is hepatic fat
infiltration, mainly due to IR. This leads to a rise in the adipose tissue lipolysis with the consequent efflux of free fatty acids to the liver. The
compensatory hyperinsulinemia exacerbates fat accumulation. Excess fat is cleared from the liver by an enhanced lipoprotein secretion
and mitochondrial β-oxidation. The latter results in increased reactive oxygen species production leading to the activation of inflammatory
pathways.

Abbreviations: IR, insulin resistance; MAFLD, metabolic associated fatty liver disease; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic
fatty liver disease; NASH, non-alcoholic steatohepatitis.
Adapted from: Dongiovanni P et al. 2021 and Heyens LJM et al. 2021. 68,69

4
As proposed by Shaffner and Thaler in 1986, NAFLD4
is an "umbrella" definition encompassing a
spectrum of histological liver changes, namely
steatosis (affecting at least 5% of hepatocytes), non-
alcoholic steatohepatitis (NASH) with/without
fibrosis, cirrhosis, and hepatocellular carcinoma
(figure 1).5 About 20% of patients with NAFLD will
develop NASH in three to seven years , which is
6
considered the potentially progressive form of the
disease.7 About 9 to 25% of individuals with NASH
develop cirrhosis over a 10 to 20 year period. The
8
imbalance between hepatic synthesis and uptake
of fatty acids and their oxidation and efflux plays a
key role in the pathogenesis of NAFLD, mainly due
to a condition of insulin resistance (IR) associated
with obesity or diabetes.9
The term NAFLD was first described in 1980 as a10
absence of other liver diseases, e.g., viral hepatitis B
and hepatitis C, alcohol intake or autoimmune
disease. Furthermore, the current threshold on
alcohol intake (2 drinks for women and 3 for men or
20g/day – 30g/day) has been a constant topic of
debate.11-13 The term NAFLD could also represent an
element of confusion since the use of words such
as “non” and “alcoholic” is disliked by patients
leading to a fear of stigma.14
Consequently, the diagnosis of the disease should
thus be based on the presence of metabolic
dysfunction, not the absence of other conditions.15
Therefore, in 2020 a milestone decision was
reached by an international panel of experts, that
recommended a name change to “metabolic
associated fatty liver disease (MAFLD)”.

condition of ‘exclusion’ since it exists only in the

To meet the diagnosis of MAFLD in adults, patients require the presence of hepatic steatosis as assessed
by either imaging or blood markers/scores indicative of fat accumulation or histology.

This feature must be accompanied by one of the following phenotypes:

• overweight or obesity (BMI ≥ 25 Kg/m2 in Caucasians and ≥ 23 Kg/m2 in Asians)

• diagnosis of T2DM
• lean or normal weight with signs of metabolic dysregulation 15,16

If you view this diagnosis in terms of concrete metabolic risk biomarkers, at least two or more of the
following conditions must be present:

• enlarged waist circumference (≥ 102/88 cm in Caucasian men and women)

• raised blood pressure (BP, ≥ 130/85 mmHg) or specific drug treatment
• raised triglycerides (TG, ≥ 150 mg/dL) or specific drug treatment
• low high-density lipoprotein (HDL) cholesterol (< 40 mg/dL for men and < 50 mg/dL for
women) or specific drug treatment
• prediabetes (as assessed by fasting plasma glucose levels, 2-hour post-load glucose levels or
haemoglobin A1c (HbA1c))
• homeostatic model assessment of insulin resistance (HOMA-IR) score ≥ 2.5
• inflammation with raised levels of high-sensitivity C-reactive protein (hs-CRP, > 2 mg/L)

5
In spite of the mounting interest in the MAFLD
definition, words of caution have also been
expressed by a distinguished group of US experts
on the possible consequences of a premature
change in NAFLD terminology. Further research is
17
GENETIC AND ENVIRONMENTAL
FACTORS ASSOCIATED WITH NAFLD
The development of NAFLD is strongly linked to
obesity and IR. However not all obese individuals
nor patients with diabetes develop NAFLD and vice
versa. NAFLD can occur in normal-weight
individuals with normal glucose and lipid levels.18
Thus, there are clearly multiple genetic and
environmental factors determining NAFLD
development and progression (figure 2).
The genetic associations with NAFLD severity are
beyond the scope of this expert opinion. Yet,
genetic predisposition must be placed in the
context of dietary habits and physical activity
which play an important role in the development of
NAFLD.
NAFLD's leading cause has been defined as a
multi-factorial behavioural phenotype that
consists of sedentary behaviour and poor diet.19
Excess food intake and lack of exercise contribute
to the development/progression of NAFLD via
overweight and obesity and the induction of
specific inflammatory pathways. 20
High intake of
low-nutrient, high-sodium and high-fat foods, and
required to better understand the risk of disease
progression among “lean” NAFLD individuals
without any metabolic dysregulation. Hence, we
will focus on NAFLD in this expert opinion.
overnutrition appear to contribute to chronic low-
grade inflammation.20-22 Moreover, diet can also
negatively affect the immune system and the gut
microbiota.23 The high salt content present in a
typical Western diet can induce interleukin 17 (IL-17)
producing T-helper cells and inflammation. Low
intakes of polyunsaturated fatty acid (PUFA) and
high intakes of saturated fat and cholesterol were
also shown to be associated with NAFLD. Fatty acids
directly affect immune cells by activating toll-like
receptors and cytokine cascades and influencing
intestinal permeability.20,24 Dietary consumption of
phosphatidylcholine and L-carnitine has been
associated with the generation of specific
metabolites and future CVD events. 25
Not only
excessive calorie consumption, but also how food
consumption is distributed throughout the day,
affects fat accumulation in the liver.19 High
carbohydrate intake, especially in soft drink
beverages, is associated with alterations in the gut
microbiota, increased intestinal permeability, and
lipid peroxidation thereby promoting fatty liver
disease.19,21
6
FIGURE 2. EFFECT OF ENVIRONMENTAL AND GENETIC FACTORS ON NAFLD DEVELOPMENT AND PROGRESSION,
DIRECTLY AND INDIRECTLY VIA COMORBIDITIES.

Solid lines show how comorbidities (obesity, IR, hyperlipidaemia and inflammation) affect the development and progression of NAFLD,
together with environmental and genetic factors. Dashed lines indicate how environmental and genetic factors affect the development of
comorbidities.

Abbreviations: NAFLD, non-alcoholic fatty liver disease.

Adapted from: Moore JB, 2010.18

PRIMARY THERAPEUTIC ADVICE:

LIFESTYLE CHANGES EMPHASIZING WEIGHT REDUCTION

To date, the primary therapeutic advice for NAFLD
is a lifestyle intervention focused on diet, physical
activity, and behaviour modification to attain a
7-10% weight reduction, that may lead to a
significant improvement in liver histology in NASH
patients (step 1 - figure 3).
Previous studies have indicated that a weight
reduction of more than ten percent can induce the
resolution of NASH and improve fibrosis by at least
one stage.19,26 Even a modest weight reduction of
five percent can improve the intrahepatic TG
content and reduce steatosis (figure 4).19,27
Unfortunately, it is often challenging for an NAFLD
patient to make and maintain these lifestyle
changes without the appropriate motivation and
background knowledge concerning their disease.

7
FIGURE 3. SCHEMATIC OVERVIEW OF THE DIFFERENT STEPS IN THE TREATMENT OF NON-ALCOHOLIC FATTY
LIVER DISEASE.

First step in the management of NAFLD patients is to achieve a weight reduction of 7-10% BW by means of lifestyle changes. Secondly, in
individuals with BMI > 35 Kg/m2 who do not reach the weight loss goal, medication or bariatric surgery, as a last resort, are advisable.

Abbreviations: BMI, body mass index; CVD, cardiovascular disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; NAFLD, non-alcoholic
fatty liver; OCA, obeticholic acid; SGLT-2, sodium-glucose cotransporter-2.
Adapted from: Polyzos et al. 2019 and Mundi et al. 2020.28,29

Remission of steatosis can be achieved by weight These macronutrients usually characterize the
reduction through different diets, such as calorie Western dietary pattern.
restriction or an isocaloric Mediterranean diet Conversely a plant-based diets typically high in
(which induces metabolic and anti-inflammatory fibre, with lower caloric density, lower saturated fat,
benefits), as indicated by several clinical trials.27,32-34 beneficial fatty acid composition (higher in
The evidence that certain foods and nutrients unsaturated fats) and anti-inflammatory
prevent the progression of liver cancer is currently compounds, has been associated with a reduced
derived only from large observational studies and risk of NAFLD.30 Researchers have also investigated
needs further confirmation.19 General functional food bioactives (omega 3 fatty acids,
recommendations encourage a reduced intake of polyphenols, vitamin E and D), whose consumption
saturated fatty acids, trans fatty acids, and fructose. may protect against NAFLD.31

8
FIGURE 4. IMPACT OF LIFESTYLE MODIFICATIONS ON HISTOLOGICAL FEAUTURES IN OVERWEIGHT/OBESE
NAFLD PATIENTS.

Lifestyle intervention includes a hypocaloric (low carbohydrate) diet, combined with exercise. A dose-response relationship is evident
between weight loss % and overall histological improvements, with the greatest reduction observed in those with the greatest weight loss.
Weight reductions of >10% are required for inducing NASH resolution (reaching 90% of patients who achieved this weight reduction) or
improving fibrosis by at least one stage (81%). A more moderate weight loss of 5-7% is associated with a clinically meaningful regression of
disease status.

Abbreviations: NASH, non-alcoholic steatohepatitis; WL, weight loss.

Adapted from: Romero-Gomez M et al. 2017.19

MEDITERRANEAN DIET

The Mediterranean diet can reduce liver fat even
without weight loss and is the
recommended dietary pattern for NAFLD.
The diet is characterized by a reduced intake of
simple carbohydrates and an increased intake of
monounsaturated and omega-3 fatty acids.
consists of high consumption of olive oil, nuts, fruits,
vegetables, fish, and a low intake of red meat and
sweets. 19
This type of diet has been shown to
reduce the risk of CVD and diabetes.
Both outcomes are relevant to NAFLD patients.19
most Moreover, adherence to the Mediterranean diet in
T2DM patients has been shown to be a protective
factor for the absence of liver fibrosis in these
patients.35 For example, in a single-arm trial among
overweight patients with NAFLD, adherence to the
19
It Mediterranean diet led to a significant reduction in
liver fat.36 Giraldi et al. also indicated that a higher
vegetable and fish consumption was associated
with protective effects against NAFLD in a large
case-control study.37

9
ROLE OF PLANT PROTEIN low-calorie, low-carbohydrate soy diet, although
the protective effect was dependent on baseline
The Mediterranean diet can reduce liver fat even
weight.46 This latter diet also reduced ALT,
when iso-caloric and not leading to changes in
malondialdehyde and serum fibrinogen levels
body weight.38 This strengthens the hypothesis that
(markers of oxidative stress) in NAFLD patients.47
specific functional foods, characterized by
Genistein is a biologically active isoflavone
components with a clear activity on specific
extracted from soybean products and contained in
metabolic pathways, may provide benefit in the
several soy-based foods. Some studies have
management of the disease.
investigated the impact of genistein on NAFLD-
related MetS. Consuming 54 mg of genistein daily
Plant proteins deserve a special consideration:
for 1 year improved the HOMA-IR and led to
plant protein-enriched diets have become a
reductions in fasting glucose and insulin in
common strategy to improve weight
postmenopausal women with MetS. Genistein
management and increased intake has a potential
increased HDL-cholesterol and adiponectin and
role in the prevention of T2DM.39
reduced low-density lipoprotein (LDL) cholesterol
and TG levels.48 In a double-blind RCT, NAFLD
Among dietary approaches, soy proteins offer an
patients received either 250 mg genistein (n= 41) or
optimal choice. Soy foods are rich sources of
placebo (n= 41) daily for 8-weeks. Genistein
protein, polyunsaturated fat, fibre, vitamins and
improved IR, reduced inflammation by lowering
isoflavones (naturally occurring plant polyphenols)
tumour necrosis factor alpha (TNF-α) and interleukin
including genistein, daidzein and glycitein.
6 (IL-6) levels, and improved fat metabolism.49
In a large population-based cross-sectional study
According to a meta-analysis from 17 observational
on 23,529 participants, the higher dietary fibre
studies, consumption of soy foods has been
intake from whole grain, soy foods, vegetables
associated with a reduced risk of CVD, which is the
and nuts was associated with lower prevalence of
most common comorbidity in NAFLD.40
newly diagnosed NAFLD in men.50 This dietary
approach can also be of value in more advanced
Moreover, a systematic review and meta-analysis of
stages of disease. Comparing a 24-week lifestyle
randomized controlled trials (RCT) have reported
intervention program with a soy protein-based
that supplementation of soy isoflavones reduces
meal replacement therapy in NASH patients, both
arterial stiffness.41 Hypertension is one of the most
lifestyle changes or soy intervention showed similar
important risk factors of CVD, as well as a major
effects on weight loss and hepatic fat content, as
condition characterizing MetS. These trials have
well as in reducing markers of liver inflammation.51
shown that soy consumption improves systolic and
Overall, it appears that the protective effect of soy
diastolic BP in adults.42 The BP-lowering effect
against fatty liver accumulation is mediated by an
appears to be ascribable to soy isoflavones and
improvement of IR, a reduction in hepatic TG
peptides: genistein activates the endothelial nitric
synthesis and inflammatory milieu. At present,
oxide (NO) synthase (eNOS) and stimulates NO
availability of robust patient series with well
release, whereas bioactive peptides found in soy
characterized dietary intakes provides satisfactory
protein inhibit the angiotensin-converting enzyme
information on the differential positive responses to
activity and reduce vasoconstrictor responses.43
vegetable-enriched dietary approaches in patients
Soy drinks (240 ml/day), as a part of low-calorie diet
diagnosed with NAFLD or MAFLD. However, further
(500-deficit calorie diet), reduce serum alanine
larger-scale research is needed to fully clarify the
aminotransferase (ALT) and hs-CRP in patients with
efficacy of soy supplementation and better define
NAFLD.44 This approach has also shown to exert a
the impact of specific diets on NAFLD versus
beneficial effect on IR and BP in overweight/obese
MAFLD.
patients with NAFLD.45 Similar conclusions were
drawn in 58 NAFLD patients who received a

10
THE ROLE OF GUT MICROBIOME
The interaction between gut microbiota and liver
is a critical player in the development and
progression of NAFLD. An intact intestinal barrier
antagonizes the translocation of bacterial products,
allowing active transport of nutrients across tight
junctions. Several studies have shown
connection between gut and liver. For example,
diet and gut dysbiosis led to increased intestinal
permeability and was associated with the degree
of hepatic steatosis in NAFLD patients.52
Microbiome derived metabolites predict fibrosis
and cirrhosis in NAFLD.53 Gut flora and intestinal
permeability regulate glucose, lipid and choline
metabolism and affect intestinal permeability.54
Increased circulating levels of lipopolysaccharides
and other bioactive compounds lead to the
intrahepatic activation of proinflammatory cells and
hepatocytes, e.g. via stimulation of toll-like
receptor-2.55
OTHER TREATMENT OPTIONS
There are currently no drugs approved by the
Food and Drug Administration (FDA) or European
Medicines Agency (EMA) specifically for NAFLD.
Nonetheless, there are antidiabetic medications
with a direct and/or indirect effect on NAFLD such
as glucagon-like peptide-1 receptor agonists
(GLP-1RAs) and glitazones. 58,59
GLP-1RAs accelerate satiety by slowing gastric
emptying, decreasing glucagon secretion, and
improving liver enzymes.56
Statins have effects on lipid metabolism and are
likely to be useful in the treatment of NAFLD, but
effects on histology or long-term prognosis of
NAFLD patients are not yet known.57 Vitamin E has a
the
proven effect on liver histology in non-diabetic and
non-cirrhotic NASH patients.58 Another potentially
useful medication in the treatment of NAFLD is
metformin (although no effect was shown on
histology).
Orlistat or GLP-1RAs are medications that support
weight loss, which is naturally difficult to maintain in
the long term for some patients.59 The only option
in high-risk patients who cannot obtain weight
reduction, is bariatric surgery such as gastric bypass
or a sleeve gastrectomy (step 3 - figure 3). These
procedures result in a potentially important effect
on weight by, amongst others, promoting satiety
and providing a reduced calorie intake. This
decrease in weight results in an improvement in the
severity of NAFLD. A recent meta-analysis described
that 59% of individuals with NAFLD who underwent
bariatric surgery saw an improvement in NASH and
30% had a reduction in fibrosis.60 But these
procedures are highly invasive, not without
complications, and long-term medical follow-up is
necessary.61
11
NAFLD AND CHILDHOOD
Not only has NAFLD reached epidemic proportions
in adults but childhood cases are also rising.62
NAFLD is a frequent complication of childhood
obesity. The incidence may be as high as 30% in
63
obese children, which increases with age and
weight.64
Paediatric NAFLD has distinctive histological and
pathogenic features and is an escalating cause of
chronic liver disease, with the potential of
impacting health outcomes in adolescents and
young adults. 65
Once developed, NAFLD in
childhood is associated with T2DM, hypertension,
increased CVD risk, and end-stage liver disease.66 A
retrospective review of 742 American children and
adolescents between the ages of 2 and 19 years
who had an autopsy, showed that NAFLD is the
most common liver abnormality.67 Aside from the
extensive knowledge on the incidence and
concomitant associated factors of NAFLD, there has
been little advancement in non-pharmacological
treatments of NAFLD up until now, particularly in
obese children. Dietary approaches to NAFLD in
children/adolescents, have been infrequently
studied, although some findings are promising.

CONCLUSION

Healthy lifestyle and weight reduction remains crucial for the prevention and treatment of NAFLD.
The weight decline will lead to a decrease in hepatic steatosis, inflammation, and fibrosis. Patients with NAFLD
should be advised to aim at losing 7–10% of their total body weight by eating a modestly hypocaloric diet
(- 500 kcal/day) and engaging in regular exercise (30–60 min on 3–5 days/week).
To achieve this weight loss, a plant-based diet (e.g. Mediterranean diet) is recommended in the
treatment of NAFLD.

The use of soy products combined with a low-calorie, low-carbohydrate diet may be effective in
ameliorating different NAFLD parameters. However, research on soy products and their specific effects on
NAFLD, especially in the long term, is still missing and needs to be addressed in future clinical studies.

To improve patient care, there is a strong need for a multidisciplinary approach from internists, gastro-
enterologists, cardiologists, diabetologists, and nutritionists.

Moreover, renaming NAFLD to MAFLD may bring this disease back to reality and closer, not only to its
pathophysiology, but also to other metabolic disorders like T2DM and CVD.

12
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