NAFLD as the metabolic hallmark of obesity

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, associated with a high risk of progression to NASH, liver cirrhosis and hepatocarcinoma. Its prevalence is closely related to obesity (understood as adipose-based disease and insulin resistance), which makes that at present NAFLD can be considered a metabolic dysfunction hallmark, regardless of the body mass index. Despite being such a prevalent condition, with such severe consequences, at present there are no reliable biomarkers for its diagnosis or specific treatment. Significant and sustained weight loss, as well as some antidiabetic treatments, has shown promising results for NAFLD but data needs confirmation in larger clinical trials and longer follow-up. Efforts should be made for a better and more accurate baseline diagnosis (including large-scale genetics), identification of patients at higher risk for progression to NASH as well as adequate treatment, to allow us to offer a personalized approach in NAFLD in the context of precision medicine.

Full text

Vol.:(0123456789)
1 3
Internal and Emergency Medicine
https://doi.org/10.1007/s11739-022-03139-x
IM - REVIEW
NAFLD asthemetabolic hallmark ofobesity
AlbaRojano1· ElenaSena2· RamiroManzano‑Nuñez2· JuanM.Pericàs2,3· AndreeaCiudin1,4,5,6
Received: 16 August 2022 / Accepted: 17 October 2022
© The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI) 2022
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, associated with a
high risk of progression to NASH, liver cirrhosis and hepatocarcinoma. Its prevalence is closely related to obesity (understood
as adipose-based disease and insulin resistance), which makes that at present NAFLD can be considered a metabolic dysfunc-
tion hallmark, regardless of the body mass index. Despite being such a prevalent condition, with such severe consequences,
at present there are no reliable biomarkers for its diagnosis or specific treatment. Significant and sustained weight loss, as
well as some antidiabetic treatments, has shown promising results for NAFLD but data needs confirmation in larger clinical
trials and longer follow-up. Efforts should be made for a better and more accurate baseline diagnosis (including large-scale
genetics), identification of patients at higher risk for progression to NASH as well as adequate treatment, to allow us to offer
a personalized approach in NAFLD in the context of precision medicine.
Keywords Obesity· Non-alcoholic fatty liver disease· Liver steatosis· Liver inflammation
Introduction
Non-alcoholic fatty liver disease (NAFLD) has become the
most common chronic liver disease worldwide and affects
25–35% of adults in the general population from western
countries [1].
Additionally, the incidences of obesity and metabolic
syndrome have exponentially increased in recent years,
reaching epidemic proportions [2]. The latest report of the
World Health Organization in 2016 estimated that 650 mil-
lion adults were living with obesity, meaning a prevalence
of 13% of the overall adult population [3].
NAFLD includes a spectrum of histopathological and
clinical features with a direct relationship with obesity,
insulin resistance (IR)/type 2 diabetes (T2D) and metabolic
syndrome (Met S) [4].
A pooled analysis from 200 countries published in 2006
showed that between 1980 and 2015 obesity prevalence dou-
bled in 73 countries [5] and this increase was linked to an
expansion from 37.4% in 2005 to 2010 to 41, 5% in 2016 to
2019 in NAFLD diagnoses in this adult subpopulation [6].
Furthermore, more recent data showed that when either obe-
sity or T2D are present the prevalence of NAFLD is about
60–80% [7] and when both conditions are present NAFLD
reaches 80–100% [8].
Alba Rojano and Elena Sena contributed equally to the manuscript.
* Juan M. Pericàs
pericasjm@gmail.com
* Andreea Ciudin
andreea.ciudin@vallhebron.cat
1 Endocrinology andNutrition Department, Vall
d’HebronInstitut de Recerca (VHIR), Hospital Universitari
Vall d’Hebron, Vall d’Hebron Barcelona Campus
Hospitalari, Barcelona, Spain
2 Liver Unit, Internal Medicine Department, Vall
d’HebronInstitut de Recerca (VHIR), Hospital Universitari
Vall d’Hebron, Vall d’Hebron Barcelona Campus
Hospitalari, Barcelona, Spain
3 Centro de Investigación Biomédica en Red de Enfermedades
Digestivas Y Hepáticas (CIBERehd), Instituto de Salud
Carlos III, Madrid, Spain
4 CIBER de Diabetes Y Enfermedades Metabólicas Asociadas
(CIBERDem), Instituto de Salud Carlos III, Madrid, Spain
5 Department ofCellular Biology, Physiology
andImmunology, Universitat Autònoma de Barcelona,
Barcelona, Spain
6 Pathology Department, Hospital Universitari Vall d’Hebron,
Vall d’Hebron Barcelona Campus Hospitalari, Barcelona,
Spain

Internal and Emergency Medicine
1 3
Moreover, at present, NAFLD is the most prevalent form
of chronic liver disease in childhood and adolescence, affect-
ing approximately 10%–20% of the general paediatric popu-
lation. NAFLD is expected to become the main cause of
liver failure and indication for liver transplantation in this
population in the Western world within the next 10years [9].
Similar to findings in adults, when overweight or obesity
was present, the prevalence of NAFLD was 6 to 26 times
higher, respectively, in children and adolescents between 6
and 18years of age [10].
Additionally, the leading cause of death among patients
with NAFLD remains cardiovascular disease, followed by
extra-hepatic cancers and liver-related complications [11,
12]. Furthermore, although it has not been widely demon-
strated, recent data have shown that NAFLD could be con-
sidered as a marker of subclinical atherosclerosis as well as
a strong cardiovascular risk factor even at a very early age
[13], reflecting the strong relationship between NAFLD and
MetS.
Insulin resistance (IR), one of the major components of
obesity and MetS [14] plays a key role in the pathophysi-
ology of NAFLD, by promoting the progression of simple
steatosis to liver inflammation and fibrosis, also known as
non-alcoholic steato-hepatitis (NASH) [15].
It is estimated that 20–30% of patients with NAFLD will
progress to non-alcoholic steatohepatitis (NASH), which is
characterized by hepatic inflammation and cellular injury,
with variable degrees of fibrosis [16]. Even though NAFLD
is usually asymptomatic in the early stages, the condition
can silently progress to advanced stages including cirrho-
sis, hepatocellular carcinoma (HCC) or liver failure [17].
Indeed, for patients with NASH-related cirrhosis has been
observed a > tenfold increase in risk for HCC [18]. Further-
more, NASH-related cirrhosis has become a leading cause
of liver transplantation in developed countries [19] Obesity
is one of the major risk factors for progression from NAFLD
to NASH [20]—Fig.1.
Additionally, in the last decade, several genetic risk fac-
tors have been identified and associated with the suscepti-
bility of NAFLD and progression to NASH and advanced
fibrosis [21]. Among them, single nucleotide polymorphism
(SNP) rs738409 of the patatin-like phospholipase domain-
containing protein 3 (PNPLA3) gene [22, 23] and SNP
rs58542926 of the transmembrane protein involved in mol-
ecule transport (TM6SF2) gene [24] have been identified in
several genome-wide association studies (GWAS) as risk
factors for progressive NASH and advanced liver fibrosis
[17].
Our group has recently shown that the presence of IR
on top of these polymorphisms significantly increased the
risk of NASH and severe fibrosis in patients with obesity
[25], highlighting the strong relationship between obesity
and MetS and NAFLD.
Due to the strong bidirectional association between MetS
and NAFLD, in 2020, worldwide expert consensus proposed
a more realistic concept of the disease, including a change
of the nomenclature of NAFLD to Metabolic dysfunction-
Associated Fatty Liver Disease (MAFLD), which now
requires, in addition to hepatic steatosis, the co-occurrence
of one of three features: 1) overweight or obesity, 2) T2DM,
or 3) lean or normal weight with evidence of metabolic dys-
regulation (26–28). The general conception is that NAFLD
is no longer an isolated disease; but rather a condition that
appears in conjunction with other metabolic factors, being
considered, at present, the hepatic manifestation of MetS
[26, 27].
It should be noted that the criteria used in this consen-
sus to define “overweight”, “obesity” and “non-obese” sub-
jects is BMI. Classically, obesity is defined worldwide as
BMI > 30kg/m2 [29] and one of the criteria for MetS is
waist circumference [30] Furthermore, in several studies
so far BMI and waist circumference positively correlates
with NAFLD presence and progression [15]. Nevertheless,
from a mechanistically point of view, obesity is defined
as the excess of body fat, regardless of the BMI [31]. The
presence of NAFLD and MAFLD features in lean subjects
(BMI < 25kg/m2), brings to front a more recent debate,
regarding the accuracy of BMI in defining obesity and the
risk of its metabolic complications. The EASO position
statement in 2019 [32] proposes the new definition of obe-
sity as adiposity-based-chronic disease and Snitker etal.,
2010 defines obesity as %body fat > 25 in males and > 35%
in females [33].
NAFLD/MAFLD is the hallmark of the body fat content,
in terms of total amount, distribution and functionality [34].
Several studies associate NAFLD with body fat accu-
mulation and loss of muscle mass. Shi etal. showed that
visceral adipose tissue (VAT) was an independent predictor
of NAFLD regardless of obesity defined by BMI [35]. Fur-
thermore, VAT accumulation induces insulin resistance and
exacerbates liver damage in NAFLD [36]. Some studies also
showed that the presence of sarcopenia (muscle mass loss)
is associated with metabolic syndrome, and cardiovascular
disease and is a risk factor for non-alcoholic steatohepatitis
(NASH) and fibrosis (≥ F29 [37]. Nevertheless, recent data
reflected that the pathophysiology of NAFLD may be more
dependent on fat accumulation than on the loss of muscle
mass [38].
NAFLD histopathology inobesity
As explained before, NAFLD physiopathology is complex
and includes metabolic, environmental, genetic, and gut
microbial factors [39]. Insulin resistance, a hallmark of obe-
sity and excess body fat, plays a key role in the development

Internal and Emergency Medicine
1 3
of the histologic features found in NAFLD- Fig.2. IR
implies an impairment in the suppression of hepatic glucose
production that correlates with increased gluconeogenesis
and free fatty acid (FFA) levels and a decrease in glycogen
synthesis. These alterations in the metabolic cascades result
in lipid accumulation, which in turn results in a preferential
shift from carbohydrate to FFA beta-oxidation (15, 40–42).
Additionally, experimental studies have shown a reduced
Fig. 1 NAFLD the metabolic hallmark in obesity. FFAs: free fatty acids, NAFLD: non-alcoholic fatty liver disease

Internal and Emergency Medicine
1 3
synthesis and secretion of very low-density lipoprotein
(VLDL) and excessive importation of FFA from adipose
tissue [43]. This lipid accumulation has been linked as a
trigger in the activation of several inflammatory pathways
related to pro-inflammatory cytokines, such as TNFα or
IL¬6 [44]. All these physiopathological changes will finally
end in an increase in oxidative stress and mitochondrial leak-
age, resulting in hepatic fibrosis and promote more insulin
resistance [45]. Recent data in fatty liver models without
fibrosis have shown that lipid accumulation associated with
obesity induces an architectural distortion, resulting in: a)
reduced sinusoidal space, b) increased intrahepatic vascular
resistance and c) potentially portal hypertension related to
obesity (PH) which will contribute to the progression to liver
cirrhosis and hemodynamic decompensation (46–48).
NAFLD diagnosis inobesity
The dramatic increase in the prevalence and impact of
NAFLD has led to the rapid development of new diagnostic
methods.
As explained before, the presence of liver steatosis (diag-
nosed by imaging, biochemical scores or liver biopsy) and
obesity will automatically convert into MAFLD diagnosis,
according to the latest consensus [26]. Nevertheless, at present
there is no effective screening method with high sensibility
and low false positives to be considered the gold-standard.
In this regard, guidelines such as the American Association
for the Study of Liver Diseases (AASLD) does not recom-
mend population screening for NAFLD [49]. By contrast,
EASL–EASD–EASO Clinical Practice Guidelines in 2016
recommend non-invasive screening to predict steatosis, NASH
and fibrosis in all the subjects living with obesity and elevated
liver enzymes. If ultrasound steatosis or high-risk fibrosis
markers are obtained a referral to hepatologist is required [50].
More recent recommendation, propose a step-by-step
approach: (50–52) to diagnose NAFLD based on: 1) the use
of serologic non-invasive tests with high negative predictive
value to exclude the presence of significant liver fibrosis, 2)
the performance of a transient elastography to identify patients
with suspicion of liver fibrosis and 3) the indication of liver
biopsy to accurately stratify the disease and for consideration
in pharmacological clinical trials.
Fig. 2 Physiopathological mechanisms that link obesity with NAFLD

Internal and Emergency Medicine
1 3
Non‑invasive biomarkers
Diagnosis ofhepatic steatosis ‑NAFLD
Serum biomarkers
Increased levels of ALT, AST, or γ-glutamyltransferase
(GGT) are used to diagnose NAFLD. Nevertheless,
although AST levels were associated with NASH in
advanced fibrosis, most patients with NASH or advanced
fibrosis had normal AST levels [53] and these values may
differ with age, sex, and ethnical origin [54].
Liver imaging
Abdominal ultrasound is usually the first diagnostic tool per-
formed to assess hepatic steatosis. Ultrasound devices are
widely available in primary and specialized care, it is easy
to perform and provides additional information (i.e., liver
structure, focal lesions or indirect signs of portal hyperten-
sion). However, hepatic ultrasound shows a low sensitivity
to detect mild steatosis, especially in subjects with obesity
and it is operator-dependent. In this regard, several serologic
non-invasive test has been developed in the recent years,
such as Hepatic Steatosis Index (HIS) and Fatty Liver Index
(FLI), which include usual blood test parameters and meta-
bolic data to detect fatty liver disease [55, 56].
The Controlled Attenuation Parameter (CAP) software
has been recently incorporated into transient elastography
devices. CAP allows a quantitative measurement of liver
steatosis with higher diagnostic performance than liver
ultrasound and serologic tests. [57].
Diagnosis ofliver fibrosis
Serum biomarkers
The most validated serologic fibrosis score for NAFLD are
FIB-4 index and NAFLD Fibrosis Score (NFS). Both test
employ usual demographic and analytical parameters (i.e.,
age and liver enzymes) and had a high negative predictive
value (> 90%) to exclude advanced fibrosis with the low-
est threshold [58]. Developed by Siemens, the Enhanced
Liver Fibrosis (ELFTM) panel predicts advanced fibro-
sis by measuring hyaluronic acid (HA), procollagen III
amino-terminal peptide (PIIINP), and the tissue inhibi-
tor of matrix metalloproteinase 1 (TIMP-1) and has been
implemented in some European guidelines [59].
Liver imaging
Transient elastography (TE) (Fibroscan®) is a ultrasound-
based technique for diagnosing liver fibrosis with adequate
diagnostic accuracy [60, 61]. Besides, TE values (liver stiff-
ness measurement-LSM- and controlled attenuation param-
eter) have been associated with the risk of developing clini-
cally significant portal hypertension (CSPH) and clinical
events [62, 63]. However, TE accuracy for liver fibrosis and
CSPH estimation significantly decreases in patients with obe-
sity, which has been proved independently of the liver disease
etiology but it is more pronounced in NASH patients. Two-
dimensional shear wave elastography (2D-SWE), shear wave
dispersion slope (SWDS), and Attenuation Imaging (ATI) are
novel techniques that quantify liver stiffness, steatohepatitis,
and steatosis of hepatic tissue, respectively, and are installed
in modern ultrasound devices. Nonetheless, only a few stud-
ies have assessed the accuracy of 2D-SWE, SWDS, and ATI
in NAFLD patients, and cutoff values are still not validated
[64]. These techniques have not been evaluated extensively
for NASH diagnosis, and, therefore, TE continues to be the
primary imaging technique to assess liver stiffness.
Magnetic resonance imaging (MRI) can measure hepatic
steatosis and fibrosis through the proton density fat frac-
tion (PDFF) software and magnetic resonance elastography
(MRE), respectively. These methods have been proven the
most accurate methods for steatosis and fibrosis detection
and staging. Nonetheless, the high cost and restricted avail-
ability (including size in patients with obesity) limit their
implementation in clinical practice and are mainly used in
clinical trials and research studies.
Liver biopsy
Liver Biopsy remains as the gold standard technique for the
diagnosis of NAFLD and for disease staging and progres-
sion of NASH (to assess ballooning and inflammation) NAS
score and CRN criteria are the most extended histological
panels to diagnose NAFLD [65]. However, due to the inva-
sive nature of the procedure, the indication is limited to
selected cases. Furthermore, in patients with obesity, the
technical difficulty, and the ability to obtain high-quality
samples might be hampered according to the width of sub-
cutaneous fat.
NAFLD management andtreatment
inobesity
Despite being a prevalent condition and a public health
concern, currently there are no pharmacological treatments
approved for NAFLD/MAFLD. New pharmacotherapy
that targets metabolic hepatic pathways, such as bile acid

Internal and Emergency Medicine
1 3
metabolism, mitochondrial lipogenesis and gluconeogenesis
and fatty acid synthesis that have demonstrated the preven-
tion of apoptosis, inflammation, and fibrosis are being stud-
ied (66–69)
The current intervention in NAFLD patients is mainly
centered in weight loss and in improving metabolic condi-
tion, such as IR and/or T2D [70, 71]. It has been shown
that a 7–10% of total weight loss can improve histological
NAFLD features and progression to NASH [72]. Addition-
ally, some antidiabetic drugs have demonstrated resolution
of the histological lesions defining NASH with no worsen-
ing of fibrosis (73–75). Nevertheless, if there is a strong
suspicion of a more advanced liver disease, patients should
be referred to a liver specialist (hepatologist or gastroenter-
ologist), as stated by current guidelines, based on blood and
imaging tests. [70]—Table1.
Dietary andlifestyle changes
Several studies examined the role of weight loss on NAFLD
progression, confirming the tight relationship between obe-
sity and liver affectation [76]. A total loss of 5–7% percent
of body weight demonstrated an improvement in hepatic
fibrosis and steatosis [77, 78]. Studies based on a calorie-
restriction diet demonstrated a decrease in intrahepatic fat
content and inflammation corresponding to insulin sensi-
tivity improvement [77, 78]. Furthermore, not only calorie
restriction but changes in diet composition, such as the Med-
iterranean diet have demonstrated improvement in NAFLD
outcomes and IR [79].
Pharmacological therapy
At present, there are no FDA or EMA-approved drugs for
NAFLD. We will refer to those drugs used for T2D and/or
obesity that significantly impact on NAFLD, such as Gluca-
gon-like peptide-1 receptor agonist (GLP-1 RA), thiazolidin-
edione and SGLT2 inhibitors.
GLP-1 RAs improve glycaemic control, facilitate
remarkable and maintained body weight loss as well as car-
diovascular beneficial effects (80–82). Furthermore, in these
studies a beneficial effect on NAFLD was seen, suggesting
once more that NAFLD is the liver complication of obe-
sity and metabolic syndrome. In the LEAN study, [83] 39%
patients with T2D and obesity achieved NASH resolution
with subcutaneous 1.8mg daily Liraglutide. Additionally,
the results of a phase-2 trial including 320 patients with
obesity and biopsy-proven NASH revealed that semaglu-
tide was superior to placebo in terms of NASH resolution.
[84]. The recent guideline from the American Association
of Clinical Endocrinologists (AACE) recommends treatment
with liraglutide 3mg daily for the management of NAFLD
in patients with obesity. [70].
Thiazolidinediones. Pioglitazone and rosiglitazone
improve peripheral insulin sensitivity and are potent acti-
vators of the nuclear receptor PPARγ implied in adipocyte
differentiation and lipid and glucose metabolism, decreasing
hepatic lip content [85, 86]. Furthermore, thiazolidinediones
have demonstrated a reduction of hepatic stellate cell activa-
tion and fibrosis experimental models [87]. Pioglitazone has
demonstrated also reductions in inflammation and hepato-
cyte degeneration as well as in fibrosis [88].
Inhibitors of SGLT2 (canagliflozin, dapagliflozin, empa-
gliflozin and ertugliflozin) lead to the increased urinary
excretion of glucose. iSGLT2 have demonstrated in numer-
ous trials the reduction of the risk of major cardiovascular
events [89–91]. Also have demonstrated in animal models
improvement in levels of liver enzymes, steatosis, hepato-
cyte damage and fibrosis [92] but there is a lack of clinical
efficacy in RCT [74, 93].
At present, there are several experimental studies with
other pharmacotherapy groups that target hepatic alterations
of metabolism in NAFLD that have demonstrated efficacy,
but a small number were tested in clinical trials. Some of the
new clinical phase III trials include inhibitors of ketohexoki-
nase that block the final step of fructose metabolism inhibit-
ing lipogenesis [67]. Mitochondrial pyruvate carrier (MPC)
inhibitors prevent the import of pyruvate into the mitochon-
dria, blocking gluconeogenesis and fatty acid synthesis path-
ways [68, 69]. Lastly, inhibitors of enzymes involved in the
synthesis of triglycerides s such as acetyl-CoA carboxylase
a and Stearoyl-CoA desaturase have also demonstrated pre-
vention in apoptosis, inflammation, and fibrosis [94, 95].
Metabolic procedural techniques: bariatric
endoscopy andbariatric surgery
Bariatric surgery and bariatric endoscopy are valid treat-
ment options for patients with obesity, especially those
that associate MeTs. At present, there is limited evidence
Table 1 Criteria for referral to liver specialist (Hepatologist or Gas-
troenterologist)
FIB-4 index for liver fibrosis, LSM liver stiffness measurement, ELF
enhanced liver fibrosis
Parameter Intermediate risk High risk
Blood transaminases level Elevated Elevated
Liver steatosis on imaging Present Present
FIB-4 1.3–2.67 2.67
LSM (kPa) 8–12 > 12
ELF 7.7–9.8 > 9.8

Internal and Emergency Medicine
1 3
for the use of endoscopic metabolic techniques in patients
with NAFLD and obesity. Some studies have shown his-
tological improvements in small series [96]. Bariatric
endoscopy is not currently incorporated in clinical prac-
tice guidelines but could be considered in highly selected
patients unable to undergo bariatric surgery in experienced
centers.
Bariatric surgery (BS) has been proven to induce signifi-
cant weight loss and potentially positively impact NAFLD
and NASH outcomes, improving necrosis, inflammation
and fibrosis in a longitudinal prospective study with serial
liver biopsies, (97–99). Nevertheless, the methodology of
these studies is heterogeneous and at present there is no
randomized clinical trial aimed to shed light on this issue.
Furthermore, recent data suggested worsening of NAFLD/
NASH features in some patients following BS [100]. On
these bases, we consider that the indication for BS in patients
with NAFLD/NASH should be individualized and carefully
analyzed in each patient.
Concluding remarks
Non-alcoholic fatty liver disease (NAFLD) has become the
most common chronic liver disease worldwide, associated
with a high risk of progression to NASH, liver cirrhosis and
hepatocarcinoma. Its prevalence is closely related to obesity
(understood as adipose-based disease and insulin resistance),
which makes that at present NAFLD can be considered a
metabolic dysfunction hallmark, regardless of the body mass
index. Despite being such a prevalent condition, with such
severe consequences, at present there are no reliable bio-
markers for its diagnosis or specific treatment. Significant
and sustained weight loss, as well as some antidiabetic treat-
ments, has shown promising results for NAFLD. Neverthe-
less, the actual data needs confirmation in larger clinical
trials and longer follow-up. Efforts should be made for a
better and accurate baseline diagnosis (including large-scale
genetics), identification of patients at higher risk for progres-
sion to NASH as well as adequate treatment, to allow us to
offer a personalized approach in NAFLD in the context of
precision medicine.
Declarations
Conflict of interest Authors declare no conflict of interest related to
this work.
Human and animal rights statement This article does not contain any
studies with human participants or animals performed by any of the
authors.
Informed consent For this type of study formal consent is not required.
References
1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L,
Wymer M (2016) Global epidemiology of nonalcoholic fatty
liver disease-meta-analytic assessment of prevalence. Incidence
Outcomes Hepatol 64(1):73–84. https:// doi. org/ 10. 1002/ hep.
28431
2. The GBD 2015 Obesity Collaborators (2015) Obesity Collabo-
rators. (2017) Health Effects of Overweight and Obesity in 195
Countries over 25 Years. N Engl J Med 377:13–27. https:// doi.
org/ 10. 1056/ NEJMo a1614 362
3. Obesity and overweight. https:// www. who. int/ news- room/ fact-
sheets/ detail/ obesi ty- and- overw eight (accessed 2022–08–11).
4. Buzzetti E, Pinzani M, Tsochatzis EA (2016) The multiple-hit
pathogenesis of non-alcoholic fatty liver disease (NAFLD).
Metabolism 65(8):1038–1048. https:// doi. org/ 10. 1016/j. metab
ol. 2015. 12. 012
5. NCD Risk Factor Collaboration (NCD-RisC) (2016) Trends in
adult body-mass index in 200 countries from 1975 to 2014: a
pooled analysis of 1698 population-based measurement studies
with 19·2 million participants. Lancet 387:1377–1396. https://
doi. org/ 10. 1016/ S0140- 6736(16) 30054-X
6. Cholongitas E, Pavlopoulou I, Papatheodoridi M, Markakis GE,
Bouras E, Haidich A-B, Papatheodoridis G (2021) Epidemiology
of nonalcoholic fatty liver disease in europe: a systematic review
and meta-analysis. Ann Gastroenterol 34:404–414
7. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo
E, Bass NM (2012) The nonalcoholic steatohepatitis clinical
research network. Association between diabetes, family history
of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
Hepatology 56:943–951. https:// doi. org/ 10. 1002/ hep. 25772
8. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contre-
ras M, Landt CL, Harrison SA (2011) Prevalence of nonalco-
holic fatty liver disease and nonalcoholic steatohepatitis among
a largely middle-aged population utilizing ultrasound and liver
biopsy: a prospective study. Gastroenterology 140(1):124–131.
https:// doi. org/ 10. 1053/j. gastro. 2010. 09. 038
9. Berardis S, Sokal E (2014) Pediatric non-alcoholic fatty
liver disease: an increasing public health issue. Eur J Pediatr
173(2):131–139
10. Sharma V, Coleman S, Nixon J, Sharples L, Hamilton-Shield
J, Rutter H, Bryant M (2019) A systematic review and meta-
analysis estimating the population prevalence of comorbidi-
ties in children and adolescents aged 5 to 18 years. Obes Rev
20(10):1341–1349. https:// doi. org/ 10. 1111/ obr. 12904
11. Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J
Hepatol 62(1 Suppl):S47-64. https:// doi. org/ 10. 1016/j. jhep. 2014.
12. 012
12. Targher G, Tilg H, Byrne CD (2021) Non-alcoholic fatty liver
disease: a multisystem disease requiring a multidisciplinary and
holistic approach. Lancet Gastroenterol Hepatol 6(7):578–588.
https:// doi. org/ 10. 1016/ S2468- 1253(21) 00020-0
13. Di Sessa A, Umano GR, Miraglia Del Giudice E (2017) The
association between non-alcoholic fatty liver disease and cardio-
vascular risk in children. Children (Basel) 4(7):E57. https:// doi.
org/ 10. 3390/ child ren40 70057
14. Roberts CK, Hevener AL, James Barnard R (2013) Metabolic
syndrome and insulin resistance: underlying causes and modifi-
cation by exercise training. Compr Physiol 3:1–58. https:// doi.
org/ 10. 1002/ cphy. c1100 62
15. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E,
Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N
(2001) Nonalcoholic fatty liver disease: a feature of the metabolic
syndrome. Diabetes 50(8):1844–1850. https:// doi. org/ 10. 2337/
diabe tes. 50.8. 1844

Internal and Emergency Medicine
1 3
16. Liu W, Baker RD, Bhatia T, Zhu L, Baker SS (2016) Patho-
genesis of nonalcoholic steatohepatitis. Cell Mol Life Sci
73(10):1969–1987. https:// doi. org/ 10. 1007/ s00018- 016- 2161-x
17. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ
(2018) Mechanisms of NAFLD development and therapeutic
strategies. Nat Med 24(7):908–922. https:// doi. org/ 10. 1038/
s41591- 018- 0104-9
18. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das
D, Aslam T, Patanwala I, Gaggar S, Cole M, Sumpter K, Stewart
S, Rose J, Hudson M, Manas D, Reeves HL (2014) Hepatocel-
lular cancer: the impact of obesity, type 2 diabetes and a multi-
disciplinary team. J Hepatol 60(1):110–117. https:// doi. org/ 10.
1016/j. jhep. 2013. 08. 011
19. Pais R, Barritt AS, Calmus Y, Scatton O, Runge T, Lebray P,
Poynard T, Ratziu V, Conti F (2016) NAFLD and liver trans-
plantation: current burden and expected challenges. J Hepatol
65(6):1245–1257. https:// doi. org/ 10. 1016/j. jhep. 2016. 07. 033
20. Kim Y, Chang Y, Cho YK, Ahn J, Shin H, Ryu S (2019) Obesity
and weight gain are associated with progression of fibrosis in
patients with nonalcoholic fatty liver disease. Clin Gastroenterol
Hepatol 17:543–550. https:// doi. org/ 10. 1016/j. cgh. 2018. 07. 006
21. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam
M, George J, Bugianesi E (2018) Global burden of NAFLD and
NASH: trends, predictions, risk factors and prevention. Nat Rev
Gastroenterol Hepatol 15(1):11–20. https:// doi. org/ 10. 1038/ nrgas
tro. 2017. 109
22. Míková I, Neroldová M, Hubácek JA, Dlouhá D, Jirsa M, Hons-
ová E, Sticová E, Lánská V, Špicák J, Trunecka P (2020) Donor
PNPLA3 and TM6SF2 variant alleles confer additive risks
for graft steatosis after liver transplantation. Transplantation
104(3):526–534. https:// doi. org/ 10. 1097/ TP. 00000 00000 002876
23. Rinaldi L, Pafundi PC, Galiero R, Caturano A, Morone MV, Sil-
vestri C, Giordano M, Salvatore T, Sasso FC (2021) Mechanisms
of non-alcoholic fatty liver disease in the metabolic syndrome.
A Narrative Review Antioxidants 10(2):270. https:// doi. org/ 10.
3390/ antio x1002 0270
24. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Don-
giovanni P, Nobili V, Mozzi E, Roviaro G, Vanni E, Bugianesi
E, Maggioni M, Fracanzani AL, Fargion S, Day CP (2010)
Homozygosity for the patatin-like phospholipase-3/adiponutrin
i148m polymorphism influences liver fibrosis in patients with
nonalcoholic fatty liver disease. Hepatology 51(4):1209–1217.
https:// doi. org/ 10. 1002/ hep. 23622
25. Gabriel-Medina P, Ferrer-Costa R, Rodriguez-Frias F, Ciudin
A, Augustin S, Rivera-Esteban J, Pericàs JM, Selva DM (2022)
Influence of type 2 diabetes in the association of PNPLA3
Rs738409 and TM6SF2 Rs58542926 polymorphisms in NASH
advanced liver fibrosis. Biomedicines 10(5):1015. https:// doi. org/
10. 3390/ biome dicin es100 51015
26. Eslam M, Sanyal AJ, George J (2020) International consen-
sus panel. mafld: a consensus-driven proposed nomenclature
for metabolic associated fatty liver disease. Gastroenterology
158:1999–2014. https:// doi. org/ 10. 1053/j. gastro. 2019. 11. 312
27. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G,
Romero-Gomez M, Zelber-Sagi S, Wong VW-S, Dufour J-F,
Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G,
Tiribelli C, Yki-Järvinen H, Fan J-G, Grønbæk H, Yilmaz Y,
Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng M-H,
Fouad Y, Chan W-K, Mendez-Sanchez N, Ahn SH, Castera L,
Bugianesi E, Ratziu V, George J (2020) A New definition for
metabolic dysfunction-associated fatty liver disease: an inter-
national expert consensus statement. J Hepatol 73(1):202–209.
https:// doi. org/ 10. 1016/j. jhep. 2020. 03. 039
28. Tilg H, Effenberger M (2020) From NAFLD to MAFLD: when
pathophysiology succeeds. Nat Rev Gastroenterol Hepatol
17(7):387–388. https:// doi. org/ 10. 1038/ s41575- 020- 0316-6
29. Apovian CM (2016) Obesity: definition, comorbidities, causes,
and burden. Am J Manag Care 22(7 Suppl):s176-185
30. Alberti KG, Zimmet PZ (1998) Definition, diagnosis and clas-
sification of diabetes mellitus and Its complications. part 1:
diagnosis and classification of diabetes mellitus provisional
report of a who consultation. Diabet Med 15:539–553
31. Mechanick JI, Hurley DL, Garvey WT (2017) Adiposity-based
chronic disease as a new diagnostic term: The American Asso-
ciation of Clinical Endocrinologists and American College of
Endocrinology Position Statement. Endocr Pract 23(3):372–
378. https:// doi. org/ 10. 4158/ EP161 688. PS
32. Frühbeck G, Busetto L, Dicker D, Yumuk V, Goossens GH,
Hebebrand J, Halford JGC, Farpour-Lambert NJ, Blaak EE,
Woodward E, Toplak H (2019) The ABCD of obesity: an
EASO position statement on a diagnostic term with clinical
and scientific implications. Obes Facts 12(2):131–136. https://
doi. org/ 10. 1159/ 00049 7124
33. Snitker S (2010) Use of body fatness cutoff points. Mayo Clin
Proc 85:1057–1058. https:// doi. org/ 10. 4065/ mcp. 2010. 0583
34. Garvey WT (2022) Is obesity or adiposity-based chronic
disease curable: the set point theory, the environment, and
second-generation medications. Endocr Pract 28(2):214–222.
https:// doi. org/ 10. 1016/j. eprac. 2021. 11. 082
35. Shi Y-X, Chen X-Y, Qiu H-N, Jiang W-R, Zhang M-Y, Huang
Y-P, Ji Y-P, Zhang S, Li C-J, Lin J-N (2021) Visceral fat area to
appendicular muscle mass ratio as a predictor for nonalcoholic
fatty liver disease independent of obesity. Scand J Gastroen-
terol 56(3):312–320. https:// doi. org/ 10. 1080/ 00365 521. 2021.
18792 44
36. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L
(2009) Molecular mechanisms involved in NAFLD progres-
sion. J Mol Med (Berl) 87(7):679–695. https:// doi. org/ 10. 1007/
s00109- 009- 0464-1
37. Kim JA, Choi KM (2019) Sarcopenia and fatty liver dis-
ease. Hepatol Int 13(6):674–687. https:// doi. org/ 10. 1007/
s12072- 019- 09996-7
38. Miyake T, Miyazaki M, Yoshida O, Kanzaki S, Nakaguchi
H, Nakamura Y, Watanabe T, Yamamoto Y, Koizumi Y,
Tokumoto Y, Hirooka M, Furukawa S, Takeshita E, Kum-
agi T, Ikeda Y, Abe M, Toshimitsu K, Matsuura B, Hiasa Y
(2021) Relationship between body composition and the his-
tology of non-alcoholic fatty liver disease: a cross-sectional
study. BMC Gastroenterol 21(1):170. https:// doi. org/ 10. 1186/
s12876- 021- 01748-y
39. Eslam M, Valenti L, Romeo S (2018) Genetics and epigenetics of
NAFLD and NASH: clinical impact. J Hepatol 68(2):268–279.
https:// doi. org/ 10. 1016/j. jhep. 2017. 09. 003
40. Krssak M, Brehm A, Bernroider E, Anderwald C, Nowotny P,
Dalla Man C, Cobelli C, Cline GW, Shulman GI, Waldhäusl
W, Roden M (2004) Alterations in postprandial hepatic glyco-
gen metabolism in type 2 diabetes. Diabetes 53(12):3048–3056.
https:// doi. org/ 10. 2337/ diabe tes. 53. 12. 3048
41. Lomonaco R, Bril F, Portillo-Sanchez P, Ortiz-Lopez C, Orsak B,
Biernacki D, Lo M, Suman A, Weber MH, Cusi K (2016) Meta-
bolic impact of nonalcoholic steatohepatitis in obese patients
with type 2 diabetes. Diabetes Care 39(4):632–638. https:// doi.
org/ 10. 2337/ dc15- 1876
42. Utzschneider KM, Van de Lagemaat A, Faulenbach MV, Goe-
decke JH, Carr DB, Boyko EJ, Fujimoto WY, Kahn SE (2010)
Insulin resistance is the best predictor of the metabolic syndrome
in subjects with a first-degree relative with type 2 diabetes. Obe-
sity (Silver Spring) 18(9):1781–1787. https:// doi. org/ 10. 1038/
oby. 2010. 77
43. Heeren J, Scheja L (2021) Metabolic-associated fatty liver dis-
ease and lipoprotein metabolism. Mol Metab 50:101238. https://
doi. org/ 10. 1016/j. molmet. 2021. 101238

Internal and Emergency Medicine
1 3
44. Tilg H, Diehl AM (2000) Cytokines in alcoholic and nonal-
coholic steatohepatitis. N Engl J Med 343(20):1467–1476.
https:// doi. org/ 10. 1056/ NEJM2 00011 16343 2007
45. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Con-
tos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN
(2001) Nonalcoholic steatohepatitis: association of insulin
resistance and mitochondrial abnormalities. Gastroenterology
120(5):1183–1192. https:// doi. org/ 10. 1053/ gast. 2001. 23256
46. Ryou M, Stylopoulos N, Baffy G (2020) Nonalcoholic fatty
liver disease and portal hypertension. Explor Med 1:149–169
47. Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E,
Pelckmans P, Van Gaal L, Michielsen P (2010) Noncirrhotic
human nonalcoholic fatty liver disease induces portal hyper-
tension in relation to the histological degree of steatosis. Eur
J Gastroenterol Hepatol 22(12):1449–1457. https:// doi. org/ 10.
1097/ MEG. 0b013 e3283 3f14a1
48. Pasarín M, La Mura V, Gracia-Sancho J, García-Calderó H,
Rodríguez-Vilarrupla A, García-Pagán JC, Bosch J, Abraldes
JG (2012) Sinusoidal endothelial dysfunction precedes
inflammation and fibrosis in a model of NAFLD. PLoS ONE
7(4):e32785. https:// doi. org/ 10. 1371/ journ al. pone. 00327 85
49. Corey KE, Klebanoff MJ, Tramontano AC, Chung RT, Hur
C (2016) Screening for Nonalcoholic steatohepatitis in
individuals with type 2 diabetes: a cost-effectiveness analy-
sis. Dig Dis Sci 61(7):2108–2117. https:// doi. org/ 10. 1007/
s10620- 016- 4044-2
50. (2016) EASL–EASD–EASO Clinical Practice Guidelines for the
Management of Non-Alcoholic Fatty Liver Disease. J Hepatol
64(6):1388–1402. https:// doi. org/ 10. 1007/ s10620- 016- 4044-2.
51. Italian Association for the Study of the Liver (AISF) (2017) AISF
position paper on nonalcoholic fatty liver disease (nafld): updates
and future directions. Dig Liver Dis 49:471–483. https:// doi. org/
10. 1016/j. dld. 2017. 01. 147
52. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella
M, Harrison SA, Brunt EM, Sanyal AJ (2018) The diagnosis
and management of nonalcoholic fatty liver disease: practice
guidance from the american association for the study of liver
diseases. Hepatology 67(1):328–357. https:// doi. org/ 10. 1002/
hep. 29367
53. Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V,
Reines HD, Goodman Z, Younossi ZM (2005) Predictors of
nonalcoholic steatohepatitis and advanced fibrosis in morbidly
obese patients. Obes Surg 15(3):310–315. https:// doi. org/ 10.
1381/ 09608 92053 576820
54. Verma S, Jensen D, Hart J, Mohanty S (2013) Predictive value
of ALT levels for non-alcoholic steatohepatitis (NASH) and
advanced fibrosis in non-alcoholic fatty liver disease (NAFLD).
Liver Int Off J Int Assoc Study Liver. https:// doi. org/ 10. 1111/ liv.
12226
55. Lee J-H, Kim D, Kim HJ, Lee C-H, Yang JI, Kim W, Kim YJ,
Yoon J-H, Cho S-H, Sung M-W, Lee H-S (2010) Hepatic stea-
tosis index: a simple screening tool reflecting nonalcoholic fatty
liver disease. Dig Liver Dis 42(7):503–508. https:// doi. org/ 10.
1016/j. dld. 2009. 08. 002
56. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M,
Castiglione A, Tiribelli C (2006) The fatty liver index: a sim-
ple and accurate predictor of hepatic steatosis in the general
population. BMC Gastroenterol 6:33. https:// doi. org/ 10. 1186/
1471- 230X-6- 33
57. Ferraioli G (2021) Quantitative assessment of liver steato-
sis using ultrasound controlled attenuation parameter (Echo-
sens). J Med Ultrason 48:489–495. https:// doi. org/ 10. 1007/
s10396- 021- 01106-1
58. Younossi ZM, Page S, Rafiq N, Birerdinc A, Stepanova M, Hos-
sain N, Afendy A, Younoszai Z, Goodman Z, Baranova A (2011)
A Biomarker panel for non-alcoholic steatohepatitis (NASH) and
NASH-related fibrosis. Obes Surg 21(4):431–439. https:// doi.
org/ 10. 1007/ s11695- 010- 0204-1
59. Overview | Non-alcoholic fatty liver disease (NAFLD): assess-
ment and management | Guidance | NICE. https:// www. nice. org.
uk/ guida nce/ ng49 (accessed 2022–08–13).
60. Vilar-Gomez E, Chalasani N (2018) Non-invasive assessment
of non-alcoholic fatty liver disease: clinical prediction rules and
blood-based biomarkers. J Hepatol 68(2):305–315. https:// doi.
org/ 10. 1016/j. jhep. 2017. 11. 013
61. Castera L, Friedrich-Rust M, Loomba R (2019) Noninvasive
assessment of liver disease in patients with nonalcoholic fatty
liver disease. Gastroenterology 156(5):1264-1281.e4. https:// doi.
org/ 10. 1053/j. gastro. 2018. 12. 036
62. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C
(2022) Baveno VII Faculty. baveno VII-renewing consensus in
portal hypertension. J Hepatol 76:959–974. https:// doi. org/ 10.
1016/j. jhep. 2021. 12. 022
63. Pons M, Augustin S, Scheiner B, Guillaume M, Rosselli M, Rod-
rigues SG, Stefanescu H, Ma MM, Mandorfer M, Mergeay-Fabre
M, Procopet B, Schwabl P, Ferlitsch A, Semmler G, Berzigotti
A, Tsochatzis E, Bureau C, Reiberger T, Bosch J, Abraldes JG,
Genescà J (2021) Noninvasive diagnosis of portal hypertension
in patients with compensated advanced chronic liver disease. Am
J Gastroenterol 116:723–732
64. Lee DH, Cho EJ, Bae JS, Lee JY, Yu SJ, Kim H, Lee KB, Han
JK, Choi BI (2021) Accuracy of two-dimensional shear wave
elastography and attenuation imaging for evaluation of patients
with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol
19(4):797-805.e7. https:// doi. org/ 10. 1016/j. cgh. 2020. 05. 034
65. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ,
Cummings OW, Ferrell LD, Liu Y-C, Torbenson MS, Unalp-
Arida A, Yeh M, McCullough AJ, Sanyal AJ (2005) onalcoholic
steatohepatitis clinical research network. design and validation of
a histological scoring system for nonalcoholic fatty liver disease.
Hepatology 41:1313–1321. https:// doi. org/ 10. 1002/ hep. 20701
66. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen
R, Angulo P, Lymp JF, Burgart L, Colin P (2004) Ursodeoxy-
cholic acid for treatment of nonalcoholic steatohepatitis: results
of a randomized trial. Hepatology 39(3):770–778. https:// doi. org/
10. 1002/ hep. 20092
67. Softic S, Gupta MK, Wang G-X, Fujisaka S, O’Neill BT, Rao
TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, New-
gard CB, Cohen DE, Kahn CR (2017) Divergent effects of glu-
cose and fructose on hepatic lipogenesis and insulin signaling.
J Clin Invest 127(11):4059–4074. https:// doi. org/ 10. 1172/ JCI94
585
68. Colca JR, McDonald WG, Cavey GS, Cole SL, Holewa DD,
Brightwell-Conrad AS, Wolfe CL, Wheeler JS, Coulter KR,
Kilkuskie PM, Gracheva E, Korshunova Y, Trusgnich M, Karr
R, Wiley SE, Divakaruni AS, Murphy AN, Vigueira PA, Finck
BN, Kletzien RF (2013) Identification of a Mitochondrial target
of thiazolidinedione insulin sensitizers (mtot)–relationship to
newly identified mitochondrial pyruvate carrier proteins. PLoS
ONE 8(5):e61551. https:// doi. org/ 10. 1371/ journ al. pone. 00615 51
69. McCommis KS, Chen Z, Fu X, McDonald WG, Colca JR, Kletz-
ien RF, Burgess SC, Finck BN (2015) Loss of mitochondrial
pyruvate carrier 2 in the liver leads to defects in gluconeogen-
esis and compensation via pyruvate-alanine cycling. Cell Metab
22(4):682–694. https:// doi. org/ 10. 1016/j. cmet. 2015. 07. 028
70. Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT,
Kashyap S, Mechanick JI, Mouzaki M, Nadolsky K, Rinella ME,
Vos MB, Younossi Z (2022) American association of clinical
endocrinology clinical practice guideline for the diagnosis and
management of nonalcoholic fatty liver disease in primary care
and endocrinology clinical settings: co-sponsored by the ameri-
can association for the study of liver diseases (AASLD). Endocr

Internal and Emergency Medicine
1 3
Pract 28(5):528–562. https:// doi. org/ 10. 1016/j. eprac. 2022. 03.
010
71. European Association for the Study of the Liver (EASL); Euro-
pean Association for the Study of Diabetes (EASD); European
Association for the Study of Obesity (EASO) (2016) EASL-
EASD-EASO clinical practice guidelines for the management
of non-alcoholic fatty liver disease. J Hepatol 64(6):1388–1402.
https:// doi. org/ 10. 1016/j. jhep. 2015. 11. 004
72. Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL, Gra-Oramas
B, Gonzalez-Fabian L, Lazo-Del Vallin S, Diago M, Adams LA
(2017) Serum Biomarkers can predict a change in liver fibrosis
1 year after lifestyle intervention for biopsy-proven NASH. Liver
Int 37(12):1887–1896. https:// doi. org/ 10. 1111/ liv. 13480
73. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies
J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ,
Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA,
Schenker S, Cusi K (2006) A placebo-controlled trial of pioglita-
zone in subjects with nonalcoholic steatohepatitis. N Engl J Med
355(22):2297–2307. https:// doi. org/ 10. 1056/ NEJMo a0603 26
74. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK,
Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary
NS, Mithal A (2018) Effect of empagliflozin on liver fat in
patients with type 2 diabetes and nonalcoholic fatty liver dis-
ease: a randomized controlled trial (E-LIFT Trial). Diabetes Care
41(8):1801–1808. https:// doi. org/ 10. 2337/ dc18- 0165
75. Kitade H, Chen G, Ni Y, Ota T (2017) Nonalcoholic fatty liver
disease and insulin resistance: new insights and potential new
treatments. Nutrients 9(4):E387. https:// doi. org/ 10. 3390/ nu904
0387
76. Zelber-Sagi S, Ratziu V, Oren R (2011) Nutrition and physi-
cal activity in NAFLD: an overview of the epidemiological evi-
dence. World J Gastroenterol 17(29):3377–3389. https:// doi. org/
10. 3748/ wjg. v17. i29. 3377
77. Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ (2003)
Cytokines and NASH: a pilot study of the effects of lifestyle
modification and vitamin E. Hepatology 38(2):413–419. https://
doi. org/ 10. 1053/ jhep. 2003. 50316
78. Shah K, Stufflebam A, Hilton TN, Sinacore DR, Klein S, Villar-
eal DT (2009) Diet and exercise interventions reduce intrahepatic
fat content and improve insulin sensitivity in obese older adults.
Obesity (Silver Spring) 17(12):2162–2168. https:// doi. org/ 10.
1038/ oby. 2009. 126
79. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth
S, O’Dea K, Desmond PV, Johnson NA, Wilson AM (2013) The
mediterranean diet improves hepatic steatosis and insulin sen-
sitivity in individuals with non-alcoholic fatty liver disease. J
Hepatol 59(1):138–143. https:// doi. org/ 10. 1016/j. jhep. 2013. 02.
012
80. Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli
A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K,
Kjær MS, Balendran C, Myers RP, Loomba R, Noureddin M
(2022) Safety and efficacy of combination therapy with semaglu-
tide, cilofexor and firsocostat in patients with non-alcoholic stea-
tohepatitis: a randomised. Open-Label Phase II Trial J Hepatol
S0168–8278(22):00235–00245. https:// doi. org/ 10. 1016/j. jhep.
2022. 04. 003
81. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Rat-
ziu V, Sanyal AJ, Sejling A-S, Harrison SA (2021) NN9931–
4296 investigators. a placebo-controlled trial of subcutaneous
semaglutide in nonalcoholic steatohepatitis. N Engl J Med
384:1113–1124. https:// doi. org/ 10. 1056/ NEJMo a2028 395
82. Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock
J, Sørrig R, Wadden TA, Wizert A, Garvey WT (2022) STEP 8
investigators. effect of weekly subcutaneous semaglutide vs daily
liraglutide on body weight in adults with overweight or obesity
without diabetes. The step 8 randomized clinical trial. JAMA
327:138–150. https:// doi. org/ 10. 1001/ jama. 2021. 23619
83. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker
R, Hazlehurst JM, Guo K, Abouda G, Aldersley MA, Stocken
D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, New-
some PN (2016) Liraglutide safety and efficacy in patients with
non-alcoholic steatohepatitis (LEAN): a multicentre, double-
blind, randomised, placebo-controlled phase 2 study. The Lancet
387(10019):679–690. https:// doi. org/ 10. 1016/ S0140- 6736(15)
00803-X
84. A Placebo-Controlled Trial of Subcutaneous Semaglutide in
Nonalcoholic Steatohepatitis | NEJM. https://www.nejm.org/
doi/full/https:// doi. org/ 10. 1056/ NEJMo a2028 395 (accessed
2022–08–14)
85. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline
GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF (2002)
The Effects of rosiglitazone on insulin sensitivity, lipolysis, and
hepatic and skeletal muscle triglyceride content in patients with
type 2 diabetes. Diabetes 51(3):797–802. https:// doi. org/ 10. 2337/
diabe tes. 51.3. 797
86. Gross B, Pawlak M, Lefebvre P, Staels B (2017) PPARs in obe-
sity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endo-
crinol 13(1):36–49. https:// doi. org/ 10. 1038/ nrendo. 2016. 135
87. Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Bar-
oni G, Ridolfi F, Trozzi L, Surrenti C, Casini A (2002) Antidia-
betic thiazolidinediones inhibit collagen synthesis and hepatic
stellate cell activation invivo and invitro. Gastroenterology
122(7):1924–1940. https:// doi. org/ 10. 1053/ gast. 2002. 33666
88. Musso G, Cassader M, Paschetta E, Gambino R (2017) Thiazo-
lidinediones and advanced liver fibrosis in nonalcoholic steato-
hepatitis: a meta-analysis. JAMA Intern Med 177(5):633–640.
https:// doi. org/ 10. 1001/ jamai ntern med. 2016. 9607
89. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel
S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC,
Inzucchi SE (2015) Empagliflozin, cardiovascular outcomes, and
mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128.
https:// doi. org/ 10. 1056/ NEJMo a1504 720
90. Neal B, Perkovic V, Matthews DR (2017) Canagliflozin and car-
diovascular and renal events in type 2 diabetes. N Engl J Med
377(21):2099. https:// doi. org/ 10. 1056/ NEJMc 17125 72
91. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A,
Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL,
Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson
IAM, Fredriksson M, Johansson PA, Langkilde A-M, Sabatine
MS (2019) Dapagliflozin and Cardiovascular outcomes in type 2
diabetes. N Engl J Med 380(4):347–357. https:// doi. org/ 10. 1056/
NEJMo a1812 389
92. Tahara A, Takasu T, Yokono M, Imamura M, Kurosaki E (2017)
Characterization and comparison of SGLT2 inhibitors: part 3.
Effects on diabetic complications in type 2 diabetic mice. Eur J
Pharmacol 809:163–171. https:// doi. org/ 10. 1016/j. ejphar. 2017.
05. 019
93. Gaborit B, Ancel P, Abdullah AE, Maurice F, Abdesselam I,
Calen A, Soghomonian A, Houssays M, Varlet I, Eisinger M,
Lasbleiz A, Peiretti F, Bornet CE, Lefur Y, Pini L, Rapacchi S,
Bernard M, Resseguier N, Darmon P, Kober F, Dutour A (2021)
Effect of empagliflozin on ectopic fat stores and myocardial ener-
getics in Type 2 diabetes: The EMPACEF Study. Cardiovasc Dia-
betol 20(1):57. https:// doi. org/ 10. 1186/ s12933- 021- 01237-2
94. Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, Ranvir
R, Kadam S, Patel H, Swain P, Roy SS, Das N, Karmakar E,
Wahli W, Patel PR (2018) Dual PPARα/γ agonist saroglitazar
improves liver histopathology and biochemistry in experimental
NASH models. Liver Int 38(6):1084–1094. https:// doi. org/ 10.
1111/ liv. 13634

Internal and Emergency Medicine
1 3
95. Inventiva’s lanifibranor meets the primary and key secondary
endpoints in the Phase IIb NATIVE clinical trial in non-alcoholic
steatohepatitis (NASH). Inventiva Pharma. https:// inven tivap
harma. com/ inven tivas- lanif ibran or- meets- the- prima ry- and-
key- secon dary- endpo ints- in- the- phase- iib- native- clini cal- trial-
in- non- alcoh olic- steat ohepa titis- nash/ (accessed 2022–08–14).
96. Ren M, Zhou X, Zhang Y, Mo F, Yang J, Yu M, Ji F (2022)
Effects of bariatric endoscopy on non-alcoholic fatty liver dis-
ease: a comprehensive systematic review and meta-analysis.
Front Endocrinol (Lausanne) 13:931519. https:// doi. org/ 10. 3389/
fendo. 2022. 931519
97. Caiazzo R, Lassailly G, Leteurtre E, Baud G, Verkindt H,
Raverdy V, Buob D, Pigeyre M, Mathurin P, Pattou F (2014)
Roux-En-Y gastric bypass versus adjustable gastric banding to
reduce nonalcoholic fatty liver disease: a 5-year controlled longi-
tudinal study. Ann Surg 260(5):893–898. https:// doi. org/ 10. 1097/
SLA. 00000 00000 000945
98. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H,
Labreuche J, Raverdy V, Leteurtre E, Dharancy S, Louvet A,
Romon M, Duhamel A, Pattou F, Mathurin P (2015) Bariatric
surgery reduces features of nonalcoholic steatohepatitis in mor-
bidly obese patients. Gastroenterology 149(2):379–388. https://
doi. org/ 10. 1053/j. gastro. 2015. 04. 014
99. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T,
Mendez-Sanchez N, Lizardi-Cervera J, Uribe M (2020) Bari-
atric surgery for non-alcoholic steatohepatitis in obese patients.
Cochrane Database Syst Rev. https:// doi. org/ 10. 1002/ 14651 858.
CD007 340. pub2
100. Kalinowski P, Paluszkiewicz R, Ziarkiewicz-Wróblewska B,
Wróblewski T, Remiszewski P, Grodzicki M, Krawczyk M
(2017) Liver function in patients with nonalcoholic fatty liver
disease randomized to Roux-En-Y gastric bypass versus sleeve
gastrectomy: a secondary analysis of a randomized clinical trial.
Ann Surg 266(5):738–745. https:// doi. org/ 10. 1097/ SLA. 00000
00000 002397
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds
exclusive rights to this article under a publishing agreement with the
author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of
such publishing agreement and applicable law.