PIIS1530891X22000908

Endocrine Practice 28 (2022) 528e562
Contents lists available at ScienceDirect
Endocrine Practice
journal homepage: www.endocrinepractice.org
Clinical Practice Guidelines
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 American Association for the Study of Liver Diseases (AASLD)
Kenneth Cusi, MD, FACE, FACP, Co-Chair 1, *, Scott Isaacs, MD, FACE, FACP, Co-Chair 2,
Diana Barb, MD, ECNU 3, Rita Basu, MD 4, Sonia Caprio, MD 5,
W. Timothy Garvey, MD, MACE 6, Sangeeta Kashyap, MD 7,
Jeffrey I. Mechanick, MD, ECNU, MACE, FACP, FACN 8, Marialena Mouzaki, MD, MSc 9,
Karl Nadolsky, DO, FACE, DABOM 10, Mary E. Rinella, MD, AASLD Representative 11,
Miriam B. Vos, MD, MSPH 12, Zobair Younossi, MD, AASLD Representative 13
1
Guideine and Algorithm Task Forces Co-Chair, Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
2
Guideline and Algorithm Task Forces Co-Chair, Division of Endocrinology, Emory University School of Medicine, Atlanta, Georgia
3
University of Florida, Gainesville, Florida
4
Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia
5
Yale University School of Medicine, New Haven, Connecticut
6
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
7
Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio
8
The Marie-Josee and Henry R. Kravis Center for Cardiovascular Health at Mount Sinai Heart, Icahn School of Medicine at Mount Sinai
9
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
10
Michigan State University College of Human Medicine, Grand Rapids, Michigan
11
AASLD Representative, University of Pritzker School of Medicine, Chicago, Illinois
12
Center for Clinical and Translational Research, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia
13
AASLD Representative, Inova Medicine, Inova Health System, Falls Church, Virginia
a r t i c l e i n f o a b s t r a c t
Article history:
Received 3 February 2022
Received in revised form Objective: To provide evidence-based recommendations regarding the diagnosis and management of
11 March 2022 nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists,
Accepted 11 March 2022 primary care clinicians, health care professionals, and other stakeholders.
Available online 12 May 2022 Methods: The American Association of Clinical Endocrinology conducted literature searches for relevant
articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed
Key words: evidence-based guideline recommendations based on a review of clinical evidence, expertise, and
NAFLD informal consensus, according to established American Association of Clinical Endocrinology protocol for
diabetes guideline development.
NAFLD Algorithm Task Force: Kenneth Cusi, MD, FACE, FACP, Co-Chair; Scott Isaacs, MD, FACE, FACP, Co-Chair; Diana Barb, MD, ECNU; Sonia Caprio, MD; Sangeeta Kashyap,
MD; Karl Nadolsky, DO, FACE, DABOM.
Disclaimer: The American Association of Clinical Endocrinology clinical practice guidelines include systematically developed recommendations to assist health care
professionals in medical decision-making for specific clinical conditions. Most of the content herein is based on scientific evidence. In areas of uncertainty, or when clar-
ification is required, expert opinion and professional judgement were applied.
This guideline is a working document that reflects the state of the field at the time of publication. Since rapid changes in this area are expected, periodic revisions are
inevitable. We encourage health care professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be
appropriate in all situations. Any decision(s) by health care professionals to apply the recommendations provided in this guideline must be made in consideration of local
resources and individual patient circumstances.
Please address reprint requests to: publications@aace.com
* Address correspondence to Dr Kenneth Cusi, Division of Endocrinology, Diabetes and Metabolism, University of Florida, 1600 SW Archer Rd; room H -2, P.O.Box: 100226,
Gainesville, Florida 32610-0226.
https://doi.org/10.1016/j.eprac.2022.03.010
1530-891X/© 2022 Published by Elsevier Inc. on behalf of the AACE.
K. Cusi, S. Isaacs, D. Barb et al. Endocrine Practice 28 (2022) 528e562
steatohepatitis
Recommendation Summary: This guideline includes 34 evidence-based clinical practice recommenda-
weight loss
GLP-1 RA tions for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations
pioglitazone that inform the evidence base.
Conclusion: NAFLD is a major public health problem that will only worsen in the future, as it is closely
linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and
primary care physicians are in an ideal position to identify persons at risk on to prevent the development
of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to
treat NAFLD are currently available, management can include lifestyle changes that promote an energy
deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like
peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some dia-
betes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with
type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce
the increased cardiovascular risk associated with this complex disease.
© 2022 Published by Elsevier Inc. on behalf of the AACE.
Lay Abstract the most common cause of death. The primary treatment of NAFLD is
weight loss with a low-calorie diet; restriction of saturated fat, starch,
Nonalcoholic fatty liver disease (NAFLD) is the most common cause and sugar; improved eating patterns (eg, Mediterranean diet and
of chronic liver disease affecting 25% of the global population. Despite minimally processed whole foods); and exercise. Cardiometabolic
the sizable and growing prevalence, disease awareness remains benefit and reduction of liver fat can be observed with >5% weight loss.
limited with <5% of persons with NAFLD being aware of their disease More weight loss provides increased benefits and may reverse stea-
compared with 38% of persons with viral hepatitis. Twelve to 14% of tohepatitis or liver fibrosis (10% weight loss). There are no U.S. Food
persons with NAFLD have a more aggressive form known as nonal- and Drug Administration-approved medications for the treatment of
coholic steatohepatitis (NASH), which can progress to advanced liver NAFLD; however, some diabetes and antiobesity medications can be
fibrosis, cirrhosis, or liver cancer. The risk of NASH is two- to threefold beneficial. Bariatric surgery is also effective for weight loss and
higher in persons with obesity and/or type 2 diabetes mellitus. NASH is reducing liver fat in persons with severe obesity.
among the top causes of liver cancer and the second most common
indication for liver transplantation in the United States after hepatitis C.
NAFLD is diagnosed by abnormal liver test results (although liver test Structure of Clinical Practice Guideline
results may be normal) and imaging studies, not related to excess
alcohol use or other causes of liver disease. NASH is diagnosed by a liver 1. Introduction
biopsy; however, specialized blood tests and imaging can determine Epidemiology of Adult and Pediatric NAFLD
the risk of significant fibrosis. NAFLD is associated with car- Purpose
diometabolic disorders: (1) obesity, (2) insulin resistance, (3) type 2 Scope
diabetes mellitus, (4) high blood pressure, and (5) atherogenic Limitations of the Literature
dyslipidemia, all of which increase the risk of a heart attack or stroke, 2. Methods
3. Summary of Recommendations: summary list of all recom-
mendations developed for this clinical practice guideline
4. Recommendations With Evidence Base
Recommendation
Abbreviations Recommendation Grade, Strength of Evidence Grade, and Best
AACE, American Association of Clinical Endocrinology; AASLD, American Evidence Level
Association for the Study of Liver Diseases; ABCD, adiposity-based chronic Evidence Base: summary of clinical background and high-
disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; lighted studies that best support the recommendation
aHR, adjusted hazard ratio; BEL, best evidence level; BMI, body mass index;
CAP, controlled attenuation parameter; CI, confidence interval; CKD, chronic
kidney disease; CMD, cardiometabolic disease; CPG, Clinical Practice
Guidelines; CV, cardiovascular; CVD, cardiovascular disease; EBMT,
Endoscopic bariatric and metabolic therapy; ELF, enhanced liver fibrosis; Introduction
ESG, endoscopic sleeve gastroplasty; FDA, U.S. Food and Drug
Administration; FIB-4, fibrosis-4 index; GH, growth hormone; GLP-1 RA, Epidemiology
glucagon-like peptide-1 receptor agonist; HCC, hepatocellular carcinoma; HR,
hazard ratio; 1H-MRS, proton magnetic resonance spectroscopy; IGB,
intragastric balloon; IHTG, intrahepatic triglyceride; IR, insulin resistance; What Is the Magnitude of the Problem/Disease Burden in Endocrine
LSM, liver stiffness measurement; MACE, major adverse cardiovascular and Primary Care Clinics?
event; MetS, metabolic syndrome; MRE, magnetic resonance elastography; Nonalcoholic fatty liver disease (NAFLD) is part of a multi-
MRI, magnetic resonance imaging; MRI-PDFF, magnetic resonance imaging- systemic disease and is closely associated with obesity, insulin
proton density fat fraction; NAFLD, nonalcoholic fatty liver disease; NAS,
NAFLD activity score; NASH, nonalcoholic steatohepatitis; NFS, NAFLD
resistance (IR), type 2 diabetes mellitus (T2D), hypertension, and
fibrosis score; NPV, negative predictive value; OR, odds ratio; PCOS, atherogenic dyslipidemia.1,2 The definition of NAFLD is based on the
polycystic ovary syndrome; PCP, primary care physician; PNPLA3, patatin- presence of hepatic steatosis in >5% of hepatocytes in the absence
like phospholipase domain-containing 3; PPAR, peroxisome proliferator- of significant ongoing or recent alcohol consumption and other
activated receptor; PPV, positive predictive value; pSWE, point shear wave
known causes of liver disease.1,2 Nonalcoholic steatohepatitis
elastography; RCT, randomized controlled trial; RYGB, Roux-en-Y gastric
bypass; SGLT2, sodium-glucose cotransporter 2; SWE, shear wave (NASH), more likely to progress to advanced stages of fibrosis, is
elastography; TBW, total body weight; TE, transient elastography; T1D, type characterized by the presence of active hepatocyte injury
1 diabetes mellitus; T2D, type 2 diabetes mellitus; US, ultrasonography; (ballooning) and inflammation in addition to steatosis (Table 1
2DSWE, 2-dimensional shear wave elastography; VCTE, vibration-controlled shows the common terms and definitions, and Table 2 shows the
transient elastography.
histologic definition of NAFLD grades and fibrosis stages).
529
Table 1
Relevant Definitions in NAFLD
NAFLDa Nonalcoholic fatty liver Term used for the broad spectrum of the disease, ranging from hepatic steatosis only to steatohepatitis (NASH)
disease to cirrhosis, in the absence of ongoing or recent consumption of significant amounts of alcohol or the
presence of other secondary causes of fatty liver disease.
NASHa Nonalcoholic Presence of 5% hepatic steatosis with inflammation and hepatocyte injury (also known as hepatocyte
steatohepatitis ballooning), with or without evidence of liver fibrosis.
NASH cirrhosisa Cirrhosis with histologic evidence of steatosis or steatohepatitis.
NASa NAFLD activity score An unweighted composite of steatosis, lobular inflammation, and ballooning scores.
Significant … Defined as ingestion of >21 standard drinks per week in men and >14 standard drinks per week in women
alcohol over a 2-year period preceding baseline liver histology.
consumptiona,b
FIB-4 Fibrosis-4 index An index to estimate the risk of hepatic cirrhosis calculated from the computation of age, plasma
aminotransferases (AST and ALT), and platelet count. This noninvasive estimate of liver scarring is used to assess the
need for biopsy. The score is calculated using a person’s age, AST level, platelet count (PLT), and ALT level.
FIB-4 score ¼ age (years) AST (U/L)/[PLT (109/L) ALT ½ (U/L).
ELF Enhanced liver fibrosis test This blood test measures the levels of tissue inhibitor of metalloproteinases 1, amino-terminal propeptide of type III
procollagen, and hyaluronic acid and is used to estimate the rate of liver extracellular matrix metabolism reflecting the
severity of liver fibrosis.
NFS NAFLD fibrosis score 1.675 þ 0.037 age (years) þ 0.094 BMI (kg/m2) þ 1.13 (impaired fasting glucose or DM) þ 0.99
(AST/ALT) 0.013 platelet ( 109/L) ¼ 0.66 albumin (g/dL) (where impaired fasting glucose/DM had
a value of 1 if the participants had impaired fasting glucose and 0 if they did not)
APRI AST-to-platelet ratio index [AST level (IU/L)/AST (upper limit of normal AST range (IU/L) 100] divided by platelet count (109/L)
1
H-MRS Proton magnetic resonance A technique for quantifying hepatic steatosis
spectroscopy
MRI-PDFF Magnetic resonance A technique for quantifying hepatic steatosis
imaging-
proton density fat
fraction
VCTE Vibration-controlled A technique for liver stiffness measurement that is correlated with the severity of liver fibrosis on histology.
transient
elastography
MRE Magnetic resonance Technology that combines MRI with low-frequency vibrations to assess liver stiffness.
elastography
Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BMI ¼ body mass index; DM ¼ diabetes mellitus.
a
Sanyal et al.3
b
A standard alcoholic drink is defined as a given drink with approximately 14 g of pure alcohol (https://pubs.niaaa.nih.gov/publications/practitioner/pocketguide/pocket_
guide2/htm). Accessed on December 10th, 2021.
Table 2
Features of NASH and Fibrosis Staging (Adapted and Reprinted With Permission From Younossi et al2 and Kleiner et al4)
Feature Definition Score or code
Steatosis grade Low- to medium-power evaluation of parenchymal involvement by steatosis <5% ¼ 0

5%-33% ¼ 1 (mild)
33%-66% ¼ 2 (moderate)
>66% ¼ 3 (severe)
Lobular inflammation Overall assessment of all inflammatory foci per 200 field No foci ¼ 0
<2 foci per 200 field ¼ 1
2-4 foci per 200 field ¼ 2
>4 foci per 200 field ¼ 3
Ballooning … None ¼ 0
Few (or borderline) balloon cells ¼ 1
Many cells/prominent ballooning ¼ 2
NAS Sum of steatosis þ lobular inflammation þ ballooning 0-8
Fibrosis stage … None ¼ 0
Mild ¼ perisinusoidal or periportal (stage 1)
Moderate ¼ perisinusoidal and portal/periportal (stage 2)
Severe ¼ bridging fibrosis (stage 3)
Cirrhosis ¼ stage 4
Abbreviation: NAS ¼ nonalcoholic fatty liver disease activity score.
Globally, the overall prevalence of NAFLD is 25%, while the liver fibrosis (stages F2),9 consistent with other recent
prevalence of the potentially progressive form of NAFLD or NASH is population-based studies in the United States.10,11
between 12% and 14%.5 The highest prevalence rates for NAFLD and The prevalence of NAFLD12 is expected to continue to increase,
NASH have been reported from the Middle Eastern countries.1 In likely with a disproportionate increase in advanced disease.13
addition, the prevalence rates are significantly higher in those with Current estimates suggest that approximately 20% of persons
T2D and visceral obesity. In fact, among those with obesity, the with NASH could potentially develop significant liver disease
prevalence of NASH is between 25% and 30%, while approximately including cirrhosis and its complications.14 NASH is now among
30% to 40% of persons with diabetes have NASH.1,6e8 A recent study the top causes of hepatocellular carcinoma (HCC)15,16 and the
indicated that in outpatient family medicine, internal medicine, second most common cause of HCC in those on the waiting list for
and endocrine clinics, approximately 70% of persons with T2D have liver transplantation in the United States after hepatitis C.17 This
NAFLD (steatosis), and approximately 15% have clinically significant growth is especially worrisome for Asia, the Middle East, and
530
North African regions, with the highest documented prevalence of Several reports have shown that obesity and diabetes interact
NAFLD.18 with genetic factors to increase the risk of cirrhosis in Hispanics,
Despite the sizable and growing prevalence of NAFLD, disease with their relative contribution being often difficult to fully un-
awareness remains quite limited, with <5% of persons with NAFLD tangle. Several genetic variants that modify hepatocyte triglyceride
being aware of their liver disease compared with liver disease metabolism have been investigated by genome-wide association
awareness in 38% of persons with viral hepatitis.19 Furthermore, a and exome sequencing. The risk variants most studied alter either
global survey of over 2200 physicians recently highlighted the lipid droplet trafficking (patatin-like phospholipase domain-
knowledge gap regarding NAFLD among providers, especially for containing 3 [PNPLA3]), secretion of low-density lipoprotein
primary care physicians (PCPs) and endocrinologists.20 Another cholesterol (transmembrane 6 superfamily member 2), lipid
recent survey of 751 clinicians in the United States, including PCPs, signaling/metabolism (hydroxysteroid 17-beta dehydrogenase), de
endocrinologists, and gastroenterologists or hepatologists, found novo lipogenesis (GCKR), or hepatic phosphatidylinositol acyl chain
that they underestimated the prevalence of NAFLD in high-risk remodeling (MBOAT7), among others.35 The PNPLA3 148I/M
groups (eg, those with severe obesity or T2D) and that there was (rs738409) is highly prevalent in Hispanics,36 likely promoting
underutilization of medications with proven efficacy in NASH.21 steatosis by interfering with lipid droplet function and hepatocyte
Finally, diagnosis and referral to specialists for management lipid turnover. The major implication is that the variant has been
remain low among endocrinologists.21,22 In contrast to other highly associated with a greater risk of NASH progression and
prevalent noncommunicable chronic conditions (ie, obesity, dia- cirrhosis.35,37,38 It appears that the genetic variants identified
betes, and cardiovascular disease [CVD]), NAFLD has received little amplify their impact across the spectrum of the disease in the
attention from a public health perspective with global health stra- presence of obesity, from steatosis to inflammation to cirrhosis.39
tegies characterized as inadequate and fragmented.23 This conun- However, there is insufficient evidence to strongly conclude that
drum of increasing disease burden, limited awareness, and clinical race, by itself, plays a central role in the development of hepatic
inertia exacerbates the public health challenge. This is especially fibrosis.36,37 Therefore, at the present time, genetic testing cannot
relevant given the fact that the vast majority of persons with T2D, be recommended in the clinical realm for the management of pa-
who may have underlying NAFLD, are predominantly seen by pri- tients with NASH, although this may change as more data become
mary care clinicians and endocrinologists but remain undiagnosed available about the clinical implications of different gene variants.
and untreated. Therefore, the aim of developing this evidence-based While the disease progression rate is relatively slow in most
guideline is to increase awareness about NAFLD and NASH and people, progression may be faster in some individuals with risk
provide easy-to-use and practical recommendations to guide clini- factors (ie, obesity and T2D),40 and approximately one third of in-
cians for the assessment of NAFLD in their practices. dividuals eventually progress to NASH, of which an estimated 20%
develop fibrosis with a high risk of extrahepatic complications,
What Is Known About the Natural History of NAFLD? cirrhosis, and liver failure.41 Development of fibrosis is a key pre-
T2D is a major driver of disease progression. A prevalence study dictor of liver-related outcomes. There is substantive evidence to
conducted across 20 countries found an alarmingly 55% prevalence support a dose-dependent effect of fibrosis on liver-related and all-
of NAFLD among individuals with T2D.6 This may be an underes- cause mortality (5- to 12-fold increase in relative risk), with a
timation of the real prevalence of steatosis as screening in greater risk of liver decompensation, HCC, liver transplantation,
approximately 90% of the studies was performed by liver ultraso- and death.42,43 Excess mortality associated with NAFLD is mostly
nography (US), considered less sensitive than elastography attributable to extrahepatic cancer, cirrhosis, CVD, and HCC. All
(controlled attenuation parameter [CAP]) or magnetic resonance NAFLD histologic stages (Table 2), including isolated steatosis with
imaging (MRI)-based techniques for hepatic steatosis.24 Higher no fibrosis, are associated with a significant increase in overall
estimates of NAFLD and liver fibrosis have been suggested in people mortality, which worsens with liver disease severity.44
with T2D based on 8 studies from 2020 and 2021 from Europe, Due to the increasing incidence of obesity and diabetes, the
Southeast Asia, and the United States using transient elastography prevalence of NAFLD-HCC is on the rise. Thus, NAFLD is likely to
(TE) and/or MRI-based techniques as screening tools for NAFLD, replace hepatitis B and C viruses as the leading cause of HCC
NASH, and fibrosis.25 globally. Some gene variants, such as PNPLA3 or transmembrane 6
Age (>50 years), IR, and features of metabolic syndrome (MetS) superfamily member 2, as discussed earlier, are associated with a
all increase the probability of NASH with a more severe fibrosis much higher risk not only of cirrhosis but also of HCC, with both
stage and cirrhosis.5,26-28 The strong association between steato- risks amplified in the presence of obesity or diabetes.38 There is an
hepatitis and T2D does not establish causality, but it does demon- increasing body of evidence for the association of NAFLD and
strate the impact of diabetes on liver due to a higher prevalence of cancer, which offers the underlying pathophysiology for long-time
obesity in Hispanics than in Caucasians disease severity.29 How- observation that diabetes is associated with a twofold higher risk of
ever, the role of poor glycemic control remains unclear, with some HCC17,45 with a modest contribution from extrahepatic cancers.46 A
studies suggesting that it increases the risk of fibrosis progres- few earlier long-term cohort studies have found extrahepatic can-
sion,30-32 while another study did not show an increased risk.11 cers to be the second leading cause of death after CVD,47 especially
Ethnicity may be another factor in disease progression. In the in those with more advanced (bridging) fibrosis.41 Hence, even
United States, the prevalence of steatohepatitis in the Hispanic though extrahepatic cancers do not pose a significant clinical
population with or without diabetes is the highest, with reports of burden, the increasing incidence of NAFLD-HCC calls for better
approximately 20%7,33 or higher.5 However, when body mass index cancer screening strategies in this population.
(BMI) is well matched, neither steatohepatitis nor fibrosis is worse
in Hispanics than in Caucasians.34 Additionally, although NASH may What Are the Extrahepatic Complications Relevant to
be more common in people of Hispanic descent than in Caucasians Endocrinologists and Practitioners Who Care for Persons With
or those with African American ancestry, a meta-analysis of 34 Endocrine and Cardiometabolic Diseases?
studies comprising 368 569 participants reported that the propor- T2D and CVD are the 2 most important extrahepatic diseases
tion of those with significant fibrosis did not significantly differ associated with NAFLD and are closely associated with visceral
among racial or ethnic groups.33 adiposity and IR. The relationship between NAFLD and T2D is
531
bidirectional, with visceral adiposity and IR being mediators in the BMI, PCOS remained associated with severity of steatohepatitis
causal pathway.48,49 Visceral adipose tissue is known to increase de (hepatocyte ballooning) (OR, 3.4; 95% CI, 1.1-10.6; P ¼ .03) and
novo gluconeogenesis, and liver fat is associated with hepatic IR.48 advanced fibrosis (OR, 7.1; 95% CI, 1.3-39; P ¼ .02).67 The underlying
NAFLD, especially NASH, exacerbates hepatic and adipose tissue IR, mechanisms for the development of NAFLD in PCOS are multifac-
which can contribute to the development of T2D.50 A 2016 meta- torial; however, IR is a key driver.68 Of interest, women with PCOS
analysis of 20 studies conducted that followed 117 020 persons and hyperandrogenism have a threefold higher prevalence of
for a median follow-up period of 5 years found an approximately NAFLD, strongly associated with severe IR.69,70
twofold greater relative risk of developing T2D among persons with Obesity, IR, and development of T2D appear to be the underlying
NAFLD than among those without NAFLD.51 This finding was factors associated with development of NAFLD in several endocrine
consistent with 2 more recent meta-analyses that reported a conditions; the most studied include hypothyroidism, growth
similar twofold increased risk of diabetes associated with having hormone (GH) deficiency, and hypogonadism. Most studies have
NAFLD.52,53 A recent study estimated that there were 18.2 million been small, of poor quality, and either case reports or uncontrolled.
people in the United States living with T2D and NAFLD, of whom 6.4 For instance, hypothyroidism appears associated with steatosis in
million had NASH. Health care costs for persons with T2D and NASH animal models and some human studies.71 Although a recent meta-
were estimated to be $55.8 billion over the next 20 years, to ac- analysis suggested a modest association,72 the results were not
count for 65 000 transplants, 1.37 million cardiovascular (CV)- conclusive. Most studies were small and used a liver US for the
related deaths, and 812 000 liver-related deaths.54 diagnosis, and 7 of 13 studies were negative. A number of other
With up to one third of persons with type 1 diabetes mellitus caveats have been raised from this meta-analysis.73 The definition
(T1D) having obesity, greater attention is being paid to their risk of of hypothyroidism was very broad including overt hypothyroidism,
developing NAFLD.55 The pooled prevalence of NAFLD was 22% in subclinical hypothyroidism, and/or levothyroxine replacement.
adults with T1D based on a systematic review and meta-analysis Moreover, it was unclear how persons receiving levothyroxine
published in 2020 (95% Confidence interval [CI], 13.9%-31.2%). The replacement actually had a higher risk of NAFLD than those with
estimation differed substantially between reports given that hypothyroidism not receiving treatment (OR, 2.19 [95% CI, 1.41-
different imaging modalities and heterogeneous populations were 3.43] vs 1.31 [95% CI, 1.04-1.66]). Moreover, in the 3 longitudinal
included.56 In addition, several studies did not use “gold standard” studies, subclinical hypothyroidism was not independently associ-
diagnostic techniques, such as MRI-based techniques or a liver bi- ated with the risk of incident NAFLD over a median of 5 years
opsy. In one of the few studies using liver MRI, in a predominantly (random-effects HR, 1.29 [95% CI, 0.89-1.86]; I2 ¼ 83.9%). In the
nonobese population (mean BMI, 26.5 kg/m2), the prevalence of largest study using “gold standard” measurements of liver fat
steatosis was 8.8%, much lower than the 68% prevalence observed (proton magnetic resonance spectroscopy [1H-MRS]) and liver
in persons with T2D.57 Because NAFLD affects mostly those with IR histology in 232 middle-aged persons with T2D, only a modest
or obesity, it is not entirely surprising that depending on the pop- relationship was observed between steatosis and low free
ulation studied, some studies have not found persons with T1D to thyroxine levels but no association with inflammation, hepatocyte
have a higher risk of NAFLD.56 injury (ballooning), or fibrosis.74 In animal models, there are re-
The relationship between NAFLD and diabetic complications ports showing an association between low sex hormone levels and
remains poorly understood. Persons with steatosis and T1D have alterations in glucose and lipid metabolism and NAFLD.75 However,
been reported to be at greater risk of developing CVD, arrhythmias, in a study including 175 men with T2D examining the relationship
and other cardiac complications.58-60 The presence of NAFLD has between lower total testosterone level and hepatic steatosis using
1
also been associated with microvascular diabetic complications, H-MRS and liver histology, the relationship disappeared when
especially chronic kidney disease (CKD).61,62 A meta-analysis adjusted for IR and obesity. Moreover, no relationship was observed
including 20 cross-sectional studies with approximately 28 000 between lower total testosterone levels and severity of liver nec-
individuals reported that NAFLD was associated with a twofold roinflammation or fibrosis.76 Finally, GH deficiency has been asso-
increased prevalence of CKD (odds ratio [OR], 2.12; 95% CI, 1.69- ciated with NAFLD given the broad effects of GH on glucose
2.66).63 In the 13 longitudinal studies included in the meta- metabolism.77 Panhypopituitarism has also been linked to
analysis, NAFLD was associated with an overall 80% increased risk NAFLD.78 GH replacement has shown some benefit,79 but studies
of incident CKD (hazard ratio [HR], 1.79; 95% CI, 1.65-1.95). Sub- have been usually small and uncontrolled. In a recent meta-anal-
group analysis suggested that advanced hepatic fibrosis was asso- ysis,80 pooled analysis showed an association between low insulin-
ciated with an even greater risk of CKD.63 Similar results have been like growth factor 1 level and NAFLD, although significant hetero-
reported in a more recent meta-analysis that included 96 500 geneity was present among the 12 studies included. In subgroup
persons (one third with NAFLD) followed for a median of 5.2 analyses, a low insulin-like growth factor 1 level was strongly
years.64 In persons with diabetic retinopathy, the relationship re- associated with obesity and IR.80 Clearly, more studies are needed,
mains controversial, with a recent meta-analysis of 9 studies but GH and testosterone replacement should be used with caution
involving 7170 persons unable to find an overall association be- and following current medical guidelines given their risk of misuse
tween NAFLD and diabetic retinopathy.65 However, significant and of adverse events. Thus, it is premature to recommend persons
heterogeneity and apparent ethnic differences were present among with endocrinopathies to be routinely evaluated for NAFLD, beyond
studies, with some studies from Italy and India demonstrating an the risk associated with the presence of obesity or T2D.
association between NAFLD and diabetic retinopathy, while other Given the high prevalence of NAFLD and CVD and their mutual
studies from the United States, China, Korea, or Iran did not association with MetS, it is not unexpected for the 2 conditions to
demonstrate such an association.65 coexist. Although end-stage liver disease and HCC are the most
Women with polycystic ovary syndrome (PCOS) are at increased common causes of death in persons with cirrhosis, CVD and
risk of T2D and NAFLD. A population-based retrospective study of a extrahepatic malignancy are the leading causes of morbidity and
primary care database of 63 000 women with PCOS and nearly mortality in most individuals with less advanced disease.60,81,82 A
121 000 age-, BMI-, and location-matched controls reported an 2015 analysis of the Framingham Heart Study found that hepatic
increased incidence of NAFLD in women with PCOS (HR, 2.23; 95% steatosis was strongly associated with subclinical CVD outcomes,
CI, 1.86-2.66).66 Recently, a retrospective study of 102 women with independent of other metabolic risk factors.83 Persons with NAFLD
biopsy-confirmed NAFLD found that after adjusting for age and have increased carotid intima-media thickness compared with
532
those without NAFLD.53,84 In a recent cross-sectional study of is an in-depth review of the epidemiology in the general population
asymptomatic individuals undergoing coronary computed tomog- or inclusion of controversial aspects of NAFLD reserved for the liver
raphy angiography, NAFLD was consistently associated with high- specialist. It is meant to provide practical patient-centered guid-
risk noncalcified atherogenic plaques, indicative of a greatly ance for endocrinologists and PCPs who often see populations at
increased CV risk.85 In a longitudinal study of 603 individuals with high risk of developing NASH (ie, those with obesity, MetS, and/or
biopsy-proven NAFLD, followed for a mean of 18.6 years, 28% of T2D). It also does not address interventions of a purely investiga-
persons with NAFLD versus 21% of controls experienced a CVD tional nature; it includes only those interventions available to the
event (HR, 1.54; 95% CI, 1.30-1.83).86 The increased risk of both fatal practicing clinician: (1) lifestyle intervention, (2) bariatric surgery,
and nonfatal CV events has been correlated in some studies with (3) weight loss and diabetes treatment agents, and (4) any other
the severity of hepatic steatosis, inflammation, or fibrosis,53,84 but agent with strong evidence from randomized controlled trials
this remains to be fully established. Finally, a recent meta-analysis (RCTs) deemed as safe and effective. There are no U.S. Food and
among 10 576 383 individuals across 24 countries in nonobese Drug Administration (FDA)-approved medications for the treat-
persons with NAFLD aiming to remove obesity as a confounding ment of NASH available at the time of publication.
factor found that there was still a much higher incidence rate of
new-onset CVD in individuals with NAFLD (18.7 per 1000 person- Limitations of the Literature
years; 95% CI, 9.2-31.2).87
Complications other than atherosclerotic CVD may be associated NAFLD has reached epidemic proportions fueled by the increase
with the presence of NAFLD. A meta-analysis of 9 cross-sectional in the incidence of obesity and T2D, creating a need for endocri-
and longitudinal studies in 2019 that included 364 919 in- nology and primary care clinicians to become engaged in its early
dividuals found a strong correlation between NAFLD and atrial diagnosis and management. Although there is a rapidly growing
fibrillation (pooled OR, 2.07; 95% CI, 1.38-3.10).88 A cross-sectional body of literature, the field still has several knowledge gaps. For
study conducted in 2015 found a significant association between instance, while the diagnosis of hepatic steatosis by imaging is
NAFLD and ventricular arrhythmias.89 However, it must be noted rather simple (ie, liver US or MRI-based techniques), there is a lack
that in the former study, individuals did not undergo 24-hour of robust and well-validated blood tests or imaging studies for the
Holter monitoring, whereas the latter included Holter monitoring noninvasive diagnosis of nonalcoholic steatohepatitis (NASH).
data. A 2020 meta-analysis found that other cardiac complications, Similar limitations apply to the accurate diagnosis of hepatic
such as cardiomyopathy, cardiac valvular calcification, and cardiac fibrosis, with liver biopsy remaining the “gold standard” test for the
arrhythmias, were also more prevalent in persons with NAFLD.84 In diagnosis of NASH and for staging the severity of fibrosis. This calls
a meta-analysis of 12 studies including approximately 280 000 for the stepwise use of noninvasive tests to minimize the need for a
individuals, early heart failure with preserved ejection fraction was liver biopsy, but still, the vast majority of persons with NASH and
found to be more prevalent in persons with well-controlled T2D advanced fibrosis (stages F2-F4; Table 2) remain undiagnosed in
and NAFLD independent of other risk factors.90 However, it will be primary care and endocrinology clinics. There is also a limited
difficult to establish a causal relationship between NAFLD and CVD understanding of the natural history of the disease and factors that
given the tangled web of overlapping metabolic disturbances pre- modulate disease progression. In the pediatric field, there is inad-
sent in these individuals (ie, IR, obesity, T2D, atherogenic dyslipi- equate evidence in terms of the optimal diagnostic and treatment
demia, and visceral adiposity). Future studies are needed to pathways, with current care being based on early diagnosis and
establish this mechanistic link, but even if not causal, endocri- promotion of healthy lifestyle changes.
nology and primary care clinicians should consider persons with Regarding management, the many lifestyle studies in the field
NAFLD as being at high risk of CV complications. have small sample sizes, heterogeneous populations, and a short
Finally, several other complications, such as gallbladder dis- duration (none beyond 12 months). The best diet for the man-
ease,91 obstructive sleep apnea,87,92 colorectal neoplasm,93 and agement of NAFLD is unclear, although weight loss in people with
other cancers90 as well as sarcopenia,94 have also been reported obesity and improved eating patterns (eg, Mediterranean diet)
with increased prevalence in those with NAFLD. Of interest, persons with modification of macronutrient composition (reduction of
with both NAFLD and sarcopenia have a higher risk of CVD (OR, saturated fat, starch, and added sugars) have consistently been
1.83; P ¼ .014) than those without NAFLD and sarcopenia.95 Addi- beneficial. There are still no FDA-approved drugs for the treat-
tionally, recent data suggest that sarcopenia in NAFLD is associated ment of NASH. Limited well-designed and adequately powered
with increased mortality.96 RCTs to assess the effectiveness of available agents, such as those
used for the treatment of diabetes (pioglitazone and glucagon-
Purpose like peptide-1 receptor agonists [GLP-1 RAs]), have been pub-
lished. However, these studies have not exceeded a duration of 2
Given the high prevalence of NAFLD in clinical endocrinology to 3 years for pioglitazone97,98 or 1.5 years for a GLP-1 RA.99
and primary care practice and the paucity of guidelines that address Several RCTs with sodium-glucose cotransporter 2 (SGLT2) in-
the metabolic and endocrinologic perspectives, little guidance is hibitors have employed an open-label design with potential bias,
available for frontline practitioners who care for persons with but some RCTs have shown a reduction in the plasma amino-
NAFLD, most of whom are undiagnosed. The purpose of this transferase levels and hepatic steatosis. However, there are no
guideline is to provide endocrinology and primary care clinicians studies with paired biopsies to assess the effect on steatohepatitis
with practical evidence-based recommendations for the diagnosis or fibrosis.
and management of NAFLD. Recognizing the aforementioned limitations, the grading of the
evidence base was informed by trial design and potential general-
Scope izability, and this guideline should be viewed as breaking new
ground by gathering the available information for endocrinologists
This guideline addresses key management questions and fo- and other stakeholders to guide the early diagnosis and treatment
cuses on the metabolic and endocrinologic aspects of prevention, of persons with NAFLD. We anticipate that it will likely be
diagnosis, treatment, and long-term prognosis for the entire pop- frequently updated as the field rapidly advances in the diagnosis
ulation of persons with NAFLD. Outside the scope of this guideline and management of the disease.
533
Methods journal citation, study design and population, limitations, com-

parison group/controls, intervention, outcomes, and limitations.
The American Association of Clinical Endocrinology (AACE) The CPG Staff assigned a grade for the quality of each
Clinical Practice Guidelines (CPG) Oversight Committee and AACE article, which informed assigned grades for the confidence and
Board of Directors identified the necessity of this guideline on strength of evidence in aggregate for each recommendation
NAFLD, confirmed the extent of literature, and empaneled a task (Supplementary Tables 2, 3, and 4). In cases where the task force
force of clinicians for its development in adherence to the 2017 determined guidance to be necessary despite a lack of available
AACE Protocol for Standardized Production of Clinical Practice supporting literature, a recommendation was developed based on
Guidelines100 (Supplementary Tables 1 through 4). expert opinion and consensus of task force authors’ collective
The AACE CPG Staff conducted comprehensive literature experience, knowledge, and judgment. Recommendation quali-
searches in PubMed using medical subject headings, field de- fiers and subjective factors informed the overall grade assigned for
scriptions, and free-text terms to identify all possible studies that each recommendation (Supplementary Table 4). Through discus-
included human participants; were published in English between sion and consensus of the full task force, the task force members
January 1, 2010, and November 15, 2021; and met inclusion criteria confirmed recommendation grades and grades for strength of
(Supplementary Table 5). Bibliographies of select articles were also evidence. The task force chairs provided oversight throughout the
reviewed to ensure inclusion of all possibly relevant studies. The entire development process.
literature searches and examination of reference lists from primary Clinical questions provide the framework for this guideline
and review articles yielded 1000 studies, of which 385 citations with answers in the form of recommendations. The task force
were included to support this guideline’s recommendations and authors submitted contributions to specific clinical questions,
provide supplementary information. which were integrated into the final document and discussed to
At least 2 task force authors screened the titles and abstracts of achieve unanimous consensus for each of the recommendations.
broad pools of evidence found in literature searches for each topic Semantic descriptors of “must,” “should,” and “may” are gener-
and submitted decisions to include or exclude each article along ally but not strictly correlated with grade A (strong), B (inter-
with rationale for exclusion. Disagreements about inclusion mediate), and C (weak) recommendations, respectively; each
among reviewers were resolved by consensus with a third semantic descriptor can be used with grade D (no conclusive
reviewer or the chairs. Through this process, the authors con- evidence and/or expert opinion) recommendations. Deviations
ducted a thorough appraisal of evidence based on the full scope of from this mapping take into consideration further decision
available literature to determine studies that best support each making based on clinical expertise. The AACE followed a rigorous
recommendation. developmental process based on strict methodology to system-
The AACE CPG Staff assigned evidence levels and study types to atically collect and objectively evaluate and clearly summarize
included studies according to established AACE evidence ratings available scientific literature to develop trustworthy recommen-
(Supplementary Table 1) and extracted data from each full-text dations for clinical practice regarding diagnosis and management
article into a structured table to document the authors, title, of NAFLD.
Table 3
Summary of Recommendations
2. Diagnosis of NAFLD in adults

Q2.1 Which adults with NAFLD should be considered at “high risk” of clinically significant fibrosis (stages F2-F4) and at risk of cirrhosis?
R2.1.1 Clinicians should consider persons with obesity and/or features of metabolic syndrome, those with prediabetes or T2D, and those with hepatic steatosis on any
imaging study and/or persistently elevated plasma aminotransferase levels (over 6 months) to be “high risk” and screen for NAFLD and advanced fibrosis.
Grade B; Intermediate/High Strength of Evidence; BEL 2
R2.1.2 Persons undergoing bariatric surgery should be evaluated for the presence and severity of NASH, and a liver biopsy should be considered at the time of bariatric
surgery. Liver biopsy should be recommended if presurgical stratification suggests indeterminate or high risk of liver fibrosis.
Grade B; Intermediate Strength of Evidence; BEL 2
Q2.2 What blood tests (eg, diagnostic panels and specific biomarkers) can be used to diagnose NAFLD with clinically significant fibrosis (stages F2-F4) in adults?
R2.2.1 Clinicians should use liver fibrosis prediction calculations to assess the risk of NAFLD with liver fibrosis. The preferred noninvasive initial test is the FIB-4.
R2.2.2 Clinicians should consider persons belonging to the “high-risk” groups (as defined under R2.1.1) who have an indeterminate or high FIB-4 score for further
workup with an LSM (transient elastography) or ELF test, as available.
Q2.3 What imaging studies can be used to diagnose NAFLD with clinically significant fibrosis (stages F2-F4) in adults?
R2.3 To stage the risk of fibrosis in persons with NAFLD, clinicians should prefer the use of VCTE as best validated to identify advanced disease and predict liver-related
outcomes. Alternative imaging approaches may be considered, including shear wave elastography (less well validated) and/or magnetic resonance elastography
(most accurate but with a high cost and limited availability; best if ordered by liver specialist for selected cases).
Q2.4 Should all persons with diabetes mellitus be screened for clinically significant fibrosis (stages F2-F4) associated with NAFLD?
R2.4.1 In persons with T2D, clinicians should consider screening for clinically significant fibrosis (stages F2-F4) using the FIB-4, even if they have normal liver enzyme
levels.
Grade B; High/Intermediate Strength of Evidence; BEL 2
R2.4.2 In persons with T1D, clinicians may consider screening for NAFLD with clinically significant fibrosis (stages F2-F4) using the FIB-4, only if there are risk factors
such as obesity, features of metabolic syndrome, elevated plasma aminotransferase levels (>30 U/L), or hepatic steatosis on imaging.
Grade C; Intermediate/Weak Strength of Evidence; BEL 2; downgraded based on the heterogeneity of studies and moderate to high probability of bias
R2.4.3 Clinicians should further risk stratify persons with T2D, or T1D with cardiometabolic risk factors and/or elevated plasma aminotransferase levels (>30 U/L)
using the FIB-4, elastography, and/or ELF test.
Grade B; High/Intermediate Strength of Evidence; BEL 2
534
Table 3 (continued )
Q2.5 When should an adult be referred to a gastroenterologist/hepatologist for management?
R2.5.1 Persons with persistently elevated ALT or AST levels and/or with hepatic steatosis on imaging and indeterminate risk (FIB-4, 1.3-2.67; LSM, 8-12 kPa; or ELF test,
7.7-9.8) or high risk (FIB-4, >2.67; LSM, >12 kPa; or ELF test, >9.8) based on blood tests and/or imaging (as described in R2.2.1, R2.2.2, and R2.3) should be referred to
a gastroenterologist or hepatologist for further assessment, which may include a liver biopsy.
R2.5.2 Clinicians should refer persons with clinical evidence of advanced liver disease (ascites, hepatic encephalopathy, esophageal varices, or evidence of hepatic
synthetic dysfunction) to a gastroenterologist/hepatologist for further care.
3. Management of NAFLD in adults

Q3.1 How should cardiometabolic risk and other extrahepatic complications be managed in the setting of NAFLD?
R3.1 Clinicians must manage persons with NAFLD for obesity, metabolic syndrome, prediabetes, diabetes mellitus, dyslipidemia, hypertension, and CVD based on the
current standards of care.
Grade A; High/Intermediate Strength of Evidence; BEL 1
Q3.2 What lifestyle modifications (dietary intervention and exercise) should be recommended in adults with NAFLD?
R3.2.1 Clinicians should recommend lifestyle changes in persons with excess adiposity and NAFLD with a goal of at least 5%, preferably 10%, weight loss, as more
weight loss is often associated with greater liver histologic and cardiometabolic benefit, depending on individualized risk assessments. Clinicians must recommend
participation in a structured weight loss program, when possible, tailored to the individual’s lifestyle and personal preferences.
Grade B; Intermediate/High Strength of Evidence; BEL 1; downgraded due to small sample sizes, large heterogeneity of interventions, short duration, and few
studies with liver biopsy
R3.2.2 Clinicians must recommend dietary modification in persons with NAFLD, including a reduction of macronutrient content to induce an energy deficit (with
restriction of saturated fat, starch, and added sugar) and adoption of healthier eating patterns, such as the Mediterranean diet.
Grade A; Intermediate Strength of Evidence; BEL 1
R3.2.3 In persons with NAFLD, clinicians must recommend physical activity that improves body composition and cardiometabolic health. Participation in a structured
exercise program should be recommended, when possible, tailored to the individual’s lifestyle and personal preferences.
Grade A; Intermediate Strength of Evidence; BEL 1
Q3.3 What medications have proven to be effective for the treatment of liver disease and cardiometabolic conditions associated with NAFLD or NASH?
R3.3.1a Pioglitazone and GLP-1 RAs are recommended for persons with T2D and biopsy-proven NASH.
Grade A; High Strength of Evidence; BEL 1
R3.3.1b Clinicians must consider treating diabetes with pioglitazone and/or GLP-1 RAs when there is an elevated probability of having NASH based on elevated plasma
aminotransferase levels and noninvasive tests.
R3.3.2 To offer cardiometabolic benefit in persons with T2D and NAFLD, clinicians must consider treatment with GLP-1 RAs, pioglitazone, or SGLT2 inhibitors;
however, there is no evidence of benefit for treatment of steatohepatitis with SGLT2 inhibitors.
R3.3.3 Due to the lack of evidence of efficacy, metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin are not recommended for the treatment of
steatohepatitis (no benefit on hepatocyte necrosis or inflammation) but may be continued as needed for the treatment of hyperglycemia in persons with T2D and
NAFLD or NASH.
Grade B; High Strength of Evidence; BEL 1; downgraded due to the use of surrogate outcome measures in many of the studies
R3.3.4 Vitamin E can be considered for the treatment of NASH in persons without T2D, but there is not enough evidence at this time to recommend for persons with
T2D or advanced fibrosis.
Grade B; High Strength of Evidence; BEL 1; downgraded due to risk/benefit
R3.3.5 Other pharmacotherapies for persons with NASH cannot be recommended at the present time due to the lack of robust evidence of clinical benefit.
Q3.4 What obesity pharmacotherapies have proven benefit for the treatment of liver disease and cardiometabolic conditions associated with NAFLD or NASH in
adults?
R3.4.1 Clinicians should recommend the use of obesity pharmacotherapy as adjunctive therapy to lifestyle modification for individuals with obesity and NAFLD or
NASH with a goal of at least 5%, preferably 10 %, weight loss, as more weight loss is often associated with greater liver histologic and cardiometabolic benefit, when
this is not effectively achieved by lifestyle modification alone.
Grade B; Intermediate Strength of Evidence; BEL 1; downgraded due to small sample sizes used in studies and short duration of trials
R3.4.2 For chronic weight management in individuals with a BMI of 27 kg/m2 and NAFLD or NASH, clinicians should give preference to semaglutide 2.4 mg/week
(best evidence) or liraglutide 3 mg/day.
Grade B; High/Intermediate Strength of Evidence; BEL 1; downgraded due to different formulations and doses used in the semaglutide and liraglutide NASH
trials
R3.4.3 Clinicians must consider obesity pharmacotherapy (with preference to semaglutide 2.4 mg/week [best evidence] or liraglutide 3 mg/day) as adjunctive therapy
to lifestyle modification for individuals with obesity and NAFLD or NASH to promote cardiometabolic health and treat or prevent T2D, CVD, and other end-stage
manifestations of obesity.
Grade A; High/Intermediate Strength of Evidence; BEL 1
Q3.5 What is the effect of bariatric surgery on liver disease and cardiometabolic conditions associated with NAFLD or NASH in adults?
R3.5.1 Clinicians should consider bariatric surgery as an option to treat NAFLD (Grade B; Intermediate/Weak Strength of Evidence; BEL 2) and improve
cardiometabolic health (Grade A; High/Intermediate Strength of Evidence; BEL 2; upgraded based on the cardiometabolic and all-cause mortality benefits in
all persons with or without NAFLD) in persons with NAFLD and a BMI of 35 kg/m2 (32.5 kg/m2 in Asian populations), particularly if T2D is present. It should also
be considered an option in those with a BMI of 30 to 34.9 kg/m2 (27.5 to 32.4 kg/m2 in Asian populations)
(Grade B; Intermediate/Weak Strength of Evidence; BEL 2).
R3.5.2 For persons with NASH and compensated cirrhosis, clinicians should exercise caution in recommending bariatric surgery, which should be highly
individualized if prescribed and performed at experienced centers
In persons with decompensated cirrhosis, bariatric surgery should not be recommended due to limited evidence and potential for harm
R3.5.3 Endoscopic bariatric and metabolic therapies and orally ingested devices should not be recommended in persons with NAFLD due to insufficient evidence.
Grade C; Intermediate/Weak Strength of Evidence; BEL 2; downgraded due to the quality of studies and small sample sizes
(continued on next page)
535
Table 3 (continued )
4. Diagnosis and management of children with NAFLD

Q4.1 Who should be screened for NAFLD and comorbidities?
R4.1.1 Children of any age and adolescents with obesity or T2D, but not T1D, should be screened for NAFLD using serum ALT.
R4.1.2 Clinicians should screen adolescent females with polycystic ovary syndrome for NAFLD using serum ALT.
R4.1.3 Clinicians should screen children and adolescents with NAFLD for prediabetes or T2D using an oral glucose tolerance test if the fasting glucose level is 100 mg/
mL or if the glycated hemoglobin (A1c) level is in the range of prediabetes (5.7% to 6.4%).
Q4.2 What tests can be used to diagnose pediatric NAFLD?
R4.2.1 Clinicians should use plasma aminotransferases to test children at high risk of NAFLD.
R4.2.2 Pediatric NAFLD can be diagnosed with imaging (ultrasound or magnetic resonance imaging-proton density fat fraction) or liver biopsy, in combination with
exclusion of non-NAFLD causes of hepatic steatosis such as Wilson syndrome, mitochondrial disease, and medications.
R4.2.3 Liver fibrosis prediction calculations and proprietary biomarkers currently available for the diagnosis of advanced fibrosis in adults should not be used in
children as they either are inaccurate or require further validation.
Q4.3 What are the lifestyle, medical, or surgical treatment options for pediatric NAFLD, and what is the role of pharmacotherapy developed for endocrine
disorders in the treatment of pediatric NAFLD?
R4.3.1 Clinicians should recommend lifestyle changes in children with NAFLD, promoting the adoption of dietary changes to create an energy deficit, with reduction in
sugar consumption as first-line lifestyle modification and increased physical activity aiming for BMI optimization.
Grade B; Intermediate Strength of Evidence; BEL 1; downgraded due to the limited number of RCTs and small sample sizes
R4.3.2 Clinicians may consider GLP-1 RAs for the treatment of pediatric obesity and T2D (Grade D; Expert Opinion; BEL 4), which may also offer benefit for pediatric
NAFLD, although not FDA-approved for this indication (Grade D; Expert Opinion; BEL 4).
Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BEL ¼ best evidence level; BMI ¼ body mass index; CVD ¼ cardiovascular disease; ELF ¼
enhanced liver fibrosis; FDA ¼ U.S. Food and Drug Administration; FIB-4 ¼ fibrosis-4 index; GLP-1 RA ¼ glucagon-like peptide-1 receptor agonist; LSM ¼ liver stiffness
measurement; NAFLD ¼ nonalcoholic fatty liver disease; NASH ¼ nonalcoholic steatohepatitis; Q ¼ question; R ¼ recommendation; SGLT2 ¼ sodium-glucose cotransporter 2;
T1D ¼ type 1 diabetes mellitus; T2D ¼ type 2 diabetes mellitus; VCTE, vibration-controlled transient elastography.
Recommendations with Evidence Base Table 4

Causes of Secondary Hepatic Steatosis101 and Laboratory Evaluation for the Sec-
ondary Causes of Liver Disease22,a
Diagnosis of NAFLD in Adults
Causes
Excessive alcohol consumption
Q2.1 Which Adults With NAFLD Should Be Considered at “High Risk”
Hepatitis C (genotype 3)
of Clinically Significant Fibrosis (Stages F2-F4) and at Risk of Lipodystrophy
Cirrhosis? Acute weight loss (bariatric surgery and starvation)
Malnutrition
Recommendation 2.1.1. Clinicians should consider persons with
Parenteral nutrition
obesity and/or features of MetS, those with prediabetes or T2D, and Abetalipoproteinemia
those with hepatic steatosis on any imaging study and/or persis- Reye syndrome
tently elevated plasma aminotransferase levels (over 6 months) to Pregnancy associated
be “high risk” and screen for NAFLD and advanced fibrosis. HELLP syndrome
Acute fatty liver of pregnancy
Grade B; Intermediate/High Strength of Evidence; best evi- Medications (eg, corticosteroids, mipomersen, lomitapide, amiodarone,
dence level (BEL) 2 methotrexate, tamoxifen, valproate, and antiretroviral medicines)
Rare causes: autoimmune hepatitis, A1AT deficiency, Wilson syndrome, and
other
Evidence Base. The diagnosis of NAFLD is based on the following: (1) Laboratory evaluation
presence of hepatic steatosis, in addition to (2) lack of significant Hepatitis C
alcohol consumption (defined as ongoing or recent alcohol con- HCV antibody with reflex testing HCV RNA
sumption of >21 standard drinks [1 drink ¼ 14 g of pure alcohol]/week Additional tests to consider:
Hepatitis B: HBsAg, HBsAb, and HBcAbb
for men and >14 standard drinks/week for women), and (3) exclusion
ANA
of other liver diseases.101 Initial evaluation in persons with suspected AMA
or incidental finding of hepatic steatosis on imaging should include ASMA
investigations to exclude competing causes for hepatic steatosis and Immunoglobulins
Ferritin
liver disease (eg, hepatitis B and C serology, antimitochondrial anti-
A1AT
bodies, antinuclear antibodies, antiesmooth muscle antibodies,
serum ferritin, alpha 1 antitrypsin, and evaluation for MetS (Table 4). Abbreviations: AMA ¼ antimitochondrial antibodies; ANA ¼ antinuclear antibodies;
A1AT ¼ alpha-1 antitrypsin; ASMA ¼ antiesmooth muscle antibodies; HBcAb ¼
In the past 20 years, it has become evident that persons with T2D
hepatitis B core antibody; HBsAb ¼ hepatitis B surface antibody; HBsAg ¼ hepatitis B
have a very high prevalence of NAFLD and associated fibrosis.5,6,9- surface antigen; HCV ¼ hepatitis C virus; HELLP ¼ Hemolysis, Elevated Liver en-
11,52,102-104
Additionally, individuals with persistently abnormal zymes and Low Platelets; RNA ¼ ribonucleic acid.
a
aminotransferase levels in the absence of other causes of liver disease In persons at high risk of nonalcoholic fatty liver disease NAFLD (eg, type 2
diabetes mellitus, obesity, and metabolic syndrome), abdominal ultrasound is not
(eg, viral hepatitis and excessive alcohol use) are also at high risk of
required to diagnose hepatic steatosis, and it is reasonable to move directly to risk
NAFLD and development of hepatic fibrosis (Table 5).105,106 It is stratification after ruling out the secondary causes of liver disease.
important to highlight that a landmark population-based study b
Not everyone should be tested for HBcAb due to high positivity and uncertain
established that the upper limit of plasma alanine aminotransferase clinical significance.
536
Table 5 common comorbidities in NAFLD.116-121 As reported in a couple of

Additional Causes of Elevated Aminotransferase Levels22,a recent meta-analyses122,123 and discussed later (under Evidence
Medications, vitamins, and supplements Base for Recommendations 3.5.1-3.5.3), weight loss induced by
Viral hepatitis (A, B, and C) bariatric surgery unquestionably improves steatosis, steatohepati-
Endocrine disordersa (hyper- or hypothyroidism, Cushing syndrome, hypo- tis, and, to a lesser extent, hepatic fibrosis. A recent meta-analysis
gonadism, growth hormone deficiency, Addison's disease, and other)b
Hemochromatosis
even reported a reduction in the risk of HCC.124 While the vast
Autoimmune hepatitis majority of persons undergoing bariatric surgery have NAFLD, only
Primary biliary cholangitis approximately 8.5% have F3 and F4 (cirrhosis) at the time of
Alpha-1 antitrypsin deficiency intraoperative liver biopsy125, and 2% to 4% have unexpected
Budd-Chiari syndrome
cirrhosis diagnosed at the time of surgery.126 This is in part related
Mass lesions
to presurgical screening and likely reluctance to proceed with
a
Causes of elevated aminotransferase levels that should be considered in the surgery in those with known stable early or advanced cirrhosis.
clinical evaluation of elevated aminotransferase levels in addition to the secondary
causes of hepatic steatosis listed in Table 4.
Bariatric surgery should not be considered in persons with
b
Steatosis in several endocrinopathies linked to associated development of decompensated cirrhosis due to the increased postoperative mor-
obesity, insulin resistance, and/or type 2 diabetes mellitus. tality. The risk of complications, including postoperative complica-
tions, decompensation, and mortality, are higher in persons with
(ALT) should be 30 U/L for men and 19 U/L for women.107 Additional cirrhosis than in those without cirrhosis. In a systematic review and
studies have made the American College of Gastroenterology consider meta-analysis of 18 studies that reported outcomes of bariatric sur-
a true normal ALT level to range from 29 to 33 U/L for males and 19 to gery in persons with cirrhosis, the risks of postoperative complica-
25 U/L for females.108 This is because a level above the upper limit of tions, liver-related complications, and liver failure-related mortality
normal, even in a population without identifiable risk factors, is were 22.14% (95% CI, 15.43%-29.55%), 4.62% (95% CI, 1.27%-9.30%), and
associated with increased liver-related mortality and should be 0.08% (95% CI, 0%-1.03%), respectively. In persons with cirrhosis,
evaluated by clinicians. In this context, it is important to remember postoperative complications appear to be significantly lower with
that persons with NAFLD and normal aminotransferase levels can still sleeve gastrectomy (10.08% [95% CI, 5.14%-16%]) than with Roux-en-Y
have significant steatohepatitis and develop advanced fibrosis or gastric bypass (RYGB) (31.53% [95% CI, 18.62%-45.68%]; P ¼ .02).127
cryptogenic cirrhosis,30,109 but the presence of high aminotransferase
levels does increase the prevalence of adverse outcomes.106 Q2.2 What Blood Tests (eg, Diagnostic Panels and Specific
Screening for NAFLD to prevent future cirrhosis is justified based Biomarkers) Can Be Used to Diagnose NAFLD With Clinically
on recent studies indicating a high prevalence of liver fibrosis (12%- Significant Fibrosis (Stages F2-F4) in Adults?
21%) in persons with T2D5,6,9-11,52,102-105,110,111 and the association of Recommendation 2.2.1. Clinicians should use liver fibrosis predic-
liver fibrosis with the future risk of developing complications of tion calculations to assess the risk of NAFLD with liver fibrosis. The
cirrhosis, including ascites, renal dysfunction, HCC, hepatic en- preferred noninvasive initial test is the fibrosis-4 index (FIB-4).
cephalopathy, and bacterial infections, and overall higher mortal- Grade B; Intermediate Strength of Evidence; BEL 2
ity.43,47,112 A recent international cohort of 299 individuals with
biopsy-proven NASH and compensated cirrhosis, during a median Evidence Base. Plasma liver aminotransferase levels can be unreli-
follow-up of 5 years, found that having T2D increased the risk of able and normal in many cases of NAFLD128 and should not be used
death (adjusted HR [aHR], 4.23; 95% CI, 1.93-9.29) and liver-related alone for the diagnosis of NAFLD. In a study in persons with T2D, up
outcomes (aHR, 2.03; 95% CI, 1.005-4.11), including HCC (aHR, 5.42; to 50% had NAFLD despite the so-called “normal” ALT levels (defined
95% CI, 1.74-16.80),46 by approximately twofold. It is well estab- as <40 U/L in this study).30 More recent studies have confirmed that
lished that cirrhosis and poor outcomes are much more common in the vast majority of persons with NAFLD in primary care or endo-
persons with diabetes.54 crinology clinics, even those with clinically significant fibrosis (F2),
In fact, individuals with multiple components of MetS or IR, have a plasma aminotransferase level of <40 U/L.9,10,102,114
obesity, or prediabetes are also at risk of significant fibrosis and Hepatic steatosis can be diagnosed on imaging, including liver US,
increased mortality.5,6,9-11,52,102-104 High-risk groups for NAFLD CAP, computed tomography, or the 2 most accurate and sensitive
with liver fibrosis are individuals who are 50 years or older and/or methods, 1H-MRS and magnetic resonance imaging-proton density
have moderate to severe obesity (BMI, >35 kg/m2), including those fat fraction (MRI-PDFF). The accuracy of liver US for the detection of
seeking consultation for bariatric surgery, or T2D and/or moderate and severe steatosis was >80% in a meta-analysis when
MetS.6,30,103,111,113-115 It should also be emphasized that the purpose compared with liver histology.129 However, this was based on data
of screening for NAFLD is to identify persons who are at risk of from hepatology clinics and does not represent the population with
disease progression and liver fibrosis, the most important predictor less severe disease observed in primary care or endocrinology clinics,
of liver and overall outcomes. Screening is important because early where liver US was shown to have suboptimal sensitivity for mild-
intervention can halt or reverse disease progression. In a recent to-moderate steatosis (below a liver fat content of 12.5%)
study in persons with T2D, screening for NAFLD followed by compared with 1H-MRS and liver biopsy in 146 individuals.24 Liver
intensive lifestyle interventions or pioglitazone was cost-effective, US is also highly operator dependent and does not inform about the
providing further support for screening recommendations.113,115 severity of liver fibrosis (unless cirrhosis is present). MRI-based
techniques (1H-MRS and MRI-PDFF) for the diagnosis of steatosis
Recommendation 2.1.2. Persons undergoing bariatric surgery are reserved at present largely to clinical trial research. Magnetic
should be evaluated for the presence and severity of NASH, and a resonance elastography (MRE) should be ordered in selected persons
liver biopsy should be considered at the time of bariatric surgery. primarily by liver specialists for the diagnosis of liver fibrosis,130-133
Liver biopsy should be recommended if presurgical stratification but the test is expensive and does not replace the “gold standard”
suggests indeterminate or high risk of liver fibrosis. liver biopsy for the diagnosis of those with NASH.2,134
Grade B; Intermediate Strength of Evidence; BEL 2 Most important for endocrinology and primary care clinicians is to
calculate liver fibrosis scores for the diagnosis of clinically significant
Evidence Base. Bariatric surgery can induce sustained weight loss, fibrosis, particularly using the FIB-4 (definition shown in Table 1),
improve diabetes, and reduce CVD and cancer risks, which are which has been the most validated among the many tested to this
537
end.43,130,135-141 The FIB-4 has strong validation in its ability to predict Recommendation 2.2.2. Clinicians should consider persons
changes over time in hepatic fibrosis 135 and allows risk stratification belonging to the “high-risk” groups (as defined under R2.1.1) who
of persons in terms of future liver-related morbidity and mortality, as have indeterminate or high FIB-4 score for further workup with a
shown in a population-based prospective survey136 and in a recent liver stiffness measurement (LSM) (TE) or ELF test, as available.
meta-analysis of 13 longitudinal studies.137 Of interest, the NAFLD Grade B; Intermediate Strength of Evidence; BEL 2
fibrosis score (NFS), a liver score commonly used in hepatology clinics,
may overestimate in the primary care setting the prevalence of Evidence Base. In endocrine and primary care clinics, the initial step
advanced liver fibrosis in persons with obesity,142 and in particular in persons at high risk of having NAFLD (prediabetes, T2D, obesity
with T2D11; therefore, it should be avoided in this setting (noninvasive and/or MetS, or elevated plasma aminotransferase level) is to
tests and screening tools shown in Table 1). Proprietary biomarkers evaluate their risk of NAFLD. Hepatic steatosis may be assessed by
include the FibroTest, enhanced liver fibrosis (ELF) test,143 propeptide means of simple noninvasive liver steatosis scores (fatty liver index,
of type III collagen,144-146 NIS4141 and others.130,134,137,147-149 US fatty liver index, and hepatic steatosis index), although these
Endocrinology and primary care clinicians must be aware of the diagnostic modalities have inherent limitations.11,115,152 A liver US is
limitations of blood panels, compared with a liver biopsy (ie, the not recommended for routine clinical diagnosis.115 Instead, TE is
“gold standard”). Overall, panels for the diagnosis of fibrosis have a preferred over liver US, where available, as it can quantify liver fat
good specificity and negative predictive value (NPV) that allow the (CAP) and fibrosis (vibration-controlled transient elastography
clinician to rule out advanced fibrosis and use this as a rule-out [VCTE]) for risk stratification during the same testing. In persons
test.130,134,137,147,148 However, they lack adequate sensitivity and with a high pretest probability of NAFLD, such as the 3 at-risk
positive predictive value (PPV) to establish the presence of advanced groups identified in the diagnostic algorithm (Algorithm Fig. 1), it
fibrosis; therefore, several individuals fall in the “indeterminate-risk” is reasonable to perform a risk stratification (FIB-4) without the
group (Algorithm Fig. 2). In this context, a multistep process must be need for a liver US for the diagnosis of hepatic steatosis (ie, in the 3
used. For example, the area under the receiver operating character- at-risk groups, the chance of having hepatic steatosis is very high
istic curve for the FIB-4 is 0.78 to 0.80135,147,150,151 but lower for NFS and 70%).5,9-11,52,102-104 It is important to perform a complete
(0.72-0.75), in particular in persons with T2D.147 Of note, their per- medical history and routine clinical chemistries that allow clini-
formance is dependent on the population being studied, with a cians to rule out secondary causes of liver steatosis (Table 4) and
better performance in hepatology clinics where more people have elevated plasma aminotransferase levels (Table 5). A thorough
advanced disease than in primary care settings, where the FIB-4 and workup should be performed to rule out competing causes for
other tests have been less well characterized. steatosis, in addition to excluding significant alcohol consumption.
Algorithm Fig. 1. Overview of management algorithm for nonalcoholic fatty liver disease (NAFLD). The assessment of persons for the risk of NAFLD and cirrhosis starts by testing
the 3 major high-risk groups for the development of NAFLD, after a careful medical history and physical examination. Clinicians should also rule out secondary causes of liver
steatosis. Once NAFLD is confirmed, assessment must stratify persons for the risk of liver cirrhosis and CVD and coordinate in a multidisciplinary approach (depending on disease
severity) the management of obesity, diabetes, hypertension, and atherogenic dyslipidemia.
538
It is important to assess further for the risk of clinically significant for NAFLD and identify those at risk of clinically significant
fibrosis (stages F2-F4), which provides prognostic information on the fibrosis has been proposed (Algorithm Fig. 2).
future risk of cirrhosis and can guide treatment strategies, as well as
need for referral to a hepatologist/gastroenterologist. A combination Q2.3 What Imaging Studies Can Be Used to Diagnose NAFLD With
of the FIB-4 followed by VCTE (description under Q2.3) seems to be Clinically Significant Fibrosis (Stages F2-F4) in Adults?
the best approach. If the FIB-4 score is >1.3, then a second level test, Recommendation 2.3. To stage the risk of fibrosis in persons with
such as VCTE or ELF, should be performed (Algorithm Fig. 2). Using the NAFLD, clinicians should prefer the use of VCTE as best validated to
FIB-4 as a first-line test, followed by VCTE, can help stratify persons in identify advanced disease and predict liver-related outcomes.
the “indeterminate zone” and greatly reduce the number of referrals Alternative imaging approaches may be considered, including
to the specialist.130,134,137,147,148,153 Of note, higher cutoffs for the FIB-4, shear wave elastography (SWE) (less well validated) and/or MRE
in the range of 1.9 to 2.0 (rather than >1.3), have been suggested with (most accurate but with a high cost and limited availability; best if
older age ( 65 years) to determine advanced fibrosis.154,155 ordered by a liver specialist for selected cases).
This combination or sequential use of tests yields a higher PPV Grade B; Intermediate Strength of Evidence; BEL 2
in identifying at-risk persons with active NASH and fibrosis. In a
study of 968 persons with biopsy-confirmed NAFLD, sequential Evidence Base. The current “gold standard” for the diagnosis of
testing with the FIB-4 or NFS followed by TE in those with an steatohepatitis is a liver biopsy. Although safe, it is an invasive
indeterminate score was more accurate than performing either procedure associated with potential adverse effects, such as pain,
test alone.156 In another cross-sectional study of 3202 persons bleeding, and infection. In addition, it has other limitations,
with bridging fibrosis and compensated cirrhosis, noninvasive including reduced acceptability, intraobserver and interobserver
tests alone or in combination with imaging (VCTE) reduced the variability, sampling variability, and cost.157
need for a liver biopsy when trying to discriminate advanced As mentioned earlier, VCTE (Table 1 and Algorithm Fig. 2) is the
fibrosis caused by NASH.150 Persons with high or intermediate most broadly used noninvasive method for LSM and, thus, for
fibrosis risk should be referred to hepatology for further evalu- establishing the risk of liver fibrosis158-160 and for eventually
ation and consideration of a liver biopsy. Liver biopsy remains the excluding cirrhosis.158 At a fixed sensitivity, a cutoff LSM of 6.5 kPa
“gold standard” for the diagnosis of NASH; however, it should not excluded advanced fibrosis with an NPV of 0.91, and a cutoff LSM of
be used as a screening method to diagnose NAFLD given its 12.1 kPa excluded cirrhosis with an NPV of 0.99.158 Minor limita-
multiple caveats: it is invasive, subject to interpretation errors,157 tions of VCTE include overestimation of LSMs at higher stages of
and difficult to apply to large populations. An algorithm to screen fibrosis and unsuccessful LSMs with inappropriate use of probes in
Algorithm Fig. 2. Cirrhosis prevention in nonalcoholic fatty liver disease (NAFLD). Once the presence of NAFLD is established, fibrosis risk stratification is essential. The first test
recommended is the FIB-4, which often allows separation of those at low risk versus those at high risk of liver fibrosis. However, a significant proportion of persons will fall in a
“gray zone” of indeterminate risk that requires additional testing to decide referral to the liver specialist. The second test recommended is LSM or, if unavailable, an ELF blood test.
This should determine the risk in most individuals. Persons with a low risk of cirrhosis should be managed in primary care and/or endocrinology clinics, while those with an
indeterminate to high risk of liver fibrosis merit referral to the liver specialist and a multidisciplinary approach to management.
539
individuals with overweight and obesity, which can be circum- Q2.4 Should All Persons With Diabetes Mellitus Be Screened for
vented using the right probe in individuals with higher BMI.161 Clinically Significant Fibrosis (Stages F2-F4) Associated With NAFLD?
With refined CAP algorithms and knowledge of steatosis preva- Recommendation 2.4.1. In persons with T2D, clinicians should
lence and covariates, there is potential for more precise CAP-based consider screening for clinically significant fibrosis (stages F2-F4)
steatosis grading.162 Therefore, from a practical perspective for using the FIB-4, even if they have normal liver enzyme levels.
endocrinologists and PCPs, there is a growing consensus8,22 to use Grade B; High/Intermediate Strength of Evidence; BEL 2
TE (FibroScan) scores to assess the risk of clinically significant
fibrosis and trigger early intervention to prevent cirrhosis Recommendation 2.4.2. In persons with T1D, clinicians may
(Algorithm Fig. 2). The best evidence comes from 2 recent studies. A consider screening for NAFLD with clinically significant fibrosis
European study in 450 adults who underwent TE and a liver biopsy (stages F2-F4) using the FIB-4, only if there are risk factors such as
using an LSM Youden cutoff value for clinically significant fibrosis obesity, features of MetS, elevated plasma aminotransferase levels
(F2) of 8.2 kPa demonstrated NPVs of 78% in persons from dia- (>30 U/L), or hepatic steatosis on imaging.
betes clinics and 97% in the general population.159 Another study in Grade C; Intermediate/Weak Strength of Evidence; BEL 2;
1073 persons with NAFLD among 10 European tertiary liver centers downgraded based on the heterogeneity of studies and moder-
confirmed these cutoffs, reporting that a cutoff of 8.0 kPa had a 93% ate to high probability of bias
sensitivity to exclude advanced fibrosis (F3-F4).163 Similarly, a
recent systematic review further supported the cutoff of 8.0 kPa for Recommendation 2.4.3. Clinicians should further risk stratify per-
screening for clinically significant liver fibrosis.164 For practical sons with T2D or T1D with cardiometabolic risk factors and/or
purposes then, people with an LSM of <8.0 kPa determined using elevated plasma aminotransferase levels (>30 U/L) using the FIB-4,
TE are considered low risk for clinically significant fibrosis (F2) elastography, and/or ELF test.
and are best managed in the nonspecialty clinics with repeat sur- Grade B; High/Intermediate Strength of Evidence; BEL 2
veillance testing in 2 to 3 years. If the LSM is >12.1 kPa based on
VCTE, the risk of advanced fibrosis is high, with PPVs of 76% and 88% Evidence Base. A bidirectional relationship exists between NAFLD and
in persons seen in diabetes and hepatology clinics, respectively, but T2D, whereby the presence of one increases the risk and severity of the
lower in primary care populations.159 It is recommended then to other.174 The rationale for universal screening is based on emerging
use rounded-off values of <8.0 kPa for the low-risk group, 8.0 to evidence that T2D is a major risk enhancer of disease burden and
12.0 for the indeterminate-risk group, and >12.0 kPa for the high- disease progression to cirrhosis among individuals with NAFLD.
risk group for advanced liver fibrosis (Algorithm Fig. 2). A referral Studies strongly suggest a relationship between NAFLD, hepatic IR and
to a hepatologist is given for all of those in the indeterminate- to MetS, and T2D.29,53 In prospective longitudinal studies, persons with
high-risk groups. T2D have approximately double the rate of NAFLD compared with the
Other methods to measure liver fibrosis are also available. As general population.6,52,81 Conversely, persons with NAFLD have dou-
discussed earlier, MRE has the best accuracy but is costly and has ble the risk of developing T2D (HR, 2.2),52 which may encourage
limited availability130-133; therefore, it is best ordered by the screening for NAFLD in individuals with prediabetes.175 Recent studies
hepatologist when additional workup is needed in selected cir- report that approximately 60% to 70% of persons with T2D have NAFLD
cumstances. Hepatologists also have significant experience with with the majority having plasma aminotransferase levels below what
SWE, either 2-dimensional (2DSWE) or point (pSWE).165-167 is reported by most clinical laboratories to be “normal” (40 IU/L).9
2DSWE and pSWE appear to have an accuracy similar to that of The global prevalence of NASH among persons with T2D based on
TE but less than that of MRE. A recent meta-analysis of 82 studies 10 studies that included results from liver biopsies is 37.3%, although
with a total of 14 609 persons compared diagnostic methods for there was some selection bias among the populations included and
fibrosis staging (53 studies with VCTE, 11 with MRE, 12 with the prevalence may be lower.6 However, a recent study in individuals
pSWE, and 4 with 2DSWE). The summary estimates of the undergoing a routine colonoscopy who agreed to be screened for
sensitivity, specificity, and area under the curve were best for NAFLD, with additional cT1 MR testing (which can estimate the risk of
MRE, while pSWE was comparable to VCTE, and 2DSWE had steatohepatitis) and/or a liver biopsy if positive, gave a similar prev-
somewhat lower estimates.165 The summary estimates of the alence.5 Of note, a meta-analysis suggested that persons with more
area under the curve varied for the diagnosis of significant “severe” NAFLD are more likely to develop T2D and the risk is even
fibrosis (F2) (0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE, and greater among those with advanced fibrosis.52
0.72 for 2DSWE) but were similar for the diagnosis of cirrhosis In a recent comprehensive analysis, the prevalence of NAFLD in
(0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE, and 0.88 for persons with T1D was relatively low (10% with MRI-based tech-
2DSWE).165 However, pSWE and 2DSWE are newer techniques niques).56,57 The pooled prevalence of NAFLD in persons with T1D
with limited evidence in terms of long-term predictive value for determined using US studies was high (27.1%; 95% CI, 19.7%-36.3%)
future liver outcomes, whereas data are already available for compared with that using the more accurate liver fat measurement
VCTE. Finally, newer imaging techniques are becoming available. with TE (2.3%; 95% CI, 0.6%-4.8%) or studies using “gold standard”
Velacur (Sonic Incytes Medical Corp.) is a point-of-care liver MRI (8.6%; 95% CI, 2.1%-18.6%).56,57 There is no high-quality study on
assessment device based on Shear Wave Absolute Vibro- the prevalence of steatohepatitis or fibrosis in persons with T1D. One
Elastography that incorporates elastography and a greater liver study examining a database of 4641 people with T1D collected over a
volume visualization.168,169 LiverMultiScan uses multiparametric period of 20 years (1991-2011) found 57 persons (1.2%) with elevated
MRI to noninvasively quantify liver fat170 and cT1 signal maps of plasma aminotransferase levels in whom a liver biopsy had been
the liver to assess disease activity (NAFLD activity score [NAS]) performed.176 Only 20.4% had NASH, the rest had other diagnoses
and potentially outcomes.171,172 These techniques are currently such as metastatic malignancy, alcoholic liver disease, hepatitis C, or
being used largely in research for screening studies5,173 or to hepatic glycogenosis. The presence of NAFLD is associated with the
assess primary end points in clinical trials for investigational use of higher insulin doses for comparable glycemic control in both
drugs in development for the treatment of NASH. Both have T1D and T2D populations.57,177,178 Obesity and IR appear to be the
received FDA-approval for use in persons with chronic liver driving factors, with significant heterogeneity among studies that
disease and await future work to fully assess their place in the makes it difficult to fully assess the impact of T1D in the develop-
diagnostic algorithm of persons with NAFLD. ment of NAFLD. Overall, screening appears justified only in persons
540
with obesity, MetS, elevated plasma aminotransferase levels (>30 serial combination of 2 tests to improve screening accuracy has been
U/L), or hepatic steatosis on imaging.152,179-183 used less commonly, but new data are emerging.5,113,115,142,150,156 In a
Although not yet established, it is likely that interventions that prospective longitudinal cohort study of 3012 adults, the results
improve NAFLD and hepatic IR may decrease the risk of developing before and after the introduction of a 2-step care pathway were
T2D,52,53 as suggested with pioglitazone that reduces the progres- compared.194 The implementation of this care pathway using the
sion from prediabetes to T2D by 70% to 80% in persons at risk of FIB-4 and ELF test resulted in an 88% reduction in unnecessary
diabetes.184-187 Individuals with T2D and NAFLD are also at specialist referrals when the pathway was followed (OR, 0.12; 95% CI,
increased risk of NASH with advanced fibrosis, particularly in those 0.042-0.449; P < .0001) and a fourfold increase in the identification
aged >50 years with T2D or obesity.81 It also appears to accelerate of individuals likely to have advanced fibrosis (OR, 4.32; 95% CI, 1.52-
the progression of liver disease in NAFLD and promote its devel- 12.25; P ¼.006). However, more long-term outcome data are needed
opment at younger ages.6 Several systematic reviews and meta- on screening strategies to prevent cirrhosis.
analyses have shown that among persons with NAFLD and T2D, Additional management of persons with NAFLD depends on the
approximately 12% to 21% have advanced liver fibrosis (stages stage and severity of liver disease. Fibrosis stage is an important
F2-F4).6,9-11,102,110,114,188-190 A 2018 systematic review and meta- predictor of long-term outcomes.43,148,195 Again, the initial steps of
analysis found that overall, 31% (ranging from 27% to 56%) of per- risk stratification using the algorithms outlined in Algorithm
sons with cirrhosis had diabetes mellitus, which is approximately Figures 1 and 2 should be performed by endocrinologists and in
threefold higher than that of the general U.S. population.191 the primary care setting.194,196-198 For persons with evidence of
advanced liver disease (eg, ascites, hepatic encephalopathy,
Q2.5 When Should an Adult Be Referred to a Gastroenterologist/ esophageal varices, hypersplenism/low platelet count, or evidence
Hepatologist for Management? of hepatic synthetic dysfunction as characterized by a low albumin
Recommendation 2.5.1. Persons with persistently elevated ALT or level and/or evidence of prolonged prothrombin time/international
aspartate aminotransferase (AST) levels and/or with hepatic steatosis normalized ratio), assessment and management by a gastroenter-
on imaging and indeterminate risk (FIB-4, 1.3- 2.67; LSM, 8-12 kPa; or ologist or hepatologist may be necessary. In this context, risk
ELF test, 7.7-9.8) or high risk (FIB-4, >2.67; LSM, >12 kPa; or ELF test, assessment with additional tests, including liver biopsy, may be
>9.8) based on blood tests and/or imaging (as described in R2.2.1, required. In fact, liver biopsy is important to not only exclude other
R2.2.2, and R2.3) should be referred to a gastroenterologist or hep- coexisting causes of liver disease (eg, autoimmune hepatitis and
atologist for further assessment, which may include a liver biopsy. iron overload) (Tables 4 and 5) but also firmly establish the stage of
Grade B; Intermediate Strength of Evidence; BEL 2 liver disease when blood tests and imaging provide conflicting
results. Furthermore, liver biopsy is required for enrollment in most
Recommendation 2.5.2. Clinicians should refer persons with clinical of the clinical trials for new pharmacologic treatment of NASH. In
evidence of advanced liver disease (ascites, hepatic encephalopa- addition to liver biopsy, gastroenterologists or hepatologists will
thy, esophageal varices, or evidence of hepatic synthetic dysfunc- manage advanced liver disease, including periodic screening for
tion) to a gastroenterologist/hepatologist for further care. HCC, large esophageal varices, and liver disease progression and
Grade B; Intermediate/High Strength of Evidence; BEL 2 timely referral to liver transplantation.
Evidence Base. The initial steps in managing persons with NAFLD Management of NAFLD in Adults
encompass the assessment and treatment of associated car-
diometabolic risks, such as visceral obesity, T2D, hypertension, and Q3.1 How Should Cardiometabolic Risk and Other Extrahepatic
dyslipidemia.192 Individuals with obesity and T2D are at increased Complications Be Managed in the Setting of NAFLD?
risk of NAFLD enriched for NASH and advanced Recommendation 3.1. Clinicians must manage persons with NAFLD
fibrosis.9,10,102,110,114,188-190 While only a minority of individuals with for obesity, MetS, prediabetes, diabetes mellitus, dyslipidemia, hy-
NAFLD progress to advanced liver disease and require specialty care, pertension, and CVD based on the current standards of care.
their identification is often challenging. Furthermore, to optimize Grade A; High/Intermediate Strength of Evidence; BEL 1
resource utilization, individuals who do not have advanced fibrosis
could be effectively managed in the nonhepatology setting. Another Evidence Base. There is broad consensus that screening and early
challenge is that most individuals with advanced liver disease in the intervention for obesity,117,199,200 prediabetes,201-205 T2D,199,205-208
context of NAFLD are asymptomatic. Thus, the risk stratification of dyslipidemia,209,210 and hypertension211,212 are warranted because
high-risk individuals or those with known NAFLD using simple it is cost-effective and safe and allows for interventions to prevent
clinically available tools is critical to identify those at higher risk of diabetic complications and CV events. This has led to guidelines
liver-related outcomes, including mortality, that should be seen in encouraging the screening for these risk factors that are commonly
specialty practices, as well as those who can be managed in a pri- present in persons with obesity and T2D.213-220 Cardiometabolic
mary care or endocrine practice setting. benefit from weight loss is apparent after 5% weight loss and
The frequency of testing for individuals considered at low risk greater with further weight loss.207
based on the FIB-4 (<1.3) or VCTE (<8.0 kPa) is not as well estab- NAFLD and NASH are integral to the nexus of these diseases that
lished as it is for the “high-risk” groups; however, it is prudent to comprise the spectrum of cardiometabolic disease (CMD).221 At the
consider repeat testing every 2 years for those at low risk, as 1 study core of CMD is IR that encompasses abnormal glucose tolerance,
showed that only a minority will progress to a higher fibrosis stage systemic inflammation, oxidative stress, mitochondrial dysfunc-
within that period of time (<20%).41,193 In a RCT, the progression of tion, endothelial dysfunction, and dysfunctional adipose tis-
persons with obesity and prediabetes or T2D in the placebo arm of sue.29,59,222 Early in CMD progression, the insulin-resistant state is
the study over 72 weeks was 26% compared with only 7% on pio- largely subclinical but over time results in prediabetes and MetS,
glitazone.98 More data are clearly needed for stronger recommen- which indicate the presence of CMD and IR and mark individuals at
dations moving forward. high risk of future T2D, NAFLD, hypertension, myocardial
Several studies have reported on the feasibility of screening for dysfunction, dyslipidemia, CVD events, and CKD.221,223 Obesity
NAFLD and liver fibrosis in persons with T2D in primary care settings plays a key role in CMD because it can exacerbate IR and impel this
using clinical and routine chemistries and/or TE.9,10,102,110,114,188-190 A disease progression. To accommodate the need for fat storage
541
under conditions of increased caloric intake, the accumulation of current immunization recommendations for those with chronic
intracellular lipid becomes more pronounced in myocytes and he- liver disease.227,228
patocytes.29,222 Based on pathophysiology, persons with NAFLD will
be at risk of other CMD manifestations, and individuals who have 1 Q3.2 What Lifestyle Modifications (Dietary Intervention and
or more CMD manifestations will be at increased risk of NAFLD, as Exercise) Should Be Recommended in Adults With NAFLD or NASH?
substantiated by multiple studies employing epidemiology, pro- Recommendation 3.2.1. Clinicians should recommend lifestyle
spectively and retrospectively followed cohorts, nested cases- changes in persons with excess adiposity and NAFLD with a goal of
controls, and related meta-analyses.213-216,221,223 For example, a at least 5%, preferably 10% weight loss, as more weight loss is
systematic review analyzing 86 studies with a sample size of often associated with greater liver histologic and cardiometabolic
8 515 431 from 22 countries has documented high rates of CMD benefit, depending on individualized risk assessments. Clinicians
manifestations in persons with NAFLD and still higher rates in must recommend participation in a structured weight loss pro-
persons with NASH for obesity (51% and 82%, respectively), T2D gram, when possible, tailored to the individual’s lifestyle and per-
(23% and 44%, respectively), hyperlipidemia (69% and 83%, sonal preferences.
respectively), hypertension (39% and 68%, respectively), and MetS Grade B; Intermediate/High Strength of Evidence; BEL 1;
(43% and 71%, respectively).221 Thus, care of persons with NAFLD downgraded due to small sample sizes, large heterogeneity of
extends beyond the liver and must comprehensively consider the interventions, short duration, and few studies with liver biopsy
broader context of CMD.
Whether NAFLD is an independent risk factor for CVD remains Recommendation 3.2.2. Clinicians must recommend dietary modi-
controversial. Individuals with NAFLD appear to have a higher fication in persons with NAFLD, including a reduction of macro-
prevalence of clinical CVD than individuals without steatosis.1,53 nutrient content to induce an energy deficit (with restriction of
Moreover, CVD is the leading cause of death in NAFLD.224 Several saturated fat, starch, and added sugar) and adoption of healthier
studies including meta-analyses have shown that NAFLD is an in- eating patterns, such as the Mediterranean diet.
dependent risk factor for CVD after controlling for other risk factors, Grade A; Intermediate Strength of Evidence; BEL 1
that it confers an independent risk of fatal and nonfatal CV events
(in both persons with and without diabetes), and that this risk Evidence Base. Lifestyle change primarily consists of nutritional
becomes greater as NAFLD progresses to more severe forms of therapy and physical activity and is the first-line therapy for ABCD
NASH.47,224,225 However, this is somewhat controversial since other and related complications, including NAFLD. While dietary
studies fail to demonstrate an independent risk of CVD and that the macronutrient content and distribution is important in NAFLD,
increased incidence of CVD events is explained by the burden of weight loss achieved through caloric deficit, irrespective of the
other risk factors that accompany NAFLD.83,86,226 The limitations of specific dietary approach, is effective in reducing hepatic steatosis,
most studies are the lack of adequate controls, short-term follow- even necroinflammation, although results are more variable for
up, and few reporting on CV events but rather surrogate end points fibrosis. Several studies have reported normalization of plasma
such as endothelial dysfunction and carotid intima-media thick- aminotransferase levels and a reduction of hepatic steatosis (most
ness test. Diagnosis of NAFLD has been made using different by imaging) that is proportional to the amount of weight loss.229-237
methodologies but mostly noninvasive tests such as elevated However, fewer studies have examined the impact of weight loss
plasma aminotransferase levels or by US and rarely by “gold stan- on necrosis, inflammation, and fibrosis by performing liver biopsies
dard” MRI-based techniques or liver biopsy. Future prospective before and after treatment. An early, small RCT (n ¼ 31) demon-
studies using more rigorous study designs may be required to strated that persons with biopsy-proven NASH randomized to
resolve this discrepancy. lifestyle intervention (diet, exercise, and behavioral modification)
The AACE213 and European Association for the Study of and who lost significant body weight (9.3%) showed improved
Obesity214 have advocated for the use of adiposity-based chronic steatosis and necroinflammation disease activity scores but not
disease (ABCD) as a medical diagnostic term for obesity, and the fibrosis.238 Those who achieved a weight loss of 7%, compared
treatment of ABCD to prevent progression to NAFLD and NASH with those who lost <7%, had significant improvements in steatosis,
underscores the complications-centric approach to treatment lobular inflammation, ballooning injury, and the overall NAS. In a
consistent with the AACE Guidelines for Comprehensive Medical more recent prospective cohort study of individuals (N ¼ 261)
Care for Patients with Obesity.216 undergoing a 52-week program of lifestyle intervention, a higher
A renewed emphasis has been put on increasing awareness of proportion of persons with 5% weight loss had NAS reductions
the need for vaccinations in persons with diabetes, chronic and NASH resolution compared with those who lost <5% of their
liver disease, and associated comorbidities. Table 6 shows the weight; all persons who lost 10% of their weight had NAS re-
ductions, 90% had NASH resolution, and 45% had fibrosis regres-
Table 6
sion.239 The authors subsequently developed a predictive model
Immunizations for Persons With Chronic Liver Disease227,228
derived from weight loss, presence of T2D, ALT normalization, age,
Hepatitis A vaccine and an NAS of 5 that exhibited a high predictive value for histo-
Hepatitis B vaccine
logic improvement (eg, NASH resolution) after lifestyle interven-
Pneumococcal polysaccharide vaccine (PPSV23)
Additional vaccines: tion.240 A 2021 meta-analysis of 43 studies involving 2809
Influenza vaccine participants (26 behavioral weight-loss programs, 9 with phar-
Tdap vaccine macotherapy, 8 with surgery) found evidence of a dose-response
Zoster vaccine relationship between the magnitude of weight loss and the de-
HPV vaccine
gree of liver improvement of steatosis and resolution of NASH but
MMR vaccine
Varicella vaccine not for fibrosis.241
COVID-19 vaccine Specific dietary patterns can exert benefit in persons with
Abbreviations: HPV ¼ human papilloma virus; MMR ¼ measles, mumps, and NAFLD, with debate as to the best dietary approach in NAFLD.
rubella; PPSV23 ¼ 23-valent pneumococcal polysaccharide vaccine; Tdap ¼ tetanus, However, a reduction in overall macronutrient content, and in
diphtheria, and pertussis. particular saturated fat, appears to be consistent across studies. For
542
instance, overfeeding 1000 kcal/day of saturated fat for 3 weeks baseline BMI.268 Subsequent controlled studies269-273 and a 2018
induced a greater increase in the intrahepatic triglyceride (IHTG) meta-analysis274 of 17 studies including 373 participants concluded
level than similar overfeeding of unsaturated fat or simple that structured exercise training elicits an absolute reduction in the
sugars.242-244 The role of restricting carbohydrates in NAFLD, IHTG level of 3.31% (95% CI, 4.41% to 2.22%) that is often pro-
particularly simple sugars in food and beverages sweetened with portional to the magnitude of the exercise training and anthropo-
high fructose corn syrup, has been examined in a number of metric improvements. The most common intervention frequency
studies.245 Several recent studies have shown the value of a Med- among studies was 3 times per week, for 30 to 60 minutes each
iterranean diet (ie, low in carbohydrates and saturated fat but session and lasting 12 weeks. However, greater intensity has not
higher in monosaturated fat) as it improves CV risk parameters and always translated into a more significant decrease in hepatic
effectively reduces hepatic fat content.229,246-252 Consistent with steatosis.271,274,275
the aforementioned, another RCT showed that a calorie-restricted Specific types of exercise exert different effects in persons with
DASH diet, rich in fruit, vegetables, whole grains, and low-fat NAFLD. There were no significant differences between aerobic and
dairy and low in saturated fat and refined grains, also results in resistance trainings, but there was more benefit with high-volume
beneficial weight loss and reduced ALT levels in persons with continuous training than with low-volume continuous training
obesity and NAFLD compared with a control diet.253 These results even with high intensity.190 While there are more data on aerobic
have led several societies including the European Association for exercise, resistance training can improve NAFLD and may be more
the Study of the Liver-European Association for the Study of feasible for persons with poor cardiorespiratory fitness or an
Diabetes-European Association for the Study of Obesity,254 Euro- inability to participate in aerobic exercise. A 2017 meta-analysis
pean Society for Clinical Nutrition and Metabolism,255 Asian Pacific (N ¼ 12 studies comparing aerobic with resistance training pro-
Association for the Study of the Liver,256 Latin American Association tocols) found that resistance training improves hepatic steatosis
for the Study of the Liver,257 and most recently the American with reduced energy requirements, compared with aerobic exer-
Gastroenterological Association258 to specifically recommend the cise.276 An RCT (N ¼ 220) of 12-month duration in people with
Mediterranean diet for persons with NAFLD. Other approaches that biopsy-proven NAFLD compared 3 interventions: (1) vigorous-
have reported benefit in decreasing hepatic steatosis include high moderate exercise (jogging 150 minutes per week at 65%-80% of
protein/lower carbohydrate intake diets with 30% protein, 40% maximum heart rate for 6 months and brisk walking 150 minutes
carbohydrates, and 30% fat259,260 and intermittent fasting and/or per week at 45%-55% of maximum heart rate for another 6 months),
time-restricted feeding.261-263 These approaches also create an (2) moderate exercise (brisk walking 150 minutes per week for 12
energy deficit that may be helpful for some persons with NAFLD.264 months), or (3) no-exercise control group. The investigators found
Structured weight-loss programs and antiobesity medications that both exercise groups were equally effective in reducing the
are usually more successful for weight loss than the efforts of cli- IHTG content measured by 1H-MRS and significantly reduced he-
nicians and dieticians at regular visits.232,235 We recommend a patic steatosis compared with those in the no-exercise controls.275
greater use of formal weight-loss programs.258 Bariatric surgery In another RCT (N ¼ 18 adults with obesity and hepatic steatosis)
performed by well-established programs is another tool that comparing energy-matched moderate-intensity exercise with
should be considered in appropriate individuals with clinically high-intensity exercise, again, both modalities reduced the IHTG
significant fibrosis and obesity with comorbidities.236 content to a similar extent as well as markers of hepatic
In summary, caloric restriction within a Mediterranean diet inflammation.277
appears to have the best evidence and likely the best chance of In summary, exercise has shown to consistently benefit persons
long-term adherence. However, comparing results across studies with NAFLD, the challenge being long-term adoption. Benefit from
remains a challenge due to heterogeneity of the study designs increasing physical activity appears more linked to the intensity
(even within the same diets, in terms of dietary and caloric and adherence to the training program rather than the type of
composition), small number of participants and diverse pop- exercise. Of note, a decrease in hepatic steatosis with exercise is
ulations included, intervention duration, and end points utilized observed even in the absence of major weight loss.265,266,269,278
(various imaging techniques vs histology). One major limitation is Overall, a larger cardiometabolic and liver histologic benefit is
that none of these studies has extended beyond 12 months, a major observed when exercise is associated with lifestyle and dietary
drawback considering NAFLD is a chronic disease. changes.
Recommendation 3.2.3. In persons with NAFLD, clinicians must Q3.3 What Medications Have Proven to Be Effective for the
recommend physical activity that improves body composition and Treatment of Liver Disease and Cardiometabolic Conditions
cardiometabolic health. Participation in a structured exercise pro- Associated With NAFLD or NASH?
gram should be recommended, when possible, tailored to the in-
dividual’s lifestyle and personal preferences. Recommendation 3.3.1. R3.3.1a Pioglitazone or GLP-1 RAs are rec-
Grade A; Intermediate Strength of Evidence; BEL 1 ommended for persons with T2D and biopsy-proven NASH.
Evidence Base. Exercise helps maintain weight loss and may have R3.3.1b Clinicians must consider treating diabetes with piogli-
benefits that are independent of weight loss on liver fat and his- tazone and/or GLP-1 RAs when there is an elevated probability of
tology. While most clinical studies on exercise in NAFLD have been having NASH based on elevated plasma aminotransferase levels
of short duration (12 months) and included small numbers of and noninvasive tests.
participants, benefit has been fairly consistent.230,265,266 In a 2016 Grade A; High Strength of Evidence; BEL 1
meta-analysis (N ¼ 8 studies prescribing exercise [2 with diet]; N ¼
433 persons with NAFLD), a reduction in the IHTG level was inde- Recommendation 3.3.2. To offer cardiometabolic benefit in persons
pendent of dietary intervention but more evident with diet plus with T2D and NAFLD, clinicians must consider treatment with GLP-
exercise than with exercise alone.267 In another 2016 meta-analysis 1 RAs, pioglitazone, or SGLT2 inhibitors; however, there is no evi-
and meta-regression (N ¼ 28 RCTs including persons with obesity dence of benefit for treatment of steatohepatitis with SGLT2
complicated by T2D or MetS and NAFLD), physical activity reduced inhibitors.
intrahepatic lipid and aminotransferase levels correlating with Grade A; High Strength of Evidence; BEL 1
543
Recommendation 3.3.3. Due to the lack of evidence of efficacy, diabetes may also be considered in the presence of elevated plasma
metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin aminotransferase levels and/or FIB-4 scores of >1.3 and confirma-
are not recommended for the treatment of steatohepatitis (no tory imaging (ie, TE and MRE) or proprietary fibrosis biomarkers,
benefit on hepatocyte necrosis or inflammation) but may be such as the ELF test,143 when suggestive of clinically significant liver
continued as needed for the treatment of hyperglycemia in persons fibrosis, if imaging not available.134,147,148 Additional biomarkers are
with T2D and NAFLD or NASH. undergoing further evaluation in NAFLD (ie, NIS4,141 propeptide of
Grade B; High Strength of Evidence; BEL 1; downgraded due type III collagen,142,144-146 and others134).
to the use of surrogate outcome measures in many of the studies Two antidiabetic agents have proven to be safe and effective to
reverse NASH in persons with obesity, prediabetes, or T2D: pioglita-
Recommendation 3.3.4. Vitamin E can be considered for the treat- zone and GLP-1 RA (Table 7). Pioglitazone is a peroxisome
ment of NASH in persons without T2D, but there is not enough proliferator-activated receptor (PPAR)-g that improves IR, primarily
evidence at this time to recommend for persons with T2D or targeting adipose tissue and improving lipid storage/redistribution
advanced fibrosis. and glucose utilization.29 It was the first diabetes agent to show ef-
Grade B; High Strength of Evidence; BEL 1; downgraded due ficacy in an early RCT in 55 individuals with prediabetes or diabetes
to risk/benefit and biopsy-proven NASH.280 This was followed by positive 12- to 24-
month RCTs showing histologic improvement in persons without
Recommendation 3.3.5. Other pharmacotherapies for persons with diabetes.97,98,281,282 A 2016 single-center study in 101 persons with
NASH cannot be recommended at the present time due to the lack obesity, and either prediabetes or T2D, confirmed its sustained
of robust evidence of clinical benefit. benefit on glucose and lipid metabolism and NASH over 36 months of
Grade A; High Strength of Evidence; BEL 1 follow-up.98 With pioglitazone treatment (45 mg), 58% of individuals
achieved the primary outcome of a reduction of at least 2 points in
Evidence Base. The rationale for pharmacologic treatment of NASH in NAS, while 51% had resolution of NASH (treatment difference of 41%
persons with T2D (in addition to lifestyle changes) is based on the and 32% vs placebo, respectively; both P < .001 vs placebo). There was
following aspects, as discussed earlier: (1) NASH has reached also improvement in the mean fibrosis score (P ¼ .039).98 A 2017
epidemic proportions with clinically significant fibrosis (stage F2) meta-analysis of available pioglitazone RCTs in persons with biopsy-
being present in approximately 12% to 21% of individuals in proven NASH noted a significant improvement versus placebo for
T2D9,10,102,110,114,188-190; (2) NASH with clinically significant fibrosis is NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001) and for any
associated with an increased risk of mortality from liver-related stage of fibrosis (OR,1.66; 95% CI,1.12-2.47; P ¼.01), with even greater
complications279; (3) early diagnosis and treatment offer a window ORs for the effect on advanced fibrosis (OR, 3.15; 95% CI,1.25-7.93; P ¼
of opportunity to prevent disease progression; (4) T2D appears to .01), with similar results for those with and without T2D.283 A 2020
accelerate progression to cirrhosis in NASH, making a dual inter- incremental cost-effectiveness ratio analysis that added a more
vention versus diabetes and NASH more cost-effective28,147; (5) while recent 2019 study combining pioglitazone with vitamin E confirmed
weight loss alone may reverse NASH, usually in proportion to the the aforementioned findings.284 The side effects of pioglitazone
magnitude of weight loss, halting fibrosis progression is less pre- include dose-dependent weight gain (1% with pioglitazone 15 mg/
dictable and highly variable among individuals106; and (6) some day up to 3%-5% with 45 mg/day), increased fracture risk, heart failure
medications effective to treat T2D and NASH (pioglitazone and GLP-1 if used in persons with preexisting heart disease, and bladder cancer.
RAs) also reduce CVD, the leading cause of death in this popula- A meta-analysis of 17 cohort or case-control studies revealed a min-
tion.29,59 Taken together, it follows that adding pharmacologic ther- imal prevalence of bladder cancer compared with robust CV benefits
apy with agents proven to reverse NASH is warranted to prevent and improvements for those with NASH (the numbers needed to treat
progression to cirrhosis more effectively. for 1 additional case of bladder cancer ranged from 899 to 6380, while
At present, there are no FDA-approved drugs for the treatment the numbers needed to benefit CVD and NASH were 4-256 and 2-12,
of NASH. Therefore, treatment recommendations for persons with respectively).285
T2D and NASH are centered on the dual purpose of treating hy- GLP-1 RAs have become pillars of pharmacotherapy for obesity
perglycemia and/or obesity and NASH, especially if clinically sig- and T2D because of robust clinical benefits, including weight loss,
nificant fibrosis (stage, F2) is present, to prevent development of glycemic control, and cardiometabolic improvements. The challenge
cirrhosis. As discussed, a liver biopsy is the optimal approach to of systematic reviews of GLP-1 RAs in NAFLD is the heterogeneity of
confirm the diagnosis and stage of the severity of liver fibrosis. populations included and study designs, with broad differences in
However, it is recognized that this may not be feasible or acceptable treatment duration, primary end points, and assessment of treatment
to several individuals. Therefore, in high-risk populations (ie, those efficacy with random liver imaging modalities and rare use of liver
with obesity and T2D), pharmacologic therapy to treat obesity or biopsy as the “gold standard” for grading NASH. However, taken
Table 7
Medications to Treat Diabetes and Their Efficacy for the Treatment of Nonalcoholic Fatty Liver Disease
Medication Liver fat Disease activity (steatohepatitis/NAS) Studies
Metformin Unchanged Neutral (298-302)

Pioglitazone Decreased Improveda (97, 98, 280-282)
Insulin Decreased Effect unknown (177, 178, 306)
GLP-1 RAs (semaglutide and liraglutide) Decreased Improveda (99, 286-288)
SGLT2 inhibitors (dapagliflozin, empagliflozin, and canagliflozin) Decreased Effect unknown (28, 294-297)
DPP-IV inhibitors (sitagliptin and vildagliptin) Unchanged (in RCTs) Effect unknown (286, 303-305)
Abbreviations: DPP-IV ¼ dipeptidyl peptidase IV; GLP-1 RAs ¼ glucagon-like peptide11 receptor agonists; NAS ¼ nonalcoholic fatty liver disease activity score; RCTs ¼
randomized controlled trials; SGLT2 ¼ sodium-glucose cotransporter 2.
a
The effect on hepatic fibrosis of diabetes medications that improve steatohepatitis has been overall small, although some individual studies98,281 and meta-analyses of
available RCTs283,284 report a decrease in fibrosis with pioglitazone.
544
together, studies agree that GLP-1 RAs normalize plasma amino- Q3.4 What Obesity Pharmacotherapies Have Proven Benefit for the
transferase levels and reduce liver fat content on imaging in in- Treatment of Liver Disease and Cardiometabolic Conditions
dividuals with NAFLD222,286,287 (Table 7). A small (n ¼ 52) 2016 proof- Associated With NAFLD or NASH in Adults?
of-concept RCT suggested that liraglutide improved some features of Recommendation 3.4.1. Clinicians should recommend the use of
liver histology in persons with NASH, including delaying fibrosis obesity pharmacotherapy as adjunctive therapy to lifestyle modi-
progression versus placebo.288 In 2021, a phase 2 RCT compared the fication for individuals with obesity and NAFLD or NASH with a goal
doses of 0.1, 0.2, and 0.4 mg of semaglutide daily with placebo in 320 of at least 5%, preferably 10%, weight loss, as more weight loss is
persons with NASH (of whom 230 had stage F2 or F3 fibrosis). Res- often associated with greater liver histologic and cardiometabolic
olution of steatohepatitis was found in 40% of those in the 0.1-mg benefit, when this is not effectively achieved by lifestyle modifi-
group, 36% of those in the 0.2-mg group, 59% of those in the 0.4-mg cation alone.
group, and 17% of those in the placebo group (P < .001 for semaglu- Grade B; Intermediate Strength of Evidence; BEL 1; down-
tide 0.4 mg vs placebo) in the context of significant weight loss (13% in graded due to small sample sizes used in studies and short
the 0.4-mg group vs 1% in the placebo group).99 There were no sig- duration of trials
nificant between-group differences in the percentage of individuals
with an improvement in fibrosis stage, but progression of liver
fibrosis was significantly less with the highest dose of the GLP-1 RA Recommendation 3.4.2. For chronic weight management in in-
(4.9%) versus placebo (18.8%). Of note, the semaglutide dose of 0.4 mg/ dividuals with a BMI of 27 kg/m2 and NAFLD or NASH, clinicians
day employed is equivalent to the dose of semaglutide 2.4 mg/week should give preference to semaglutide 2.4 mg/week (best evidence)
shown in phase 3 trials to be highly effective for weight loss in persons or liraglutide 3 mg/day.
with obesity.289-292 Grade B; High/Intermediate Strength of Evidence; BEL 1;
SGLT2 inhibitors, approved for the treatment of T2D and heart downgraded due to different formulations and doses used in
failure and associated with robust cardiorenal benefits, have been the semaglutide and liraglutide NASH trials
considered potentially beneficial for NAFLD because of the reduced
lipid burden on the liver from glycosuria creating energy deficit and Evidence Base. Among persons with NASH, weight loss of >5%
weight loss.293 Several small, open-label studies have suggested total body weight (TBW) can reduce hepatic steatosis, weight loss
benefit in persons with T2D and NAFLD.29,222,294 More recent RCTs of >7% TBW can improve NASH, and weight loss of >10% TBW can
have been performed showing the potential benefit of these med- result in fibrosis regression/stability.238,239,241 Weight loss assis-
ications in NAFLD and NASH in persons with obesity and T2D via ted by several obesity medications as an adjunct to lifestyle
imaging of hepatic steatosis using “gold standard” MRI-based therapy can ameliorate NAFLD and NASH in persons who have
techniques, but none yet has been performed with histologic obesity. Although this is recommended, it is acknowledged that
evaluation295-297 (Table 7). SGLT2 inhibitors may be considered as access to these medications can be a challenge due to their high
adjunctive pharmacotherapy for individuals with T2D and NAFLD cost, lack of health insurance, and inadequate coverage by payers.
as they reduce hepatic steatosis and offer significant car- Insurance plans should guarantee access to these medications to
diometabolic and renal protection. treat obesity. Medications approved for the chronic treatment of
Metformin is a biguanide that improves hepatic and muscular obesity include the centrally acting oral combinations phenter-
insulin sensitivity; however, in several paired-biopsy studies in mine/topiramate ER and naltrexone/bupropion ER, the oral lipase
persons with NASH, there was no clinical evidence of benefit on inhibitor orlistat, and subcutaneous GLP-1 receptor agonists lir-
disease activity or liver fibrosis (Table 7). Early studies suggested a aglutide (titrated up to 3 mg daily) and semaglutide (titrated up to
modest effect, largely on hepatic steatosis and associated with 2.4 mg weekly).310 Obesity medications are approved by the FDA
weight loss,298,299 but a meta-analysis of metformin trials has for chronic weight management for individuals with a BMI of 30
shown that weighted liver histologic scores for steatosis, kg/m2 or those with a BMI of 27 to 29.9 kg/m2 and at least 1
ballooning, and fibrosis did not significantly improve and lobular weight-related complication. Early response to therapy is a key
inflammation significantly worsened (weighted mean increase, predictor of long-term success, and the medications should be
0.21; 95% CI, 0.11-0.31; P < .0001),300 consistent with other sys- continued if 5% weight loss has been achieved within 3 months of
tematic reviews and meta-analyses.301,302 Early studies suggested using the full dose of medication. The amount of weight loss
benefit from dipeptidyl peptidase IV inhibitors, but this was not anticipated from obesity medications is greater than 10% or more
confirmed in recent RCTs.286,303-305 Insulin may reduce hepatic of body weight and is associated with cardiometabolic and T2D
steatosis, but the effect is modest, and no liver biopsy study to risk reduction, if the early 3-month efficacy threshold is ach-
assess its effects on liver histology is available.177,178,306 ieved.310,311 While head-to-head trials have not been performed,
Among other agents, only vitamin E showed efficacy to there is a range of efficacy for obesity medications when
ameliorate steatohepatitis (but not fibrosis) in individuals without compared according to placebo-subtracted (included lifestyle
T2D and biopsy-proven NASH in a 2-year RCT.97 Improvement in intervention) weight loss in RCTs. When combined with a lifestyle
steatohepatitis has also been reported in a single-center, uncon- intervention, the efficacy for weight loss ranges between 7% and
trolled retrospective observational study in persons with advanced 18% of baseline weight at 1 year on average. Of the medications
liver fibrosis.307 However, the results in persons with T2D have currently approved for chronic obesity therapy, semaglutide has
been mixed, and vitamin E cannot be recommended with the shown the most efficacy in achieving 10%, 15%, and even 20%
current evidence, as benefit has been modest overall, and fibrosis weight loss.289-292
has not been improved in any of the studies.282 Controversy re- Medications for the management of obesity have not undergone
mains about vitamin E being associated with a modest increased rigorous testing in RCTs using liver histology (ie, paired liver bi-
risk of cardiovascular disease and of prostate cancer,101 although opsies) as the primary outcome in persons with NAFLD. Available
not confirmed in more recent studies. Finally, a number of agents data come from a 48-week pilot study (n ¼ 52) with liraglutide and
have been tested in individuals with NAFLD or NASH; however, a larger study (n ¼ 320) with semaglutide for 72 weeks,99 as dis-
studies have been generally uncontrolled, small, used only imaging cussed earlier, and recently summarized in 2 narrative
as the primary end point, and/or been overall negative.300,301,308,309 reviews.286,287
545
Weight loss associated with orlistat may also exert beneficial Q3.5 What Is the Effect of Bariatric Surgery on Liver Disease and
effects on hepatic fat content and histology in NAFLD. A recent Cardiometabolic Conditions Associated With NAFLD or NASH in
meta-analysis including 3 RCTs and 4 single-arm trials of 330 par- Adults?
ticipants with NAFLD or NASH concluded that orlistat reduced the Recommendation 3.5.1. Clinicians should consider bariatric surgery
aminotransferase levels in persons with NAFLD but failed to as an option to treat NAFLD (Grade B; Intermediate Strength of
improve liver histology in NASH.312 However, studies have been Evidence; BEL 2) and improve cardiometabolic health (Grade A;
usually small and of short duration (up to 36 weeks) with overall High/Intermediate Strength of Evidence; BEL 2; upgraded based
modest or no liver histologic improvement. A 2009 prospective trial on the cardiometabolic and all-cause mortality benefits in all
over 36 weeks compared 23 participants given orlistat/diet/vitamin persons with or without NAFLD) in persons with NAFLD and a BMI
E and 18 given diet/vitamin E.313 The orlistat group lost a mean of of 35 kg/m2 (32.5 kg/m2 in Asian populations), particularly if
8.3% body weight compared with 6.0% in the diet plus vitamin E T2D is present. It should also be considered an option in those with
group (not significant). While orlistat does not appear to have drug- a BMI of 30 to 34.9 kg/m2 (27.5 to 32.4 kg/m2 in Asian pop-
specific effects in steatohepatitis, improvement in insulin sensi- ulations) (Grade B; Intermediate/Weak Strength of Evidence;
tivity and liver histology is proportional to the magnitude of weight BEL 2).
loss. When stratified according to weight loss, persons who lost
9% of body weight (n ¼ 16) showed improved liver steatosis,
ballooning, and inflammation (P < .01) compared with those who Recommendation 3.5.2. For persons with NASH and compensated
failed to do so (n ¼ 25).313 A 2006 RCT studied 52 persons with cirrhosis, clinicians should exercise caution in recommending bar-
NAFLD on liver US (confirmed by liver biopsy in 40 persons) from iatric surgery, which should be highly individualized if prescribed
Israel.314 There was a modest improvement in plasma amino- and performed at experienced centers (Grade B; Intermediate/
transferase levels and in steatosis by liver US, but histology did not Weak Strength of Evidence; BEL 2). In persons with decom-
change significantly in the 22 in whom the biopsy was repeated. A pensated cirrhosis, bariatric surgery should not be recommended
post hoc analysis of phase 3 trials of naltrexone/bupropion ER due to limited evidence and potential for harm (Grade B; Inter-
showed improved ALT levels linearly correlating with weight loss in mediate/Weak Strength of Evidence; BEL 2).
responders who achieved at least 5% weight loss on average at 12
months.315 Evidence Base. It is well established that bariatric surgery induces
sustained weight loss with improvement of common comorbidities
in NAFLD, such as hypertension, sleep apnea, atherogenic dyslipi-
Recommendation 3.4.3. Clinicians must consider obesity pharma-
demia, hyperglycemia with frequent resolution of diabetes, and
cotherapy (with preference to semaglutide 2.4 mg/week [best ev-
amelioration of the risk of CVD and HCC.116-118,120,121,322 A system-
idence] or liraglutide 3 mg/day) as adjunctive therapy to lifestyle
atic review and meta-analysis of 32 studies of persons undergoing
modification for individuals with obesity and NAFLD or NASH to
bariatric surgery, including 3093 liver biopsies obtained during and
promote cardiometabolic health and treat or prevent T2D, CVD, and
after bariatric surgery, reported that 66% had complete resolution
other end-stage manifestations of obesity.
of steatosis, while 50% and 76% had resolution of inflammation and
Grade A; High/intermediate Strength of Evidence; BEL 1
ballooning, respectively. Although fibrosis improved in 40% of in-
dividuals, fibrosis worsened in approximately 12%. Of note, the
Evidence Base. Meta-analyses of weight-loss medication RCTs overall quality of the individual studies included was low.123 In
suggest modest overall benefit for improving the car- another meta-analysis of 21 studies including 2374 persons who
diometabolic risk profile in persons with obesity.199,310 Phen- underwent primarily RYGB, the pooled proportion of steatosis
termine/topiramate ER has been shown to delay progression to improvement was 88%, that of NASH resolution was 59%, and that of
T2D in those at high cardiometabolic risk (MetS or prediabetes), fibrosis improvement was 30%.122 More recently, the impact of
improve glycemic control with weight loss in T2D, and improve bariatric surgery on the natural history of cirrhosis and CVD asso-
lipids and blood pressure with significant improvement in car- ciated with NASH has been reported.323 The investigators examined
diometabolic parameters.316-318 The indication for the reduction 25 828 liver biopsies performed at a U.S. health system between
of CVD risk with liraglutide was substantiated in the Liraglutide 2004 and 2016, where 1158 adults with obesity met enrollment
Effect and Action in Diabetes: Evaluation of Cardiovascular criteria for bariatric surgery and had a confirmed histologic diag-
Outcome Results trial showing that liraglutide reduced the HR nosis of NASH with stage 1 to 3 liver fibrosis. The median follow-up
for the composite major adverse cardiovascular event (MACE) was 7 years (interquartile range, 4-10 years). Bariatric surgery,
outcome by 13%.319 A CV outcome trial has not been performed compared with nonsurgical management, was associated with a
for liraglutide 3 mg in persons with obesity, although clinicians 12.4% lower risk of incident major adverse liver outcomes (95% CI,
can be reassured by cardioprotection demonstrated in the Lir- 5.7%-19.7%), aHR of 0.12 (95% CI, 0.02-0.63; P ¼ .01), and a 13.9%
aglutide Effect and Action in Diabetes: Evaluation of Cardiovas- decrease in MACE (95% CI, 5.9%-21.9%), aHR of 0.30 (95% CI, 0.12-
cular Outcome Results trial for liraglutide 1.8 mg in those with 0.72; P ¼ .007).323
T2D.319 Semaglutide reduces the risk of MACEs supported by The degree of weight loss resulting from bariatric surgery im-
findings in the Trial to Evaluate Cardiovascular and Other Long- proves NAFLD as assessed by either imaging technologies or liver
term Outcomes with Semaglutide in Subjects with Type 2 Dia- histology. A recent meta-analysis of 43 studies with 2809 in-
betes CV outcome trial that enrolled persons with T2D and dividuals examined the outcomes of NAFLD and NASH 6 months
established CVD and/or CKD,320 where it significantly reduced following weight loss with either behavioral/lifestyle intervention,
MACE by 26% compared with placebo. Other GLP-1 RAs have pharmacotherapy, or bariatric surgery and reported a weight loss-
reported CV and renal benefits, with a network analysis sug- dependent improvement in ALT, AST, and hepatic steatosis
gesting that semaglutide has the highest probability to reduce assessed by imaging and/or histology; however, there was limited
myocardial infarction and stroke events,321 but other GLP-1 RAs evidence of a dose-response relationship with changes in hepatic
have not been systematically tested with paired liver biopsies in fibrosis.241 There is limited information about the best surgical
persons with NASH.287 approach for persons with NAFLD. In recent reports from the
546
Oseberg study, the reduction of liver fat content at 1 year was therapy by means of a gastrostomy. Only 2 studies reported on liver
similar with sleeve gastrectomy compared with that of RYBG,324 histology as the primary outcome in persons with NASH.335,336
although the latter was found to be superior for remission of Limited acceptance is due to limited evidence arising from un-
T2D.325 Of note, follow-up was too short to make strong conclu- controlled, small (<50 participants), and short-duration (most of 6-
sions. The average durability of weight loss induced by RYGB has month duration) studies.337,338 Long-term trials339,340 are associ-
been reported to be 21%, with 72% having more than 20% and 40% ated with significant participant attrition from adverse events or
having more than 30% estimated weight loss at 10 years, compared participants being lost to follow-up. Studies have been prone to
with 11% and 4%, respectively, in nonsurgical matched controls.116 potential bias from participant selection by recruiting highly
In a prospective study examining the impact of bariatric surgery, motivated individuals agreeable to substantial time commitment
NASH resolution was observed in 85% after 1 year326 and in 90.5% at and/or follow-up (ie, usually, those better able to tolerate the pro-
5 years and with 70% having fibrosis regression.327 In the subset cedure continue the study). Thus, the generalizability of these trials
with stage 3 fibrosis (precirrhosis) at baseline (n ¼ 19), fibrosis has been questioned. Finally, studies have reported that approxi-
improved in 68% and resolved in 45% after 5 years. This study only mately one third of participants have adverse events ranging from
had paired biopsies for 3 persons with cirrhosis at baseline, of gastrointestinal side effects to (less frequently) surgical leaks, in-
which 2 remained cirrhotic at the 5-year assessment. These results fections, and occasionally serious adverse events.
make it difficult to draw firm conclusions about the role of bariatric In contrast to the significant evidence about the cardiometabolic
surgery in reversing cirrhosis.327 Caution is necessary when and liver benefits of bariatric surgery in NAFLD, EBMT appears less
considering individuals for bariatric surgery who have advanced efficacious and with more limited short- and long-term data. A
fibrosis or cirrhosis. In a retrospective study of 29 persons with meta-analysis of long-term data from 4 published trials with
cirrhosis and stage 3 fibrosis,328 the risk of hepatic decompensation aspiration therapy (n ¼ 373) reported a weight loss between 16%
in individuals with cirrhosis and history of decompensation and 21%.338 Approximately 20% of participants withdrew per year
(presence of hepatic encephalopathy, variceal bleeding, or ascites) or were lost to follow-up, with only 46 and 27 participants in the
was very high. While bariatric surgery can be effective at reducing meta-analysis being followed at years 3 and 4, respectively. Two
metabolic comorbidity in persons with cirrhosis, weight loss studies found plasma aminotransferase levels to decrease. One
without adequate protein intake in such persons can be detri- prospective cohort study of 216 persons undergoing ESG reported
mental. Furthermore, the potential benefit of bariatric surgery in 15% weight loss in 5 years, although no liver-specific outcomes
the context of cirrhosis with respect to histologic improvement or were included.340 Caveats were as outlined earlier: (1) missing data
liver-related outcomes is unclear. While there are limited data, the from 25% to 30% of participants per year of follow-up and (2)
safety of bariatric surgery in selected persons with cirrhosis ap- limited long-term data with only 56 participants enrolled at year 5.
pears to be comparable to those with less advanced fibrosis; Within 3 to 9 months after ESG, 27% of participants had weight
however, persons with hepatic decompensation have a mortality of regain and needed concomitant antiobesity medication, and 6%
7.68% versus 0.94% (OR, 8.78; 95% CI, 3.41-22.59; P < .001) in those required a repeat ESG, making data difficult to interpret. Finally, a
with compensated cirrhosis.329 Thus, individuals with advanced meta-analysis of 18 EBMT studies in 863 participants reported an
fibrosis need to be carefully selected, and a risk-benefit analysis overall modest improvement in ALT, with steatosis on imaging (US
should be performed. Finally, a potential benefit was suggested in a or MRI) improving in 2 studies.338 Only 2 studies examined the
case-controlled meta-analysis of 9 studies in over 19 000 in- impact of IGB on liver histology before and after 6 months of IGB.
dividuals following bariatric surgery that demonstrated a signifi- One RCT treated 18 participants with NASH with diet plus exercise
cant risk reduction in the incidence of HCC compared to those with plus IGB or sham-IGB placement. Although BMI significantly
no surgery.124 decreased, there was no significant improvement in steatosis,
There are no prospective studies or RCTs with CV end points (ie, lobular inflammation, hepatocellular ballooning, or fibrosis scores
MACE) comparing the benefit of bariatric surgery in persons with in either group after treatment. However, there was a modest
T2D or obesity stratified for the presence or absence of NAFLD. improvement in the median NAS (combining steatosis, inflamma-
Further studies along these lines are warranted. Nevertheless, there tion, and ballooning). More recently, a prospective cohort study
is ample evidence that bariatric surgery can produce profound examined the use of IGB in 20 participants with NASH. The mean
health benefits in individuals with obesity and CMD, including body weight loss 6 months following IGB was 11.7% ± 7.7%. Stea-
persons with NAFLD, and is associated with reduced CVD and all- tohepatitis improved, but the results on fibrosis were mixed,
cause mortality.117,118,200,330-332 Recently, a population-based improving by 1 stage in 3 participants and worsening in 5
matched cohort study comparing 13 679 persons who underwent participants.336
bariatric surgery who were matched to 13 679 nonsurgical partic- Clearly, more work is needed to establish the role of EBMT in the
ipants reported that bariatric surgery was associated with signifi- management of people with NASH, and current data are insufficient
cantly lower all-cause, CV, and cancer mortality.333 Finally, a recent to support their use in this population.
meta-analysis that included 74 042 participants with obesity and
CVD demonstrated that bariatric surgery was responsible for an Diagnosis and Management of Children With NAFLD
approximately 43% reduction in the combined MACE outcome after
adjustment for confounding variables.334 Epidemiology of NAFLD in the Pediatric Population: What Is the
Prevalence, Spectrum of Liver Disease, and Natural History,
Recommendation 3.5.3. Endoscopic bariatric and metabolic thera- Particularly in Those With Underlying Endocrine Conditions?
pies (EBMTs) should not be recommended in persons with NAFLD NAFLD is the most common liver disease in pediatrics in the
due to insufficient evidence. United States,341 coexisting with obesity, multiorgan IR, an
Grade C; Intermediate/Weak Strength of Evidence; BEL 2; increased risk of prediabetes/T2D, and cardiac dysfunction.341-343
downgraded due to the quality of studies and small sample sizes The prevalence of NAFLD varies by sex (higher in males) and
race/ethnicity (higher in Hispanic, White, and Asian children
Evidence Base. There are limited data for the treatment of NASH than in African American children).344 Pediatric NAFLD can occur
with EBMT. These therapies encompass devices such as intragastric as early as in utero and can be detected in infancy.345-347 A
balloon (IGB), endoscopic sleeve gastroplasty (ESG), and aspiration meta-analysis, using liver chemistry and imaging (US or MRI) to
547
detect NAFLD, estimated a prevalence of 7.6% in the general Q4.2 What Tests Can Be Used to Diagnose Pediatric NAFLD?
pediatric population, increasing to 34.2% in children with Recommendation 4.2.1. Clinicians should use plasma aminotrans-
obesity.348 ferases to test children at high risk of NAFLD.
In children with prediabetes/T2D, approximately half are esti- Grade B; Intermediate Strength of Evidence; BEL 2
mated to have NAFLD. In a retrospective cohort study of 118 chil-
dren with T2D from the United States, 42% had serum Recommendation 4.2.2. Pediatric NAFLD can be diagnosed with
aminotransferase data available, and of those, 48% were above the imaging (US or MRI-PDFF) or liver biopsy in combination with
normal range.349 In another retrospective study of 57 newly diag- exclusion of non-NAFLD causes of hepatic steatosis such as Wilson
nosed children with T2D, 88% of non-Hispanic Whites, 71% of syndrome, mitochondrial disease, and medications.
Hispanics, and 20% of African Americans had serum ALT levels Grade B; Intermediate Strength of Evidence; BEL 2
above the upper limit of normal.350 In terms of PCOS, a prospective
study of 199 adolescent females from Australia found that PCOS Recommendation 4.2.3. Liver fibrosis prediction calculations and
was an independent predictor of NAFLD (diagnosed with US) in proprietary biomarkers currently available for the diagnosis of
these individuals, with an OR for NAFLD of 2.99 (95% CI, 1.01- advanced fibrosis in adults should not be used in children as they
8.82).351 either are inaccurate or require further validation.
Q4.1 Who Should Be Screened for NAFLD and for Comorbidities?
Evidence Base. Pediatric NAFLD diagnosis requires histologic
Recommendation 4.1.1. Children of any age and adolescents with
confirmation; however, this is not always possible considering the
obesity or T2D, but not T1D, should be screened for NAFLD using
high prevalence of the disease. The diagnosis requires exclusion of
serum ALT.
other causes of liver disease (eg, autoimmune hepatitis, viral hep-
atitis, Wilson disease, alpha 1 antitrypsin deficiency, hemochro-
matosis, celiac disease, and thyroid dysfunction), even though the
Recommendation 4.1.2. Clinicians should screen adolescent females
most common diagnosis in children with obesity referred for sus-
with PCOS for NAFLD using serum ALT.
pected fatty liver disease is NAFLD.363 Often, imaging evidence of
steatosis is also sought. US is inaccurate in this context, with a low
PPV for the diagnosis of fatty liver in the range of 47% to 62%.364
Recommendation 4.1.3. Clinicians should screen children and ado- In contrast, MRI-PDFF-based estimates of steatosis are more
lescents with NAFLD for prediabetes or T2D using an oral glucose accurate and can be used for the diagnosis of NAFLD (PPV, 88%-
tolerance test if the fasting glucose level is 100 mg/mL or if the 100%).360-362,365 However, the test is expensive, and access is often
glycated hemoglobin (A1c) level is in the range of prediabetes limited to tertiary academic centers; therefore, it is not recom-
(5.7% to 6.4%). mended for routine use but should be individualized and ordered
Grade B; Intermediate Strength of Evidence; BEL 2 by the liver specialist. With regard to diagnosing disease severity,
there are currently no noninvasive approaches to determine the
Evidence Base. Children at risk of NAFLD should undergo screening. presence of NASH in children. In terms of fibrosis, prediction scores
A 2019 meta-analysis revealed that the prevalence ratio of NAFLD in developed in adults (eg, AST-to-platelet ratio, NFS, FIB-4, and AST/
children with overweight/obesity is 26.1 (95% CI, 9.4-72.3).352 Se- ALT ratio) are inaccurate in children.366 Other biomarkers (eg,
vere obesity further increases the risk.353 PCOS is another risk combination of cytokeratin 18 and waist circumference and
factor for NAFLD.351 Low-quality (retrospective and small sample microbiome signatures) have been studied with encouraging re-
size) studies suggest that youth with T2D are also at increased risk sults but require further validation.361,367 MRE has been studied in
of NAFLD.349,350 In contrast, children with T1D are not at increased children with NAFLD and found to have a PPV for the presence of
risk and do not require screening.354,355 In clinical practice, the any fibrosis of 74% to 76%.368 Other imaging approaches, such as TE,
serum ALT levels have traditionally been used for screening and are are becoming more widely available; however, pediatric-specific
considered the most validated tool in pediatrics.341,356,357 norms have not yet been developed for NAFLD.369-372
Prediction scores developed for the diagnosis of pediatric NAFLD
are inaccurate and should not be used for screening.358 MRI-PDFF is Q4.3 What Are the Lifestyle, Medical, or Surgical Treatment Options
accurate for the detection of hepatic steatosis in children359-361 of for Pediatric NAFLD, and What Is the Role of Pharmacotherapy
various ethnic backgrounds362; however, it is not widely used as a Developed for Endocrine Disorders in the Treatment of Pediatric
screening tool in part due to availability and cost. In summary, the NAFLD?
serum ALT levels remain the most validated, practical biomarker of Recommendation 4.3.1. Clinicians should recommend lifestyle
histologic disease severity in children with NAFLD, and until better changes in children with NAFLD, promoting the adoption of dietary
biomarkers become available, should continue to be used for changes to create an energy deficit, with reduction in sugar con-
screening. If normal, repeat screening can be considered on an sumption as first-line lifestyle modification, and increased physical
annual basis if the risk factors persist. activity aiming for BMI optimization.
Robust data regarding the natural history of pediatric NAFLD are Grade B; Intermediate Strength of Evidence; BEL 1; down-
limited. A recent analysis of histologic outcomes of children graded due to the limited number of RCTs and small sample size
enrolled in the placebo arms of RCTs revealed that the majority of
participants do not improve with lifestyle interventions alone.356 In Recommendation 4.3.2. Clinicians may consider GLP-1 RAs for the
fact, 23% of participants have evidence of worsened fibrosis over a treatment of pediatric obesity and T2D (Grade D; Expert Opinion;
mean time of 1.6 years. Among predictors of progression to definite BEL 4), which may also offer benefit for pediatric NAFLD, although
NASH and/or fibrosis were an increasing A1c level and the devel- not FDA-approved for this indication (Grade D; Expert Opinion;
opment of T2D. Epidemiologic data of children and adolescents BEL 4).
with severe obesity, who are at increased risk of NAFLD, show an
increased risk of CV and all-cause mortality in adulthood.353 More Evidence Base. The mainstay of treatment for pediatric NAFLD is
pediatric NAFLD-specific studies are needed. dietary and physical activity modifications. A study of children
548
participating in the placebo arms of RCTs receiving lifestyle advice Future Directions
showed that dietary and physical activity recommendations lead to
NASH resolution in 29% and fibrosis improvement in 34% of chil- NAFLD is a growing public health problem likely affecting many
dren over a mean of 1.6 years.356 However, in the same timeframe, of those seen by endocrinologists and primary health care pro-
18% of children progressed to definite NASH, and 23% had worse fessionals, as it is closely linked to the epidemics of obesity and T2D
fibrosis. and other comorbidities. People at greatest risk of NASH and
To assess the effects of <3% of total calories from free sugars cirrhosis are those with MetS and prediabetes, T2D, or the presence
versus usual diet, an 8-week open-label, randomized (1:1) trial was of elevated plasma aminotransferase levels or steatosis on imaging.
performed in 40 adolescent boys with NAFLD.373 The primary Those with NASH and cirrhosis are also at increased risk of HCC and
outcome was change in hepatic steatosis estimated by MRI-PDFF. future T2D, CVD and other comorbidities. Given the aforemen-
The mean decrease in hepatic steatosis was significantly greater tioned findings, there are 3 major areas that will likely be trans-
for the intervention diet group (25% to 17%) versus the usual diet formed in the care of people with NAFLD in the near future:
group (21% to 20%). Long-term clinical outcomes remain unknown.
Both aerobic and resistance exercise trainings, at vigorous or 1. Greater awareness: education of all health care providers and
moderate-to-vigorous intensities aiming to improve cardiorespi- people with the disease about the magnitude of the problem
ratory fitness and muscular strength, had benefits on hepatic fat and need for early diagnosis and treatment.
content reduction in youth.374 2. Diagnosis: with the development and implementation of sim-
There are no FDA-approved pharmacotherapies for pediatric ple, cost-effective, and accurate diagnostic tests to screen and
NAFLD. The Treatment of Nonalcoholic Fatty Liver Disease in diagnose early on large numbers of people at risk.
Children and Adolescents RCT found no benefit of metformin or 3. Treatment: in addition to improved lifestyle approaches and CV
vitamin E in achieving a reduction in the NAS of 2 in chil- risk reduction strategies, greater awareness of the benefits from
dren.375 However, the secondary analyses found a significantly some currently available diabetes medications (ie, pioglitazone
greater resolution of NASH with 400 IU twice a day of vitamin E and GLP-1 RAs) and new drugs in development to become FDA-
daily versus placebo. The long-term efficacy and safety of approved will radically change the treatment of NASH.
vitamin E in children with NASH remain unknown. Metformin at
a dose of 500 mg orally twice a day was not effective, possibly Greater awareness will be critical among endocrinologists as
due to the underdosing effect of the drug.375 The effects of well as PCPs and all health care professionals. There is an urgent
treatment with polyunsaturated fatty acids or probiotics have need for health care providers to educate and detect early on those
not been validated with histologic analysis.376 at highest risk of cirrhosis and improve their early referral to liver
Despite the mounting evidence from recent RCTs in specialists. Endocrinology and primary care clinicians are at the
adults indicating a favorable effect of GLP-1 RAs on NAFLD in frontline in the battle to identify those at risk early on, as recent
adults,99,286-288 similar studies in children and adolescents with studies suggest that persons with NASH and clinically significant
NASH are lacking and greatly needed. Liraglutide appears to be safe liver fibrosis (stages F2-F4) concentrate in endocrinology and pri-
in this population377-379 and is effective for the treatment of pedi- mary care clinics. Endocrinology and primary care clinicians will
atric T2D and obesity.380,381 It has been approved for use in children have to incorporate calculation of the individual’s liver fibrosis risk
aged 10 years and 12 years, respectively. However, there are no (FIB-4) as the initial step in screening for NAFLD and liver fibrosis, in
RCTs of a GLP-1 RA for the treatment of NAFLD in children and the same way as we do today for ordering microalbumin or
adolescents with NASH. ordering an annual dilated eye examination to prevent diabetic
Bariatric surgery is an accepted treatment for youth with nephropathy or retinopathy, respectively. Knowledge about the
class II severe obesity with significant comorbid conditions and best next steps, such as the use of additional liver imaging and/or
for those with class III with or without comorbid conditions plasma biomarkers, will be mandatory, followed by fibrosis risk
(Table 8).382,383 Adolescents who underwent RYGB had marked stratification into low, indeterminate, or high risk of developing
weight loss 5 years after surgery showing remission of diabetes future cirrhosis and when referral to the liver specialist will be
and hypertension more often than adults.384,385 A small pediatric needed in the higher risk groups.
study showed that bariatric surgery is superior to lifestyle in- With a growing body of evidence that NASH and clinically sig-
terventions at treating NASH and NAFLD-related fibrosis.385 The nificant liver fibrosis are common in endocrine and primary care
risks of surgery in adolescents in general are comparable to clinics, it is likely that this experience and a growing literature will
those in adults but with the potential for long-term nutritional assist in the development of the optimal use of current and novel
complications.384 diagnostic tests for people at risk. Future tests being developed
include the use of metabolomics, proteomics, and other strategies
that, when combined, will further increase diagnostic sensitivity
and specificity, allowing optimization of referrals to liver specialists
Table 8 and more cost-effective approaches.
BMI-for-Age Weight Status Categories in Children and Adolescents and the Corre-
Lifestyle changes that lead to an energy deficit, if overweight or
sponding Percentiles382,383
obesity, and improve cardiometabolic health have proven effective
Weight status BMI percentile range in NAFLD, but large, long-term controlled studies are needed.
category
Future studies will establish if there is a particular macronutrient
Underweight <5th percentile dietary recommendation that yields the best results in reversing
Healthy weight 5th percentile to <85th percentile
steatohepatitis and/or liver fibrosis or if histologic improvement is
Overweight 85th to <95th percentile
Obesity class I 95th percentile to <120% of the 95th percentile for age
largely dependent on the magnitude of weight loss. Future studies
and sex should also determine with more precision the threshold to reverse
Obesity class II 120% to <140% of the 95th percentile or BMI 35 kg/m2 steatohepatitis and/or liver fibrosis. Finally, there is a lack of large,
Obesity class III 140% of the 95th percentile or BMI 40 kg/m2 long-term controlled studies in bariatric surgery to establish the
Abbreviation: BMI ¼ body mass index; best surgical approach in NASH.
549
Several studies are testing a broad array of pharmaceutical agents Subcommittee. All members of the expert Task Force completed the
with multiple biologic targets versus NASH. Despite many recent AACE’s disclosure form regarding any multiplicities of interests
failures, agents that promote weight loss (ie, GLP-1 RAs such as lir- related to commercial and direct financial relationships within the
aglutide and semaglutide) have improved NASH. New weight-loss preceding 12 months with companies that develop products con-
medications are undergoing testing in NASH, including dual GLP-1 nected with endocrine disorders. Categories for disclosure include
RA/gastric inhibitory polypeptide (ie, tirzepatide) analogs and employment, stock or other ownership, direct financial relation-
GLP-1 RA/glucagon agonists (ie, cotadutide). Another approach un- ships (eg, speaker or consultant), research funding, authorship or
dergoing phase 3 testing are medications, similar to pioglitazone, panel involvement on a guideline related to an overlapping topic, or
that restore dysfunctional adipose in obesity to normal and reverse other situations related to a perceived COI. The AACE COI Sub-
IR in those with or without diabetes, improving both steatohepatitis committee reviewed these disclosures against an AACE-approved
and fibrosis (ie, lanifibranor, a pan-PPAR, with PPAR-alpha, PPAR- list of affected companies for this guideline and reached
delta, and PPAR-gamma activity). Other approaches in large phase 3 consensus regarding members who could serve on the Task Force in
RCTs include FXR agonists (having predominantly antifibrotic ac- the nonconflicted majority, those who could serve in the conflicted
tivity) and thyroid hormone receptor agonists (largely improving minority with management strategy, and those who were dis-
steatohepatitis), with many other drugs being in phase 2a and 2b. qualified from serving on the Task Force. The AACE Clinical Practice
In the meantime, clinicians should become more familiar with Guidelines Oversight Committee reviewed and approved the AACE
the utilization of diabetes agents, such as pioglitazone (inexpensive COI Subcommittee’s decisions regarding manageable COI and
generic) or the GLP-1 RAs (best evidence for semaglutide), proven empanelment. The members of this Task Force were reminded to
to reverse steatohepatitis in controlled clinical trials of 1.5- to 3- update potential disclosures if new potential conflicts arose during
year duration in persons with or without diabetes. Vitamin E has their appointments and verify currency of disclosures. The AACE
also shown benefit in people with NASH without diabetes. How- made every effort to minimize the potential for conflicts of interest
ever, these agents are not FDA approved for the treatment of NASH. that could influence the recommendations of this clinical practice
Future management should also include more careful control of CV guideline.
risk factors, such as hypertension and atherogenic dyslipidemia, K.C. has received research support towards the University of
incorporating newer agents as needed to reach treatment targets. Florida as principal investigator from the National Institute of
Pediatric NAFLD is also becoming a growing concern, but there Health (NIH), Echosens, Inventiva, Nordic Bioscience, Novo Nordisk,
is limited awareness among the public and health care pro- Poxel, Labcorp, and Zydus. K.C. is a consultant for Altimmune,
fessionals about the problem. Future studies must improve the Akero, Arrowhead, AstraZeneca, 89Bio, BMS, Coherus, Intercept,
quality of the evidence in terms of the optimal diagnostic and Lilly, Madrigal, Merck, Novo Nordisk, Quest, Sagimet, Sonic Incytes,
treatment pathways and the optimal healthy lifestyle changes in Terns and Thera Technologies. R.B. reports research grant support
children at different ages. from AstraZeneca. W.T.G. reports research grant support from Novo
Nordisk, Eli Lilly, Epitomee, and Sanofi/Lexicon. S.K. reports
Conclusions research grant support from Fractyl Health. M.E.R. is consultant for
Intercept and Bristol Myers Squibb, reports research grant support
Endocrinologists and primary care clinicians are in an ideal from Novartis, and is author of AASLD NAFLD practice guidance
position to identify those at risk early on to prevent the devel- document 2018. M.B.V. is consultant for BMS, Intercept, and
opment of cirrhosis and comorbidities. Screening should involve Boehringer Ingelheim and reports research grant support from
calculation of the individual’s liver fibrosis risk (FIB-4), followed BMS. Z.Y. is consultant for Novo Nordisk. The other authors have no
by additional plasma biomarkers and/or liver imaging based on multiplicity of interest to disclose.
fibrosis risk stratification into low, indeterminate, or high risk of
developing future cirrhosis, with referral to a liver specialist for Panel Composition
those in the higher-risk groups. Lifestyle changes leading to an
energy deficit if overweight or obese and improved car- The Task Force was empaneled in accordance with the AACE’s
diometabolic health are essential to reduce CVD risk. Treatment COI Policy and Diversity, Equity, and Inclusion Policy. This evidence-
must include consideration of weight-loss medications, particu- based clinical practice guideline was developed by a multidisci-
larly GLP-1 RAs with proven benefit for steatohepatitis and bar- plinary group of credentialed medical professionals in the fields of
iatric surgery. Some diabetes medications, such as pioglitazone endocrinology and hepatology. The members of the task force
and GLP-1 RAs, should be preferred for those with T2D and NASH, included current AACE members in good standing and 2 AASLD
particularly when at indeterminate or high risk of developing representatives.
future cirrhosis. Management should also include careful control
of CV risk factors, such as hypertension and atherogenic dyslipi- Review Process
demia. Pediatric NAFLD is also becoming a growing concern, but
there is limited awareness among health care professionals about Drafts of this guideline were reviewed and approved by the
the problem. Inadequate evidence in terms of the optimal diag- writing task force, AACE CPG Oversight Committee, AACE Board of
nostic and treatment pathways is a major barrier with current Directors, and peer reviewers for Endocrine Practice.
care being based on early diagnosis and promotion of healthy
lifestyle changes. Rapid changes in diagnostic tools and in drug Updating Policy
development promise to offer new options for endocrinologists
and other health care professionals involved in the management The AACE reviews and updates or retires its evidence-based
of NAFLD. guidelines every 3 to 5 years or after significant scientific de-
velopments or change in public policy as determined by the AACE
Disclosures executive leadership, AACE CPG Oversight Committee, and relevant
AACE Disease-State Network.
The Task Force was empaneled in accordance with the AACE’s
Conflict of Interest (COI) Policy and approved by the AACE COI Document Expiration Date: May 2027
550
551
552
553
554
Acknowledgment 24. Bril F, Ortiz-Lopez C, Lomonaco R, et al. Clinical value of liver ultrasound for
the diagnosis of nonalcoholic fatty liver disease in overweight and obese
patients. Liver Int. 2015;35(9):2139e2146.
We thank the AACE CPG Oversight Committee, AACE Board of 25. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty
Directors, and AASLD for their thoughtful reviews and insightful liver disease and diabetes. Lancet Diabetes Endocrinol. 2022. https://doi.org/
comments on this guideline. 10.1016/S2213-8587(22)00003-1.
26. Doycheva I, Cui J, Nguyen P, et al. Non-invasive screening of diabetics in
This clinical practice guideline on NAFLD was developed with primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment
financial support from the AACE. All members who served on this Pharmacol Ther. 2016;43(1):83e95.
AACE Task Force completed work on the manuscript electronically 27. Jinjuvadia R, Antaki F, Lohia P, Liangpunsakul S. The association between
nonalcoholic fatty liver disease and metabolic abnormalities in the United
and met via video conferences. The AACE received no outside States population. J Clin Gastroenterol. 2017;51(2):160e166.
funding for the development of this guideline. 28. Kanwal F, Kramer JR, Li L, et al. Effect of metabolic traits on the risk of cirrhosis
and hepatocellular cancer in nonalcoholic fatty liver disease. Hepatology.
2020;71(3):808e819.
29. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH:
References mechanisms and treatment options. JHEP Rep. 2019;1(4):312e328.
30. Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalco-
1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global holic fatty liver disease in patients with type 2 diabetes mellitus and
epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of normal plasma aminotransferase levels. J Clin Endocrinol Metab.
prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73e84. 2015;100(6):2231e2238.
2. Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonal- 31. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of
coholic fatty liver disease, nonalcoholic steatohepatitis, and associated NAFLD progression from steatosis to fibrosing-steatohepatitis using paired
fibrosis. Hepatology. 2018;68(1):349e360. biopsies: implications for prognosis and clinical management. J Hepatol.
3. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for 2015;62(5):1148e1155.
nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344e353. 32. Alexopoulos AS, Crowley MJ, Wang Y, et al. Glycemic control predicts severity
4. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histo- of hepatocyte ballooning and hepatic fibrosis in nonalcoholic fatty liver dis-
logical scoring system for nonalcoholic fatty liver disease. Hepatology. ease. Hepatology. 2021;74(3):1220e1233.
2005;41(6):1313e1321. 33. Rich NE, Oji S, Mufti AR, et al. Racial and ethnic disparities in nonalcoholic
5. Harrison SA, Gawrieh S, Roberts K, et al. Prospective evaluation of the prev- fatty liver disease prevalence, severity, and outcomes in the United States: a
alence of non-alcoholic fatty liver disease and steatohepatitis in a large systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):
middle-aged US cohort. J Hepatol. 2021;75(2):284e291. 198e210.e2.
6. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and 34. Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Role of ethnicity in overweight and
NASH in patients with type 2 diabetes: a systematic review and meta-anal- obese patients with nonalcoholic steatohepatitis. Hepatology. 2011;54(3):
ysis. J Hepatol. 2019;71(4):793e801. 837e845.
7. Kim D, Kim W, Adejumo AC, et al. Race/ethnicity-based temporal changes in 35. Romeo S, Sanyal A, Valenti L. Leveraging human genetics to identify potential
prevalence of nafld-related advanced fibrosis in the United States, 2005-2016. new treatments for fatty liver disease. Cell Metab. 2020;31(1):35e45.
Hepatol Int. 2019;13(2):205e213. 36. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers sus-
8. Kanwal F, Kramer JR, Duan Z, Yu X, White D, El-Serag HB. Trends in the burden ceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):
of nonalcoholic fatty liver disease in a United States cohort of veterans. Clin 1461e1465.
Gastroenterol Hepatol. 2016;14(2):301e308. e1-e2. 37. Bonacini M, Kassamali F, Kari S, Lopez Barrera N, Kohla M. Racial differences in
9. Lomonaco R, Godinez Leiva E, Bril F, et al. Advanced liver fibrosis is common prevalence and severity of non-alcoholic fatty liver disease. World J Hepatol.
in patients with type 2 diabetes followed in the outpatient setting: the need 2021;13(7):763e773.
for systematic screening. Diabetes Care. 2021;44(2):399e406. 38. Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tyb-
10. Ciardullo S, Monti T, Perseghin G. High prevalence of advanced liver fibrosis jaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and
assessed by transient elastography among U.S. adults with type 2 diabetes. HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the
Diabetes Care. 2021;44(2):519e525. general population. Hepatology. 2020;72(3):845e856.
11. Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus 39. Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH,
increases the risk of hepatic fibrosis in individuals with obesity and Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred
nonalcoholic fatty liver disease. Obesity (Silver Spring). 2021;29(11): by multiple loci. Nat Genet. 2017;49(6):842e847.
1950e1960. 40. Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression
12. Younossi ZM, Stepanova M, Younossi Y, et al. Epidemiology of chronic liver and regression in NASH. J Hepatol. 2018;68(2):238e250.
diseases in the USA in the past three decades. Gut. 2020;69(3):564e568. 41. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as
13. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of a determinant of cause-specific mortality in patients with advanced nonal-
nonalcoholic fatty liver disease demonstrates an exponential increase in coholic fatty liver disease: a multi-national cohort study. Gastroenterology.
burden of disease. Hepatology. 2018;67(1):123e133. 2018;155(2):443e457.e17.
14. Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Com- 42. Hagstro €m H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts
ponents of metabolic syndrome increase the risk of mortality in nonalcoholic mortality and time to development of severe liver disease in biopsy-proven
fatty liver disease (NAFLD). Medicine (Baltimore). 2018;97(13):e0214. NAFLD. J Hepatol. 2017;67(6):1265e1273.
15. Paik JM, Henry L, De Avila L, Younossi E, Racila A, Younossi ZM. Mortality 43. Taylor RS, Taylor RJ, Bayliss S, et al. Association between fibrosis stage and
related to nonalcoholic fatty liver disease is increasing in the United States. outcomes of patients with nonalcoholic fatty liver disease: a systematic re-
Hepatol Commun. 2019;3(11):1459e1471. view and meta-analysis. Gastroenterology. 2020;158(6):1611e1625.e12.
16. Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM. Changes in the global 44. Simon TG, Roelstraete B, Khalili H, Hagstro €m H, Ludvigsson JF. Mortality in
burden of chronic liver diseases from 2012 to 2017: the growing impact of biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide
NAFLD. Hepatology. 2020;72(5):1605e1616. cohort. Gut. 2021;70(7):1375e1382.
17. Younossi Z, Stepanova M, Ong JP, et al. Nonalcoholic steatohepatitis is the 45. Doycheva I, Zhang T, Amjad W, Thuluvath PJ. Diabetes and hepatocellular
fastest growing cause of hepatocellular carcinoma in liver transplant candi- carcinoma: incidence trends and impact of liver disease etiology. J Clin Exp
dates. Clin Gastroenterol Hepatol. 2019;17(4):748e755.e3. Hepatol. 2020;10(4):296e303.
18. Golabi P, Paik JM, AlQahtani S, Younossi Y, Tuncer G, Younossi ZM. Burden of 46. Simon TG, Roelstraete B, Sharma R, Khalili H, Hagstro €m H, Ludvigsson JF.
non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Cancer risk in patients with biopsy-confirmed nonalcoholic fatty liver disease:
data from global burden of disease 2009-2019. J Hepatol. 2021;75(4): a population-based cohort study. Hepatology. 2021;74(5):2410e2423.
795e809. 47. Ekstedt M, Hagstro €m H, Nasr P, et al. Fibrosis stage is the strongest predictor
19. Alqahtani SA, Paik JM, Biswas R, Arshad T, Henry L, Younossi ZM. Poor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
awareness of liver disease among adults with NAFLD in the United States. Hepatology. 2015;61(5):1547e1554.
Hepatol Commun. 2021;5(11):1833e1847. 48. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat
20. Younossi ZM, Ong JP, Takahashi H, et al. A global survey of physicians and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.
knowledge about nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. Gastroenterology. 2007;133(2):496e506.
2021. https://doi.org/10.1016/j.cgh.2021.06.048. 49. Gastaldelli A, Sabatini S, Carli F, et al. PPAR-g-induced changes in visceral fat
21. Kanwal F, Shubrook JH, Younossi Z, et al. Preparing for the NASH epidemic: a and adiponectin levels are associated with improvement of steatohepatitis in
call to action. Diabetes Care. 2021;44(9):2162e2172. patients with NASH. Liver Int. 2021;41(11):2659e2670.
22. Kanwal F, Shubrook JH, Adams LA, et al. Clinical care pathway for the risk 50. Lomonaco R, Bril F, Portillo-Sanchez P, et al. Metabolic impact of nonalcoholic
stratification and management of patients with nonalcoholic fatty liver dis- steatohepatitis in obese patients with type 2 diabetes. Diabetes Care.
ease. Gastroenterology. 2021;161(5):1657e1669. 2016;39(4):632e638.
23. Lazarus JV, Anstee QM, Hagstro € m H, et al. Defining comprehensive models of 51. Ballestri S, Zona S, Targher G, et al. Nonalcoholic fatty liver disease is asso-
care for NAFLD. Nat Rev Gastroenterol Hepatol. 2021;18(10):717e729. ciated with an almost twofold increased risk of incident type 2 diabetes and
555
metabolic syndrome. Evidence from a systematic review and meta-analysis. 80. Yao Y, Miao X, Zhu D, et al. Insulin-like growth factor-1 and non-alcoholic
J Gastroenterol Hepatol. 2016;31(5):936e944. fatty liver disease: a systemic review and meta-analysis. Endocrine.
52. Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease 2019;65(2):227e237.
and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 81. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA.
2018;41(2):372e382. 2015;313(22):2263e2273.
53. Morrison AE, Zaccardi F, Khunti K, Davies MJ. Causality between non-alcoholic 82. Akshintala D, Chugh R, Amer F, Cusi K. Nonalcoholic fatty liver disease: the
fatty liver disease and risk of cardiovascular disease and type 2 diabetes: a overlooked complication of type 2 diabetes. In: Feingold KR, Anawalt B,
meta-analysis with bias analysis. Liver Int. 2019;39(3):557e567. Boyce A, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000-
54. Younossi ZM, Tampi RP, Racila A, et al. Economic and clinical burden of 2019 Jul 9.
nonalcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Dia- 83. Mellinger JL, Pencina KM, Massaro JM, et al. Hepatic steatosis and cardio-
betes Care. 2020;43(2):283e289. vascular disease outcomes: an analysis of the Framingham Heart study.
55. Corbin KD, Driscoll KA, Pratley RE, Smith SR, Maahs DM, Mayer-Davis EJ. J Hepatol. 2015;63(2):470e476.
Obesity in type 1 diabetes: pathophysiology, clinical impact, and mechanisms. 84. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular dis-
Endocr Rev. 2018;39(5):629e663. ease: clinical associations, pathophysiological mechanisms and pharmaco-
56. de Vries M, Westerink J, Kaasjager KHAH, de Valk HW. Prevalence of nonal- logical implications. Gut. 2020;69(9):1691e1705.
coholic fatty liver disease (NAFLD) in patients with type 1 diabetes mellitus: a 85. Lee SB, Park GM, Lee JY, et al. Association between non-alcoholic fatty liver
systematic review and meta-analysis. J Clin Endocrinol Metab. 2020;105(12): disease and subclinical coronary atherosclerosis: an observational cohort
3842e3853. study. J Hepatol. 2018;68(5):1018e1024.
57. Cusi K, Sanyal AJ, Zhang S, et al. Non-alcoholic fatty liver disease (NAFLD) 86. Hagstro €m H, Nasr P, Ekstedt M, et al. Cardiovascular risk factors in non-
prevalence and its metabolic associations in patients with type 1 diabetes and alcoholic fatty liver disease. Liver Int. 2019;39(1):197e204.
type 2 diabetes. Diabetes Obes Metab. 2017;19(11):1630e1634. 87. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-
58. Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic obese or lean non-alcoholic fatty liver disease: a systematic review and meta-
vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14(2): analysis. Lancet Gastroenterol Hepatol. 2020;5(8):739e752.
99e114. 88. Mantovani A, Dauriz M, Sandri D, et al. Association between non-alcoholic
59. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD fatty liver disease and risk of atrial fibrillation in adult individuals: an
and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastro- updated meta-analysis. Liver Int. 2019;39(4):758e769.
enterol Hepatol. 2021;18(9):599e612. 89. Mantovani A, Rigamonti A, Bonapace S, et al. Nonalcoholic fatty liver disease is
60. Cusi K, Godinez Leiva E. Cardiovascular risk in patients with nonalcoholic fatty associated with ventricular arrhythmias in patients with type 2 diabetes
liver disease: looking at the liver to shield the heart. Curr Opin Lipidol. referred for clinically indicated 24-hour holter monitoring. Diabetes Care.
2020;31(6):364e366. 2016;39(8):1416e1423.
61. Marcuccilli M, Chonchol M. NAFLD and chronic kidney disease. Int J Mol Sci. 90. Wijarnpreecha K, Lou S, Panjawatanan P, et al. Association between diastolic
2016;17(4):562. cardiac dysfunction and nonalcoholic fatty liver disease: a systematic review
62. Byrne CD, Targher G. NAFLD as a driver of chronic kidney disease. J Hepatol. and meta-analysis. Dig Liver Dis. 2018;50(11):1166e1175.
2020;72(4):785e801. 91. Jaruvongvanich V, Sanguankeo A, Upala S. Significant association between
63. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver gallstone disease and nonalcoholic fatty liver disease: a systematic review and
disease with chronic kidney disease: a systematic review and meta-analysis. meta-analysis. Dig Dis Sci. 2016;61(8):2389e2396.
PLoS Med. 2014;11(7):e1001680. 92. Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R. Association
64. Mantovani A, Zaza G, Byrne CD, et al. Nonalcoholic fatty liver disease increases of obstructive sleep apnoea with the presence and severity of non-alcoholic
risk of incident chronic kidney disease: a systematic review and meta-anal- fatty liver disease. A systematic review and meta-analysis. Obes Rev.
ysis. Metabolism. 2018;79:64e76. 2013;14(5):417e431.
65. Song D, Li C, Wang Z, Zhao Y, Shen B, Zhao W. Association of non-alcoholic fatty 93. Cho Y, Lim SK, Joo SK, et al. Nonalcoholic steatohepatitis is associated with a
liver disease with diabetic retinopathy in type 2 diabetic patients: a meta- higher risk of advanced colorectal neoplasm. Liver Int. 2019;39(9):1722e1731.
analysis of observational studies. J Diabetes Investig. 2021;12(8):1471e1479. 94. Koo BK, Kim D, Joo SK, et al. Sarcopenia is an independent risk factor for non-
66. Kumarendran B, O'Reilly MW, Manolopoulos KN, et al. Polycystic ovary syn- alcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017;66(1):123e131.
drome, androgen excess, and the risk of nonalcoholic fatty liver disease in 95. Han E, Lee YH, Kim YD, et al. Nonalcoholic fatty liver disease and sarcopenia
women: a longitudinal study based on a United Kingdom primary care are independently associated with cardiovascular risk. Am J Gastroenterol.
database. PLoS Med. 2018;15(3):e1002542. 2020;115(4):584e595.
67. Sarkar M, Terrault N, Chan W, et al. Polycystic ovary syndrome (PCOS) is 96. Golabi P, Gerber L, Paik JM, Deshpande R, de Avila L, Younossi ZM. Contri-
associated with NASH severity and advanced fibrosis. Liver Int. 2020;40(2): bution of sarcopenia and physical inactivity to mortality in people with non-
355e359. alcoholic fatty liver disease. JHEP Rep. 2020;2(6):100171.
68. Falzarano C, Lofton T, Osei-Ntansah A, et al. Nonalcoholic fatty liver disease in 97. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo
women and girls with polycystic ovary syndrome. J Clin Endocrinol Metab. for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675e1685.
2022;107(1):258e272. 98. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients
69. Vassilatou E, Vassiliadi DA, Salambasis K, et al. Increased prevalence of with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus:
polycystic ovary syndrome in premenopausal women with nonalcoholic fatty a randomized trial. Ann Intern Med. 2016;165(5):305e315.
liver disease. Eur J Endocrinol. 2015;173(6):739e747. 99. Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcu-
70. Wu J, Yao XY, Shi RX, Liu SF, Wang XY. A potential link between polycystic taneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med.
ovary syndrome and non-alcoholic fatty liver disease: an update meta-anal- 2021;384(12):1113e1124.
ysis. Reprod Health. 2018;15(1):77. 100. Mechanick JI, Pessah-Pollack R, Camacho P, et al. American Association of
71. Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, Targher G. Clinical Endocrinologists and American College of Endocrinology protocol for
Pathogenesis of hypothyroidism-induced NAFLD: evidence for a distinct dis- standardized production of clinical practice guidelines, algorithms, and
ease entity? Dig Liver Dis. 2019;51(4):462e470. checklists - 2017 update. Endocr Pract. 2017;23(8):1006e1021.
72. Mantovani A, Nascimbeni F, Lonardo A, et al. Association between primary 101. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of
hypothyroidism and nonalcoholic fatty liver disease: a systematic review and nonalcoholic fatty liver disease: practice guidance from the American Asso-
meta-analysis. Thyroid. 2018;28(10):1270e1284. ciation for the Study of Liver Diseases. Hepatology. 2018;67(1):328e357.
73. Bril F, Kadiyala S, Cusi K. Re: “Association between primary hypothyroidism 102. Lai LL, Wan Yusoff WNI, Vethakkan SR, Nik Mustapha NR, Mahadeva S,
and nonalcoholic fatty liver disease: a systematic review and meta-analysis” Chan WK. Screening for non-alcoholic fatty liver disease in patients with type
by Mantovani et al. (Thyroid 2018;28:1270-1284). Thyroid. 2019;29(3):452. 2 diabetes mellitus using transient elastography. J Gastroenterol Hepatol.
74. Bril F, Kadiyala S, Portillo Sanchez P, et al. Plasma thyroid hormone concen- 2019;34(8):1396e1403.
tration is associated with hepatic triglyceride content in patients with type 2 103. Petta S, Eslam M, Valenti L, et al. Metabolic syndrome and severity of fibrosis
diabetes. J Investig Med. 2016;64(1):63e68. in nonalcoholic fatty liver disease: an age-dependent risk profiling study.
75. Shen M, Shi H. Sex hormones and their receptors regulate liver energy ho- Liver Int. 2017;37(9):1389e1396.
meostasis. Int J Endocrinol. 2015;2015:294278. 104. Bril F, McPhaul MJ, Caulfield MP, et al. Performance of plasma biomarkers and
76. Dayton KA, Bril F, Barb D, Lai J, Kalavalapalli S, Cusi K. Severity of non- diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in
alcoholic steatohepatitis is not linked to testosterone concentration in pa- patients with type 2 diabetes. Diabetes Care. 2020;43(2):290e297.
tients with type 2 diabetes. PLoS One. 2021;16(6):e0251449. 105. Wong RJ, Liu B, Bhuket T. Significant burden of nonalcoholic fatty liver disease
77. Adamek A, Kasprzak A. Insulin-like growth factor (IGF) system in liver dis- with advanced fibrosis in the US: a cross-sectional analysis of 2011-2014
eases. Int J Mol Sci. 2018;19(5):1308. national health and nutrition examination survey. Aliment Pharmacol Ther.
78. Sumida Y, Yonei Y, Tanaka S, et al. Lower levels of insulin-like growth factor-1 2017;46(10):974e980.
standard deviation score are associated with histological severity of non- 106. Younossi Z, Stepanova M, Sanyal AJ, et al. The conundrum of cryptogenic
alcoholic fatty liver disease. Hepatol Res. 2015;45(7):771e781. cirrhosis: adverse outcomes without treatment options. J Hepatol. 2018;69(6):
79. Nishizawa H, Iguchi G, Murawaki A, et al. Nonalcoholic fatty liver disease in 1365e1370.
adult hypopituitary patients with GH deficiency and the impact of GH 107. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for
replacement therapy. Eur J Endocrinol. 2012;167(1):67e74. serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1e10.
556
108. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal 134. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver dis-
liver chemistries. Am J Gastroenterol. 2017;112(1):18e35. ease in patients with nonalcoholic fatty liver disease. Gastroenterology.
109. Maximos M, Bril F, Portillo Sanchez P, et al. The role of liver fat and insulin 2019;156(5):1264e1281.e4.
resistance as determinants of plasma aminotransferase elevation in nonal- 135. Siddiqui MS, Yamada G, Vuppalanchi R, et al. Diagnostic accuracy of nonin-
coholic fatty liver disease. Hepatology. 2015;61(1):153e160. vasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol
110. Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non- Hepatol. 2019;17(9):1877e1885.e5.
alcoholic fatty liver disease with controlled attenuation parameter and 136. Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in
liver stiffness measurements: a prospective cohort study. Gut. 2016;65(8): the United States population. Hepatology. 2017;66(1):84e95.
1359e1368. 137. Lee J, Vali Y, Boursier J, et al. Prognostic accuracy of FIB-4, NAFLD fibrosis score
111. Roulot D, Roudot-Thoraval F, NKontchou G, et al. Concomitant screening for and APRI for NAFLD-related events: a systematic review. Liver Int. 2021;41(2):
liver fibrosis and steatosis in French type 2 diabetic patients using FibroScan. 261e270.
Liver Int. 2017;37(12):1897e1906. 138. Morling JR, Fallowfield JA, Guha IN, et al. Using non-invasive biomarkers to
112. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histo- identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edin-
logic features, is associated with long-term outcomes of patients with burgh type 2 diabetes study. J Hepatol. 2014;60(2):384e391.
nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389e397.e10. 139. Tomeno W, Imajo K, Kuwada Y, et al. Distribution of liver stiffness in non-
113. Noureddin M, Jones C, Alkhouri N, Gomez EV, Dieterich DT, Rinella ME. alcoholic fatty liver disease with higher fibrosis-4 index than low cut-off in-
Screening for nonalcoholic fatty liver disease in persons with type 2 diabetes dex. J Gastroenterol Hepatol. 2019;34(8):1411e1416.
in the United States is cost-effective: a comprehensive cost-utility analysis. 140. Boursier J, Guillaume M, Leroy V, et al. New sequential combinations of non-
Gastroenterology. 2020;159(5):1985e1987.e4. invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in
114. Sporea I, Mare R, Popescu A, et al. Screening for liver fibrosis and steatosis in a NAFLD. J Hepatol. 2019;71(2):389e396.
large cohort of patients with type 2 diabetes using vibration controlled 141. Harrison SA, Ratziu V, Boursier J, et al. A blood-based biomarker panel (NIS4)
transient elastography and controlled attenuation parameter in a single- for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis:
center real-life experience. J Clin Med. 2020;9(4):1032. a prospective derivation and global validation study. Lancet Gastroenterol
115. Procino F, Misciagna G, Veronese N, et al. Reducing NAFLD-screening time: a Hepatol. 2020;5(11):970e985.
comparative study of eight diagnostic methods offering an alternative to ul- 142. Qadri S, Ahlholm N, Lønsmann I, et al. Obesity modifies the performance of
trasound scans. Liver Int. 2019;39(1):187e196. fibrosis biomarkers in nonalcoholic fatty liver disease. J Clin Endocrinol Metab.
116. Maciejewski ML, Arterburn DE, Van Scoyoc L, et al. Bariatric surgery and long- 2021:dgab933.
term durability of weight loss. JAMA Surg. 2016;151(11):1046e1055. 143. Vali Y, Lee J, Boursier J, et al. Enhanced liver fibrosis test for the non-invasive
117. Sjo€ stro
€ m L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-
long-term remission of type 2 diabetes and with microvascular and macro- analysis. J Hepatol. 2020;73(2):252e262.
vascular complications. JAMA. 2014;311(22):2297e2304. 144. Bril F, Leeming DJ, Karsdal MA, et al. Use of plasma fragments of propeptides
118. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive of type III, V, and VI procollagen for the detection of liver fibrosis in type 2
medical therapy for diabetes - 5-year outcomes. N Engl J Med. 2017;376(7): diabetes. Diabetes Care. 2019;42(7):1348e1351.
641e651. 145. Kerbert AJC, Gupta S, Alabsawy E, et al. Biomarkers of extracellular matrix
119. Kwok R, Tse YK, Wong GL, et al. Systematic review with meta-analysis: non- formation are associated with acute-on-chronic liver failure. JHEP Rep.
invasive assessment of non-alcoholic fatty liver disease–the role of transient 2021;3(6):100355.
elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther. 146. Erhardtsen E, Rasmussen DGK, Frederiksen P, et al. Determining a healthy
2014;39(3):254e269. reference range and factors potentially influencing PRO-C3 - a biomarker of
120. Zhou X, Yu J, Li L, et al. Effects of bariatric surgery on mortality, cardiovascular liver fibrosis. JHEP Rep. 2021;3(4):100317.
events, and cancer outcomes in obese patients: systematic review and meta- 147. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with
analysis. Obes Surg. 2016;26(11):2590e2601. type 2 diabetes: a call to action. Diabetes Care. 2017;40(3):419e430.
121. Wiggins T, Guidozzi N, Welbourn R, Ahmed AR, Markar SR. Association of 148. Younossi ZM, Anstee QM, Wai-Sun Wong V, et al. The association of histologic
bariatric surgery with all-cause mortality and incidence of obesity-related and noninvasive tests with adverse clinical and patient-reported outcomes in
disease at a population level: a systematic review and meta-analysis. PLoS patients with advanced fibrosis due to nonalcoholic steatohepatitis. Gastro-
Med. 2020;17(7):e1003206. enterology. 2021;160(5):1608e1619.e13.
122. Fakhry TK, Mhaskar R, Schwitalla T, Muradova E, Gonzalvo JP, Murr MM. 149. Masoodi M, Gastaldelli A, Hyo € tyl€
ainen T, et al. Metabolomics and lipidomics
Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary in NAFLD: biomarkers and non-invasive diagnostic tests. Nat Rev Gastroenterol
systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(3): Hepatol. 2021;18(12):835e856.
502e511. 150. Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accurately identify
123. Lee Y, Doumouras AG, Yu J, et al. Complete resolution of nonalcoholic fatty advanced fibrosis due to NASH: baseline data from the stellar trials. Hep-
liver disease after bariatric surgery: a systematic review and meta-analysis. atology. 2019;70(5):1521e1530.
Clin Gastroenterol Hepatol. 2019;17(6):1040e1060.e11. 151. Singh A, Gosai F, Siddiqui MT, et al. Accuracy of noninvasive fibrosis scores to
124. Ramai D, Singh J, Lester J, et al. Systematic review with meta-analysis: bar- detect advanced fibrosis in patients with type-2 diabetes with biopsy-proven
iatric surgery reduces the incidence of hepatocellular carcinoma. Aliment nonalcoholic fatty liver disease. J Clin Gastroenterol. 2020;54(10):891e897.
Pharmacol Ther. 2021;53(9):977e984. 152. Sviklane L, Olmane E, Dze rve Z, Kup cs K, Pır
ags V, Sokolovska J. Fatty liver
125. Soresi M, Cabibi D, Giglio RV, et al. The prevalence of NAFLD and fibrosis in index and hepatic steatosis index for prediction of non-alcoholic fatty liver
bariatric surgery patients and the reliability of noninvasive diagnostic disease in type 1 diabetes. J Gastroenterol Hepatol. 2018;33(1):270e276.
methods. Biomed Res Int. 2020;2020:5023157. 153. Chan WK, Treeprasertsuk S, Goh GB, et al. Optimizing use of nonalcoholic
126. Mahawar KK, Parmar C, Graham Y, et al. Routine liver biopsy during bariatric fatty liver disease fibrosis score, fibrosis-4 score, and liver stiffness mea-
surgery: an analysis of evidence base. Obes Surg. 2016;26(1):177e181. surement to identify patients with advanced fibrosis. Clin Gastroenterol Hep-
127. Agarwal L, Sahu AK, Baksi A, Agarwal A, Aggarwal S. Safety of metabolic and atol. 2019;17(12):2570e2580.e37.
bariatric surgery in obese patients with liver cirrhosis: a systematic review 154. Ishiba H, Sumida Y, Tanaka S, et al. The novel cutoff points for the FIB4 index
and meta-analysis. Surg Obes Relat Dis. 2021;17(3):525e537. categorized by age increase the diagnostic accuracy in NAFLD: a multi-center
128. Gawrieh S, Wilson LA, Cummings OW, et al. Histologic findings of advanced study. J Gastroenterol. 2018;53(11):1216e1224.
fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease who 155. McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the
have normal aminotransferase levels. Am J Gastroenterol. 2019;114(10): accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastro-
1626e1635. enterol. 2017;112(5):740e751.
129. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of 156. Petta S, Wai-Sun Wong V, Bugianesi E, et al. Impact of obesity and alanine
ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. aminotransferase levels on the diagnostic accuracy for advanced liver fibrosis
2011;54(3):1082e1090. of noninvasive tools in patients with nonalcoholic fatty liver disease. Am J
130. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, Gastroenterol. 2019;114(6):916e928.
ultrasound, or magnetic resonance elastography to detect fibrosis in patients 157. Davison BA, Harrison SA, Cotter G, et al. Suboptimal reliability of liver biopsy
with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. evaluation has implications for randomized clinical trials. J Hepatol.
2017;66(5):1486e1501. 2020;73(6):1322e1332.
131. Cui J, Heba E, Hernandez C, et al. Magnetic resonance elastography is superior 158. Siddiqui MS, Vuppalanchi R, Van Natta ML, et al. Vibration-controlled
to acoustic radiation force impulse for the diagnosis of fibrosis in patients transient elastography to assess fibrosis and steatosis in patients with
with biopsy-proven nonalcoholic fatty liver disease: a prospective study. nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17(1):
Hepatology. 2016;63(2):453e461. 156e163.e2.
132. Chen J, Yin M, Talwalkar JA, et al. Diagnostic performance of MR elastography 159. Eddowes PJ, Sasso M, Allison M, et al. Accuracy of fibroscan controlled
and vibration-controlled transient elastography in the detection of hepatic attenuation parameter and liver stiffness measurement in assessing steatosis
fibrosis in patients with severe to morbid obesity. Radiology. 2017;283(2): and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology.
418e428. 2019;156(6):1717e1730.
133. Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately 160. Bazerbachi F, Haffar S, Wang Z, et al. Range of normal liver stiffness and
classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease factors associated with increased stiffness measurements in apparently
than transient elastography. Gastroenterology. 2016;150(3):626e637.e7. healthy individuals. Clin Gastroenterol Hepatol. 2019;17(1):54e64.e1.
557
161. de Le dinghen V, Hiriart JB, Vergniol J, Merrouche W, Bedossa P, Paradis V. 188. Chen K, Sng WK, Quah JH, et al. Clinical spectrum of non-alcoholic fatty
Controlled attenuation parameter (CAP) with the XL probe of the FibroScan ®: liver disease in patients with diabetes mellitus. PLoS One. 2020;15(8),
a comparative study with the M probe and liver biopsy. Dig Dis Sci. e0236977.
2017;62(9):2569e2577. 189. Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and
162. Petroff D, Blank V, Newsome PN, et al. Assessment of hepatic steatosis by steatosis is associated with liver stiffness in a general population: the Rot-
controlled attenuation parameter using the M and XL probes: an individual terdam study. Hepatology. 2016;63(1):138e147.
patient data meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(3):185e198. 190. Mantovani A, Turino T, Lando MG, et al. Screening for non-alcoholic fatty liver
163. Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI disease using liver stiffness measurement and its association with chronic
elastography criteria for the definition of compensated advanced chronic liver kidney disease and cardiovascular complications in patients with type 2
disease. J Hepatol. 2021;74(5):1109e1116. diabetes. Diabetes Metab. 2020;46(4):296e303.
164. Mo zes FE, Lee JA, Selvaraj EA, et al. Diagnostic accuracy of non-invasive tests 191. Lee WG, Wells CI, McCall JL, Murphy R, Plank LD. Prevalence of diabetes in
for advanced fibrosis in patients with NAFLD: an individual patient data meta- liver cirrhosis: a systematic review and meta-analysis. Diabetes Metab Res Rev.
analysis. Gut. 2021. https://doi.org/10.1136/gutjnl-2021-324243. 2019;35(6):e3157.
165. Selvaraj EA, Mo zes FE, Jayaswal ANA, et al. Diagnostic accuracy of elastog- 192. Moolla A, Motohashi K, Marjot T, et al. A multidisciplinary approach to
raphy and magnetic resonance imaging in patients with NAFLD: a systematic the management of NAFLD is associated with improvement in markers of
review and meta-analysis. J Hepatol. 2021;75(4):770e785. liver and cardio-metabolic health. Frontline Gastroenterol. 2019;10(4):
166. Lefebvre T, Wartelle-Bladou C, Wong P, et al. Prospective comparison of 337e346.
transient, point shear wave, and magnetic resonance elastography for staging 193. Lee HW, Wong GL, Kwok R, et al. Serial transient elastography examinations
liver fibrosis. Eur Radiol. 2019;29(12):6477e6488. to monitor patients with type 2 diabetes: a prospective cohort study. Hep-
167. Jiang W, Huang S, Teng H, et al. Diagnostic accuracy of point shear wave atology. 2020;72(4):1230e1241.
elastography and transient elastography for staging hepatic fibrosis in pa- 194. Srivastava A, Gailer R, Tanwar S, et al. Prospective evaluation of a primary care
tients with non-alcoholic fatty liver disease: a meta-analysis. BMJ Open. referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol.
2018;8(8), e021787. 2019;71(2):371e378.
168. Zeng Q, Honarvar M, Schneider C, et al. Three-dimensional multi-frequency 195. Augustin S, Ahmed A, Alkhouri N, et al. Identification of patients with
shear wave absolute vibro-elastography (3D S-WAVE) with a matrix array advanced fibrosis due to nonalcoholic fatty liver disease: considerations for
transducer: implementation and preliminary in vivo study of the liver. IEEE best practice. J Gastrointestin Liver Dis. 2020;29(2):235e245.
Trans Med Imaging. 2021;40(2):648e660. 196. Crossan C, Majumdar A, Srivastava A, et al. Referral pathways for patients
169. Bernstein D, Kovalic AJ. Noninvasive assessment of fibrosis among patients with NAFLD based on non-invasive fibrosis tests: diagnostic accuracy and cost
with nonalcoholic fatty liver disease [NAFLD]. Metabol Open. 2022;13:100158. analysis. Liver Int. 2019;39(11):2052e2060.
170. Beyer C, Hutton C, Andersson A, et al. Comparison between magnetic reso- 197. Shaheen AA, Riazi K, Medellin A, et al. Risk stratification of patients with
nance and ultrasound-derived indicators of hepatic steatosis in a pooled nonalcoholic fatty liver disease using a case identification pathway in primary
NAFLD cohort. PLoS One. 2021;16(4), e0249491. care: a cross-sectional study. CMAJ Open. 2020;8(2):E370eE376.
171. Eddowes PJ, McDonald N, Davies N, et al. Utility and cost evaluation of 198. Srivastava A, Jong S, Gola A, et al. Cost-comparison analysis of FIB-4, elf and
multiparametric magnetic resonance imaging for the assessment of non- FibroScan in community pathways for non-alcoholic fatty liver disease. BMC
alcoholic fatty liver disease. Aliment Pharmacol Ther. 2018;47(5):631e644. Gastroenterol. 2019;19(1):122.
172. Jayaswal ANA, Levick C, Selvaraj EA, et al. Prognostic value of multiparametric 199. Gregg EW, Jakicic JM, Blackburn G, et al. Association of the magnitude of
magnetic resonance imaging, transient elastography and blood-based fibrosis weight loss and changes in physical fitness with long-term cardiovascular
markers in patients with chronic liver disease. Liver Int. 2020;40(12): disease outcomes in overweight or obese people with type 2 diabetes: a post-
3071e3082. hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes
173. Dennis A, Kelly MD, Fernandes C, et al. Correlations between MRI biomarkers Endocrinol. 2016;4(11):913e921.
PDFF and CT1 with histopathological features of non-alcoholic steatohepatitis. 200. Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery
Front Endocrinol (Lausanne). 2020;11:575843. with major adverse cardiovascular outcomes in patients with type 2 diabetes
174. Budd J, Cusi K. Role of agents for the treatment of diabetes in the management and obesity. JAMA. 2019;322(13):1271e1282.
of nonalcoholic fatty liver disease. Curr Diab Rep. 2020;20(11):59. 201. Galaviz KI, Weber MB, Straus A, Haw JS, Narayan KMV, Ali MK. Global diabetes
175. Ortiz-Lopez C, Lomonaco R, Orsak B, et al. Prevalence of prediabetes and prevention interventions: a systematic review and network meta-analysis of
diabetes and metabolic profile of patients with nonalcoholic fatty liver disease the real-world impact on incidence, weight, and glucose. Diabetes Care.
(NAFLD). Diabetes Care. 2012;35(4):873e878. 2018;41(7):1526e1534.
176. Harman DJ, Kaye PV, Harris R, Suzuki A, Gazis A, Aithal GP. Prevalence and 202. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of
natural history of histologically proven chronic liver disease in a longitudinal type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.
cohort of patients with type 1 diabetes. Hepatology. 2014;60(1):158e168. 2002;346(6):393e403.
177. Lingvay I, Raskin P, Szczepaniak LS. Effect of insulin-metformin combination 203. Lindstro€ m J, Ilanne-Parikka P, Peltonen M, et al. Sustained reduction in the
on hepatic steatosis in patients with type 2 diabetes. J Diabetes Complications. incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish
2007;21(3):137e142. diabetes prevention study. Lancet. 2006;368(9548):1673e1679.
178. Juurinen L, Tiikkainen M, Ha €kkinen AM, Hakkarainen A, Yki-J€ arvinen H. Ef- 204. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and
fects of insulin therapy on liver fat content and hepatic insulin sensitivity in diabetes incidence after lifestyle intervention for people with impaired
patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292(3): glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-
E829eE835. up study. Lancet Diabetes Endocrinol. 2014;2(6):474e480.
179. Cipponeri E, Vitturi N, Mariano V, et al. Vitamin D status and non-alcoholic 205. Laichuthai N, Abdul-Ghani M, Kosiborod M, Parksook WW, Kerr SJ,
fatty liver disease in patients with type 1 diabetes. J Endocrinol Invest. DeFronzo RA. Newly discovered abnormal glucose tolerance in patients with
2019;42(9):1099e1107. acute myocardial infarction and cardiovascular outcomes: a meta-analysis.
180. de Le dinghen V, Vergniol J, Gonzalez C, et al. Screening for liver fibrosis by Diabetes Care. 2020;43(8):1958e1966.
using FibroScan(®) and FibroTest in patients with diabetes. Dig Liver Dis. 206. Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION)
2012;44(5):413e418. Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes
181. Targher G, Bertolini L, Padovani R, et al. Prevalence of non-alcoholic fatty liver Follow-On (ACCORDION) Study Group. Persistent effects of intensive glycemic
disease and its association with cardiovascular disease in patients with type 1 control on retinopathy in type 2 diabetes in the Action to Control Cardio-
diabetes. J Hepatol. 2010;53(4):713e718. vascular Risk in Diabetes (ACCORD) follow-on study. Diabetes Care.
182. Vendhan R, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical profile 2016;39(7):1089e1100.
of nonalcoholic fatty liver disease among young patients with type 1 diabetes 207. Franz MJ, Boucher JL, Rutten-Ramos S, VanWormer JJ. Lifestyle weight-loss
mellitus seen at a diabetes speciality center in India. Endocr Pract. intervention outcomes in overweight and obese adults with type 2 dia-
2014;20(12):1249e1257. betes: a systematic review and meta-analysis of randomized clinical trials.
183. Mantovani A, Mingolla L, Rigolon R, et al. Nonalcoholic fatty liver disease is J Acad Nutr Diet. 2015;115(9):1447e1463.
independently associated with an increased incidence of cardiovascular 208. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of
disease in adult patients with type 1 diabetes. Int J Cardiol. 2016;225: intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):
387e391. 1577e1589.
184. DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes pre- 209. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-
vention in impaired glucose tolerance. N Engl J Med. 2011;364(12): lowering treatment: prospective meta-analysis of data from 90,056
1104e1115. participants in 14 randomised trials of statins. Lancet. 2005;366(9493):
185. Espinoza SE, Wang CP, Tripathy D, et al. Pioglitazone is equally effective for 1267e1278.
diabetes prevention in older versus younger adults with impaired glucose 210. Fulcher J, O'Connell R, Voysey M, et al. Efficacy and safety of LDL-lowering
tolerance. Age (Dordr). 2016;38(5-6):485e493. therapy among men and women: meta-analysis of individual data from
186. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):
transient ischemic attack. N Engl J Med. 2016;374(14):1321e1331. 1397e1405.
187. Inzucchi SE, Viscoli CM, Young LH, et al. Pioglitazone prevents diabetes in 211. Brunstro €m M, Carlberg B. Effect of antihypertensive treatment at different
patients with insulin resistance and cerebrovascular disease. Diabetes Care. blood pressure levels in patients with diabetes mellitus: systematic review
2016;39(10):1684e1692. and meta-analyses. BMJ. 2016;352:i717.
558
212. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of 238. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing
cardiovascular disease and death: a systematic review and meta-analysis. the effects of weight loss on nonalcoholic steatohepatitis. Hepatology.
Lancet. 2016;387(10022):957e967. 2010;51(1):121e129.
213. Mechanick JI, Hurley DL, Garvey WT. Adiposity-based chronic disease as a 239. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss
new diagnostic term: the American Association of Clinical Endocrinologists through lifestyle modification significantly reduces features of nonalcoholic
and American College of Endocrinology position statement. Endocr Pract. steatohepatitis. Gastroenterology. 2015;149(2):367e378.e5. quiz e14-e15.
2017;23(3):372e378. 240. Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, et al. Development
214. Frühbeck G, Busetto L, Dicker D, et al. The ABCD of obesity: an EASO position and validation of a noninvasive prediction model for nonalcoholic steatohe-
statement on a diagnostic term with clinical and scientific implications. Obes patitis resolution after lifestyle intervention. Hepatology. 2016;63(6):
Facts. 2019;12(2):131e136. 1875e1887.
215. Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical 241. Koutoukidis DA, Koshiaris C, Henry JA, et al. The effect of the magnitude of
Endocrinologists and American College of Endocrinology position statement weight loss on non-alcoholic fatty liver disease: a systematic review and
on the 2014 advanced framework for a new diagnosis of obesity as a chronic meta-analysis. Metabolism. 2021;115:154455.
disease. Endocr Pract. 2014;20(9):977e989. 242. Parry SA, Rosqvist F, Mozes FE, et al. Intrahepatic fat and postprandial gly-
216. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical cemia increase after consumption of a diet enriched in saturated fat compared
Endocrinologists and American College of Endocrinology comprehensive with free sugars. Diabetes Care. 2020;43(5):1134e1141.
clinical practice guidelines for medical care of patients with obesity. Endocr 243. Luukkonen PK, S€ adevirta S, Zhou Y, et al. Saturated fat is more metabolically
Pract. 2016;22(suppl 3):1e203. harmful for the human liver than unsaturated fat or simple sugars. Diabetes
217. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the Care. 2018;41(8):1732e1739.
American Association of Clinical Endocrinologists and American College of 244. Rosqvist F, Kullberg J, Ståhlman M, et al. Overeating saturated fat promotes
Endocrinology on the comprehensive type 2 diabetes management algorithm fatty liver and ceramides compared with polyunsaturated fat: a randomized
- 2018 executive summary. Endocr Pract. 2018;24(1):91e120. trial. J Clin Endocrinol Metab. 2019;104(12):6207e6219.
218. American Diabetes Association. 8. Obesity management for the treatment of 245. Roeb E, Weiskirchen R. Fructose and non-alcoholic steatohepatitis. Front
type 2 diabetes: standards of medical care in diabetes-2022. Diabetes Care. Pharmacol. 2021;12:634344.
2022;45(Suppl 1):S113eS124. https://doi.org/10.2337/dc22-S008. 246. Marin-Alejandre BA, Abete I, Cantero I, et al. The metabolic and hepatic
219. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: impact of two personalized dietary strategies in subjects with obesity and
standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1): nonalcoholic fatty liver disease: the Fatty Liver in Obesity (FLIO) randomized
S39eS45. https://doi.org/10.2337/dc22-S003. controlled trial. Nutrients. 2019;11(10):2543.
220. American Diabetes Association. 10. Cardiovascular Disease and Risk Man- 247. Ma J, Hennein R, Liu C, et al. Improved diet quality associates with reduction
agement: Standards of Medical Care in Diabetes-2022. Diabetes Care. in liver fat, particularly in individuals with high genetic risk scores for
2022;45(Suppl 1):S144eS174. nonalcoholic fatty liver disease. Gastroenterology. 2018;155(1):107e117.
221. Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-based 248. Misciagna G, Del Pilar Díaz M, Caramia DV, et al. Effect of a low glycemic index
chronic disease, adiposity and dysglycemia drivers: JACC state-of-the-art re- Mediterranean diet on non-alcoholic fatty liver disease. A randomized
view. J Am Coll Cardiol. 2020;75(5):525e538. controlled clinici trial. J Nutr Health Aging. 2017;21(4):404e412.
222. Stefan N, Ha €ring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diag- 249. Romero-Go mez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet,
nosis, cardiometabolic consequences, and treatment strategies. Lancet Dia- physical activity and exercise. J Hepatol. 2017;67(4):829e846.
betes Endocrinol. 2019;7(4):313e324. 250. Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet improves
223. Guo F, Moellering DR, Garvey WT. The progression of cardiometabolic dis- hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty
ease: validation of a new cardiometabolic disease staging system applicable liver disease. J Hepatol. 2013;59(1):138e143.
to obesity. Obesity (Silver Spring). 2014;22(1):110e118. 251. Properzi C, O'Sullivan TA, Sherriff JL, et al. Ad libitum Mediterranean and low-
224. Mantovani A, Petracca G, Beatrice G, Tilg H, Byrne CD, Targher G. Non-alco- fat diets both significantly reduce hepatic steatosis: a randomized controlled
holic fatty liver disease and risk of incident diabetes mellitus: an updated trial. Hepatology. 2018;68(5):1741e1754.
meta-analysis of 501 022 adult individuals. Gut. 2021;70(5):962e969. 252. Kawaguchi T, Charlton M, Kawaguchi A, et al. Effects of Mediterranean diet in
225. Chen Y, Xu M, Wang T, et al. Advanced fibrosis associates with atherosclerosis patients with nonalcoholic fatty liver disease: a systematic review, meta-
in subjects with nonalcoholic fatty liver disease. Atherosclerosis. 2015;241(1): analysis, and meta-regression analysis of randomized controlled trials.
145e150. Semin Liver Dis. 2021;41(3):225e234.
226. Wong VW, Wong GL, Yip GW, et al. Coronary artery disease and cardiovas- 253. Razavi Zade M, Telkabadi MH, Bahmani F, Salehi B, Farshbaf S, Asemi Z. The
cular outcomes in patients with non-alcoholic fatty liver disease. Gut. effects of DASH diet on weight loss and metabolic status in adults with non-
2011;60(12):1721e1727. alcoholic fatty liver disease: a randomized clinical trial. Liver Int. 2016;36(4):
227. Murthy N, Wodi AP, Bernstein H, McNally V, Cineas S, Ault K. Advisory 563e571.
committee on immunization practices recommended immunization schedule 254. European Associati-on for the Study of the Liver (EASL), European Association
for adults aged 19 years or older d United States, 2022. MMWR Morb Mortal for the Study of Diabetes (EASD), European Association for the Study of
Wkly Rep. 2022;71(7):229e233. Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the man-
228. Centers for Disease Control and Prevention. Liver disease and adult vaccina- agement of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):
tion. Accessed December 17, 2021. https://www.cdc.gov/vaccines/adults/rec- 1388e1402.
vac/health-conditions/liver-disease.html 255. Plauth M, Bernal W, Dasarathy S, et al. ESPEN guideline on clinical nutrition in
229. Gepner Y, Shelef I, Komy O, et al. The beneficial effects of Mediterranean diet liver disease. Clin Nutr. 2019;38(2):485e521.
over low-fat diet may be mediated by decreasing hepatic fat content. 256. Eslam M, Sarin SK, Wong VW, et al. The Asian Pacific Association for the
J Hepatol. 2019;71(2):379e388. Study of the Liver clinical practice guidelines for the diagnosis and man-
230. Lazo M, Solga SF, Horska A, et al. Effect of a 12-month intensive lifestyle agement of metabolic associated fatty liver disease. Hepatol Int. 2020;14(6):
intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care. 889e919.
2010;33(10):2156e2163.
257. Arab JP, Dirchwolf M, Alvares-da-Silva MR, et al. Latin American Association
231. Haufe S, Engeli S, Kast P, et al. Randomized comparison of reduced fat and for the Study of the Liver (ALEH) practice guidance for the diagnosis and
reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and treatment of non-alcoholic fatty liver disease. Ann Hepatol. 2020;19(6):
obese human subjects. Hepatology. 2011;53(5):1504e1514. 674e690.
232. Koutoukidis DA, Astbury NM, Tudor KE, et al. Association of weight loss in- 258. Younossi ZM, Corey KE, Lim JK. AGA clinical practice update on lifestyle
terventions with changes in biomarkers of nonalcoholic fatty liver disease: a modification using diet and exercise to achieve weight loss in the manage-
systematic review and meta-analysis. JAMA Intern Med. 2019;179(9): ment of nonalcoholic fatty liver disease: expert review. Gastroenterology.
1262e1271. 2021;160(3):912e918.
233. Ahn J, Jun DW, Lee HY, Moon JH. Critical appraisal for low-carbohydrate diet 259. Xu C, Markova M, Seebeck N, et al. High-protein diet more effectively reduces
in nonalcoholic fatty liver disease: review and meta-analyses. Clin Nutr. hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.
2019;38(5):2023e2030. Liver Int. 2020;40(12):2982e2997.
234. Chawla S, Tessarolo Silva F, Amaral Medeiros S, Mekary RA, Radenkovic D. The 260. Markova M, Pivovarova O, Hornemann S, et al. Isocaloric diets high in animal
effect of low-fat and low-carbohydrate diets on weight loss and lipid levels: a or plant protein reduce liver fat and inflammation in individuals with type 2
systematic review and meta-analysis. Nutrients. 2020;12(12):3774. diabetes. Gastroenterology. 2017;152(3):571e585.e8.
235. Konerman MA, Walden P, Joseph M, Jackson EA, Lok AS, Rubenfire M. Impact 261. Johari MI, Yusoff K, Haron J, et al. A randomised controlled trial on the
of a structured lifestyle programme on patients with metabolic syndrome effectiveness and adherence of modified alternate-day calorie restriction in
complicated by non-alcoholic fatty liver disease. Aliment Pharmacol Ther. improving activity of non-alcoholic fatty liver disease. Sci Rep. 2019;9(1):
2019;49(3):296e307. 11232.
236. Baldwin D, Chennakesavalu M, Gangemi A. Systematic review and meta- 262. Cai H, Qin YL, Shi ZY, et al. Effects of alternate-day fasting on body weight and
analysis of Roux-en-y gastric bypass against laparoscopic sleeve gastrec- dyslipidaemia in patients with non-alcoholic fatty liver disease: a randomised
tomy for amelioration of NAFLD using four criteria. Surg Obes Relat Dis. controlled trial. BMC Gastroenterol. 2019;19(1):219.
2019;15(12):2123e2130. 263. Holmer M, Lindqvist C, Petersson S, et al. Treatment of NAFLD with inter-
237. Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: mittent calorie restriction or low-carb high-fat diet - a randomised controlled
systematic review. Can Fam Physician. 2020;66(2):117e125. trial. JHEP Rep. 2021;3(3):100256.
559
264. Yin C, Li Z, Xiang Y, et al. Effect of intermittent fasting on non-alcoholic fatty liver 291. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in
disease: systematic review and meta-analysis. Front Nutr. 2021;8:709683. adults with overweight or obesity. N Engl J Med. 2021;384(11):989.
265. Hallsworth K, Fattakhova G, Hollingsworth KG, et al. Resistance exercise re- 292. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2$4 mg once a week in
duces liver fat and its mediators in non-alcoholic fatty liver disease inde- adults with overweight or obesity, and type 2 diabetes (step 2): a randomised,
pendent of weight loss. Gut. 2011;60(9):1278e1283. double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet.
266. Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized 2021;397(10278):971e984.
trial of exercise effect on intrahepatic triglyceride content and lipid ki- 293. Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment
netics in nonalcoholic fatty liver disease. Hepatology. 2012;55(6): of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(10):556e577.
1738e1745. 294. Cusi K. Time to include nonalcoholic steatohepatitis in the management of
267. Golabi P, Locklear CT, Austin P, et al. Effectiveness of exercise in hepatic fat patients with type 2 diabetes. Diabetes Care. 2020;43(2):275e279.
mobilization in non-alcoholic fatty liver disease: systematic review. World J 295. Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on hepatic tri-
Gastroenterol. 2016;22(27):6318e6327. glyceride content and glucose metabolism in patients with type 2 diabetes.
268. Orci LA, Gariani K, Oldani G, Delaune V, Morel P, Toso C. Exercise-based in- Diabetes Obes Metab. 2019;21(4):812e821.
terventions for nonalcoholic fatty liver disease: a meta-analysis and meta- 296. Latva-Rasku A, Honka MJ, Kullberg J, et al. The SGLT2 inhibitor dapagliflozin
regression. Clin Gastroenterol Hepatol. 2016;14(10):1398e1411. reduces liver fat but does not affect tissue insulin sensitivity: a randomized,
269. Sargeant JA, Bawden S, Aithal GP, et al. Effects of sprint interval training on double-blind, placebo-controlled study with 8-week treatment in type 2
ectopic lipids and tissue-specific insulin sensitivity in men with non-alcoholic diabetes patients. Diabetes Care. 2019;42(5):931e937.
fatty liver disease. Eur J Appl Physiol. 2018;118(4):817e828. 297. Kahl S, Gancheva S, Straßburger K, et al. Empagliflozin effectively lowers liver
270. Cuthbertson DJ, Shojaee-Moradie F, Sprung VS, et al. Dissociation between fat content in well-controlled type 2 diabetes: a randomized, double-blind,
exercise-induced reduction in liver fat and changes in hepatic and peripheral phase 4, placebo-controlled trial. Diabetes Care. 2020;43(2):298e305.
glucose homoeostasis in obese patients with non-alcoholic fatty liver disease. 298. Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of met-
Clin Sci (Lond). 2016;130(2):93e104. formin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol
271. Keating SE, Hackett DA, Parker HM, et al. Effect of aerobic exercise training Ther. 2009;29(2):172e182.
dose on liver fat and visceral adiposity. J Hepatol. 2015;63(1):174e182. 299. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of
272. Houghton D, Thoma C, Hallsworth K, et al. Exercise reduces liver lipids and metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver
visceral adiposity in patients with nonalcoholic steatohepatitis in a random- disease. Am J Gastroenterol. 2005;100(5):1082e1090.
ized controlled trial. Clin Gastroenterol Hepatol. 2017;15(1):96e102.e3. 300. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on
273. O'Gorman P, Naimimohasses S, Monaghan A, et al. Improvement in histo- liver disease, glucose metabolism and cardiovascular risk in non-alcoholic
logical endpoints of MAFLD following a 12-week aerobic exercise interven- fatty liver disease (NAFLD): a systematic review and meta-analysis of rand-
tion. Aliment Pharmacol Ther. 2020;52(8):1387e1398. omised trials. Diabetologia. 2012;55(4):885e904.
274. Sargeant JA, Gray LJ, Bodicoat DH, et al. The effect of exercise training on 301. Sawangjit R, Chongmelaxme B, Phisalprapa P, et al. Comparative efficacy of
intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review interventions on nonalcoholic fatty liver disease (NAFLD): a prisma-compliant
and meta-analysis. Obes Rev. 2018;19(10):1446e1459. systematic review and network meta-analysis. Medicine (Baltimore).
275. Zhang HJ, He J, Pan LL, et al. Effects of moderate and vigorous exercise on 2016;95(32):e4529.
nonalcoholic fatty liver disease: a randomized clinical trial. JAMA Intern Med. 302. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver
2016;176(8):1074e1082. disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57e64.
276. Hashida R, Kawaguchi T, Bekki M, et al. Aerobic vs. resistance exercise in non- 303. Smits MM, Tonneijck L, Muskiet MH, et al. Twelve week liraglutide or sita-
alcoholic fatty liver disease: a systematic review. J Hepatol. 2017;66(1): gliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-
142e152. controlled trial. Diabetologia. 2016;59(12):2588e2593.
277. Winn NC, Liu Y, Rector RS, Parks EJ, Ibdah JA, Kanaley JA. Energy-matched 304. Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-
moderate and high intensity exercise training improves nonalcoholic fatty alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J
liver disease risk independent of changes in body mass or abdominal Gastroenterol. 2017;23(1):141e150.
adiposity - a randomized trial. Metabolism. 2018;78:128e140. 305. Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic
278. Oh S, Tsujimoto T, Kim B, et al. Weight-loss-independent benefits of exercise fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65(2):
on liver steatosis and stiffness in Japanese men with NAFLD. JHEP Rep. 369e376.
2021;3(3):100253. 306. Cusi K, Sanyal AJ, Zhang S, et al. Different effects of basal insulin peglispro and
279. Sanyal AJ, Van Natta ML, Clark J, et al. Prospective study of outcomes in adults insulin glargine on liver enzymes and liver fat content in patients with type 1
with nonalcoholic fatty liver disease. N Engl J Med. 2021;385(17):1559e1569. and type 2 diabetes. Diabetes Obes Metab. 2016;18(suppl 2):50e58.
280. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglita- 307. Vilar-Gomez E, Vuppalanchi R, Gawrieh S, et al. Vitamin E improves
zone in subjects with nonalcoholic steatohepatitis. N Engl J Med. transplant-free survival and hepatic decompensation among patients with
2006;355(22):2297e2307. nonalcoholic steatohepatitis and advanced fibrosis. Hepatology. 2020;71(2):
281. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of 495e509.
pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. 308. Barb D, Portillo-Sanchez P, Cusi K. Pharmacological management of nonal-
Gastroenterology. 2008;135(4):1176e1184. coholic fatty liver disease. Metabolism. 2016;65(8):1183e1195.
282. Bril F, Biernacki DM, Kalavalapalli S, et al. Role of vitamin E for nonalcoholic 309. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized
steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. trials for the treatment of nonalcoholic fatty liver disease. Hepatology.
Diabetes Care. 2019;42(8):1481e1488. 2010;52(1):79e104.
283. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and 310. Khera R, Pandey A, Chandar AK, et al. Effects of weight-loss medications on
advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA cardiometabolic risk profiles: a systematic review and network meta-analysis.
Intern Med. 2017;177(5):633e640. Gastroenterology. 2018;154(5):1309e1319.e7.
284. Rind DM, Hansen R, Guzauskas G, Beinfeld M, Chapman R, Bradt P, 311. Fujioka K, O'Neil PM, Davies M, et al. Early weight loss with liraglutide 3.0 mg
Pearson SD. Obeticholic acid for the treatment of nonalcoholic steatohepatitis predicts 1-year weight loss and is associated with improvements in clinical
with fibrosis: effectiveness and value. Institute for Clinical and Economic markers. Obesity (Silver Spring). 2016;24(11):2278e2288.
Review, July 21,2020. Accessed December 17, 2021. https://icer-review.org/ 312. Wang H, Wang L, Cheng Y, Xia Z, Liao Y, Cao J. Efficacy of orlistat in non-
material/nash-evidence-report/ alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed
285. Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone and the risk of bladder Rep. 2018;9(1):90e96.
cancer: a meta-analysis. Diabetes Ther. 2017;8(4):705e726. 313. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for over-
286. Cusi K. Incretin-based therapies for the management of nonalcoholic fatty weight subjects with nonalcoholic steatohepatitis: a randomized, prospective
liver disease in patients with type 2 diabetes. Hepatology. 2019;69(6): trial. Hepatology. 2009;49(1):80e86.
2318e2322. 314. Zelber-Sagi S, Kessler A, Brazowsky E, et al. A double-blind randomized
287. Patel Chavez C, Cusi K, Kadiyala S. The emerging role of glucagon-like peptide- placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver
1 receptor agonists for the management of NAFLD. J Clin Endocrinol Metab. disease. Clin Gastroenterol Hepatol. 2006;4(5):639e644.
2022;107(1):29e38. 315. Bajaj HS, Burrows M, Blavignac J, et al. Extended-release naltrexone/bupro-
288. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in pion and liver health: pooled, post hoc analysis from four randomized
patients with non-alcoholic steatohepatitis (lean): a multicentre, double- controlled trials. Diabetes Obes Metab. 2021;23(3):861e865.
blind, randomised, placebo-controlled phase 2 study. Lancet. 316. Garvey WT, Ryan DH, Bohannon NJ, et al. Weight-loss therapy in type 2
2016;387(10019):679e690. diabetes: effects of phentermine and topiramate extended release. Diabetes
289. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly sub- Care. 2014;37(12):3309e3316.
cutaneous semaglutide vs placebo on weight loss maintenance in adults with 317. Garvey WT, Ryan DH, Henry R, et al. Prevention of type 2 diabetes in subjects
overweight or obesity: the STEP 4 randomized clinical trial. JAMA. with prediabetes and metabolic syndrome treated with phentermine and
2021;325(14):1414e1425. topiramate extended release. Diabetes Care. 2014;37(4):912e921.
290. Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs 318. Guo F, Garvey WT. Cardiometabolic disease staging predicts effectiveness of
placebo as an adjunct to intensive behavioral therapy on body weight in weight-loss therapy to prevent type 2 diabetes: pooled results from phase III
adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. clinical trials assessing phentermine/topiramate extended release. Diabetes
2021;325(14):1403e1413. Care. 2017;40(7):856e862.
560
319. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular 343. Pacifico L, Di Martino M, De Merulis A, et al. Left ventricular dysfunction in
outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311e322. obese children and adolescents with nonalcoholic fatty liver disease. Hep-
320. Marso SP, Holst AG, Vilsbøll T. Semaglutide and cardiovascular outcomes in atology. 2014;59(2):461e470.
patients with type 2 diabetes. N Engl J Med. 2017;376(9):891e892. 344. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver
321. Alfayez OM, Almohammed OA, Alkhezi OS, Almutairi AR, Al Yami MS. Indirect disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr.
comparison of glucagon like peptide-1 receptor agonists regarding cardio- 2013;162(3):496e500.e1.
vascular safety and mortality in patients with type 2 diabetes mellitus: 345. Brumbaugh DE, Tearse P, Cree-Green M, et al. Intrahepatic fat is increased in
network meta-analysis. Cardiovasc Diabetol. 2020;19(1):96. the neonatal offspring of obese women with gestational diabetes. J Pediatr.
322. Kwok CS, Pradhan A, Khan MA, et al. Bariatric surgery and its impact on 2013;162(5):930e936.e1.
cardiovascular disease and mortality: a systematic review and meta-analysis. 346. Modi N, Murgasova D, Ruager-Martin R, et al. The influence of maternal body
Int J Cardiol. 2014;173(1):20e28. mass index on infant adiposity and hepatic lipid content. Pediatr Res.
323. Aminian A, Al-Kurd A, Wilson R, et al. Association of bariatric surgery with 2011;70(3):287e291.
major adverse liver and cardiovascular outcomes in patients with biopsy- 347. Patel KR, White FV, Deutsch GH. Hepatic steatosis is prevalent in stillborns
proven nonalcoholic steatohepatitis. JAMA. 2021;326(20):2031e2042. delivered to women with diabetes mellitus. J Pediatr Gastroenterol Nutr.
324. Seeberg KA, Borgeraas H, Hofsø D, et al. Gastric bypass versus sleeve gas- 2015;60(2):152e158.
trectomy in type 2 diabetes: effects on hepatic steatosis and fibrosis: a ran- 348. Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prev-
domized controlled trial. Ann Intern Med. 2022;175(1):74e83. alence of non-alcoholic fatty liver disease in children and adolescents: a
325. Hofsø D, Fatima F, Borgeraas H, et al. Gastric bypass versus sleeve gastrec- systematic review and meta-analysis. PLoS One. 2015;10(10), e0140908.
tomy in patients with type 2 diabetes (oseberg): a single-centre, triple- 349. Nadeau KJ, Klingensmith G, Zeitler P. Type 2 diabetes in children is frequently
blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(12): associated with elevated alanine aminotransferase. J Pediatr Gastroenterol
912e924. Nutr. 2005;41(1):94e98.
326. Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of 350. Hudson OD, Nunez M, Shaibi GQ. Ethnicity and elevated liver transaminases
nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. among newly diagnosed children with type 2 diabetes. BMC Pediatr. 2012;12:
2015;149(2):379e388. quiz e15-e16. 174.
327. Lassailly G, Caiazzo R, Ntandja-Wandji LC, et al. Bariatric surgery provides 351. Ayonrinde OT, Adams LA, Doherty DA, et al. Adverse metabolic phenotype of
long-term resolution of nonalcoholic steatohepatitis and regression of adolescent girls with non-alcoholic fatty liver disease plus polycystic ovary
fibrosis. Gastroenterology. 2020;159(4):1290e1301.e5. syndrome compared with other girls and boys. J Gastroenterol Hepatol.
328. Singh T, Kochhar GS, Goh GB, et al. Safety and efficacy of bariatric surgery in 2016;31(5):980e987.
patients with advanced fibrosis. Int J Obes (Lond). 2017;41(3):443e449. 352. Sharma V, Coleman S, Nixon J, et al. A systematic review and meta-analysis
329. Lee DU, Fan GH, Hastie DJ, et al. The clinical impact of cirrhosis on the hospital estimating the population prevalence of comorbidities in children and ado-
outcomes of patients admitted with influenza infection: propensity score lescents aged 5 to 18 years. Obes Rev. 2019;20(10):1341e1349.
matched analysis of 2011-2017 US hospital data. J Clin Exp Hepatol. 353. Bendor CD, Bardugo A, Pinhas-Hamiel O, Afek A, Twig G. Cardiovascular
2021;11(5):531e543. morbidity, diabetes and cancer risk among children and adolescents with
330. Ikramuddin S, Korner J, Lee WJ, et al. Lifestyle intervention and medical severe obesity. Cardiovasc Diabetol. 2020;19(1):79.
management with vs without Roux-en-Y gastric bypass and control of he- 354. Kummer S, Klee D, Kircheis G, et al. Screening for non-alcoholic fatty liver
moglobin A1c, LDL cholesterol, and systolic blood pressure at 5 years in the disease in children and adolescents with type 1 diabetes mellitus: a cross-
Diabetes Surgery Study. JAMA. 2018;319(3):266e278. sectional analysis. Eur J Pediatr. 2017;176(4):529e536.
331. Johnson BL, Blackhurst DW, Latham BB, et al. Bariatric surgery is associated 355. Regnell SE, Peterson P, Trinh L, et al. Magnetic resonance imaging reveals
with a reduction in major macrovascular and microvascular complications in altered distribution of hepatic fat in children with type 1 diabetes compared
moderately to severely obese patients with type 2 diabetes mellitus. J Am Coll to controls. Metabolism. 2015;64(8):872e878.
Surg. 2013;216(4):545e556. discussion 556-548. 356. Xanthakos SA, Lavine JE, Yates KP, et al. Progression of fatty liver disease in
332. Benotti PN, Wood GC, Carey DJ, et al. Gastric bypass surgery produces a children receiving standard of care lifestyle advice. Gastroenterology.
durable reduction in cardiovascular disease risk factors and reduces the 2020;159(5):1731e1751.e10.
long-term risks of congestive heart failure. J Am Heart Assoc. 2017;6(5), 357. Schwimmer JB, Lavine JE, Wilson LA, et al. In children with nonalcoholic fatty
e005126. liver disease, cysteamine bitartrate delayed release improves liver enzymes
333. Doumouras AG, Hong D, Lee Y, Tarride JE, Paterson JM, Anvari M. Association but does not reduce disease activity scores. Gastroenterology. 2016;151(6):
between bariatric surgery and all-cause mortality: a population-based 1141e1154.e9.
matched cohort study in a universal health care system. Ann Intern Med. 358. Koot BG, van der Baan-Slootweg OH, Bohte AE, et al. Accuracy of prediction
2020;173(9):694e703. scores and novel biomarkers for predicting nonalcoholic fatty liver disease in
334. Sutanto A, Wungu CDK, Susilo H, Sutanto H. Reduction of major adverse obese children. Obesity (Silver Spring). 2013;21(3):583e590.
cardiovascular events (MACE) after bariatric surgery in patients with obesity 359. Di Martino M, Pacifico L, Bezzi M, et al. Comparison of magnetic resonance
and cardiovascular diseases: a systematic review and meta-analysis. Nutri- spectroscopy, proton density fat fraction and histological analysis in the
ents. 2021;13(10):3568. quantification of liver steatosis in children and adolescents. World J Gastro-
335. Lee YM, Low HC, Lim LG, et al. Intragastric balloon significantly improves enterol. 2016;22(39):8812e8819.
nonalcoholic fatty liver disease activity score in obese patients with nonal- 360. Middleton MS, Van Natta ML, Heba ER, et al. Diagnostic accuracy of magnetic
coholic steatohepatitis: a pilot study. Gastrointest Endosc. 2012;76(4): resonance imaging hepatic proton density fat fraction in pediatric nonalco-
756e760. holic fatty liver disease. Hepatology. 2018;67(3):858e872.
336. Bazerbachi F, Vargas EJ, Rizk M, et al. Intragastric balloon placement in- 361. Schwimmer JB, Middleton MS, Behling C, et al. Magnetic resonance imaging
duces significant metabolic and histologic improvement in patients with and liver histology as biomarkers of hepatic steatosis in children with
nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2021;19(1): nonalcoholic fatty liver disease. Hepatology. 2015;61(6):1887e1895.
146e154.e4. 362. Zhao YZ, Gan YG, Zhou JL, et al. Accuracy of multi-echo dixon sequence in
337. Jirapinyo P, Kumar N, Saumoy M, Copland A, Sullivan S. Association for bar- quantification of hepatic steatosis in Chinese children and adolescents. World
iatric endoscopy systematic review and meta-analysis assessing the American J Gastroenterol. 2019;25(12):1513e1523.
Society for Gastrointestinal Endoscopy preservation and incorporation of 363. Yodoshi T, Orkin S, Arce-Clachar AC, et al. Alternative etiologies of liver dis-
valuable endoscopic innovations thresholds for aspiration therapy. Gastro- ease in children with suspected NAFLD. Pediatrics. 2021;147(4),
intest Endosc. 2021;93(2):334e342.e1. e2020009829.
338. Jirapinyo P, McCarty TR, Dolan RD, Shah R, Thompson CC. Effect of endoscopic 364. Awai HI, Newton KP, Sirlin CB, Behling C, Schwimmer JB. Evidence and rec-
bariatric and metabolic therapies on nonalcoholic fatty liver disease: a sys- ommendations for imaging liver fat in children, based on systematic review.
tematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20(3): Clin Gastroenterol Hepatol. 2014;12(5):765e773.
511e524.e1. 365. Tyagi A, Yeganeh O, Levin Y, et al. Intra- and inter-examination repeatability of
339. Nystro €m M, Machytka E, Nore n E, et al. Aspiration therapy as a tool to treat magnetic resonance spectroscopy, magnitude-based MRI, and complex-based
obesity: 1- to 4-year results in a 201-patient multi-center post-market Eu- mri for estimation of hepatic proton density fat fraction in overweight and
ropean registry study. Obes Surg. 2018;28(7):1860e1868. obese children and adults. Abdom Imaging. 2015;40(8):3070e3077.
340. Sharaiha RZ, Hajifathalian K, Kumar R, et al. Five-year outcomes of endoscopic 366. Mansoor S, Yerian L, Kohli R, et al. The evaluation of hepatic fibrosis scores in
sleeve gastroplasty for the treatment of obesity. Clin Gastroenterol Hepatol. children with nonalcoholic fatty liver disease. Dig Dis Sci. 2015;60(5):
2021;19(5):1051e1057.e2. 1440e1447.
341. Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN clinical practice guideline 367. Mandelia C, Collyer E, Mansoor S, et al. Plasma cytokeratin-18 level as a novel
for the diagnosis and treatment of nonalcoholic fatty liver disease in biomarker for liver fibrosis in children with nonalcoholic fatty liver disease.
children: recommendations from the Expert Committee on NAFLD (ECON) J Pediatr Gastroenterol Nutr. 2016;63(2):181e187.
and the North American Society of Pediatric Gastroenterology, Hepatology 368. Schwimmer JB, Behling C, Angeles JE, et al. Magnetic resonance elastography
and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2): measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic
319e334. fatty liver disease. Hepatology. 2017;66(5):1474e1485.
342. D'Adamo E, Cali AM, Weiss R, et al. Central role of fatty liver in the patho- 369. Alkhouri N, Sedki E, Alisi A, et al. Combined paediatric NAFLD fibrosis index
genesis of insulin resistance in obese adolescents. Diabetes Care. 2010;33(8): and transient elastography to predict clinically significant fibrosis in children
1817e1822. with fatty liver disease. Liver Int. 2013;33(1):79e85.
561
370. Mandelia C, Kabbany MN, Worley S, Conjeevaram Selvakumar PK. Perfor- assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Pediatr
mance characteristics, intra- and inter-operator agreement of transient Obes. 2019;14(5), e12495.
elastography in pediatric nonalcoholic fatty liver disease. J Pediatr Gastro- 378. Danne T, Biester T, Kapitzke K, et al. Liraglutide in an adolescent population
enterol Nutr. 2021;72(3):430e435. with obesity: a randomized, double-blind, placebo-controlled 5-week trial to
371. Fitzpatrick E, Quaglia A, Vimalesvaran S, Basso MS, Dhawan A. Transient elas- assess safety, tolerability, and pharmacokinetics of liraglutide in adolescents
tography is a useful noninvasive tool for the evaluation of fibrosis in paediatric aged 12-17 years. J Pediatr. 2017;181:146e153.e3.
chronic liver disease. J Pediatr Gastroenterol Nutr. 2013;56(1):72e76. 379. Petri KC, Jacobsen LV, Klein DJ. Comparable liraglutide pharmacokinetics in
372. Nobili V, Vizzutti F, Arena U, et al. Accuracy and reproducibility of transient pediatric and adult populations with type 2 diabetes: a population pharma-
elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohe- cokinetic analysis. Clin Pharmacokinet. 2015;54(6):663e670.
patitis. Hepatology. 2008;48(2):442e448. 380. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial
373. Schwimmer JB, Ugalde-Nicalo P, Welsh JA, et al. Effect of a low free sugar diet of liraglutide for adolescents with obesity. N Engl J Med. 2020;382(22):
vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a ran- 2117e2128.
domized clinical trial. JAMA. 2019;321(3):256e265. 381. Tamborlane WV, Barrientos-Pe rez M, Fainberg U, et al. Liraglutide in children
374. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, Arslanian S. Effects of aerobic and adolescents with type 2 diabetes. N Engl J Med. 2019;381(7):637e646.
versus resistance exercise without caloric restriction on abdominal fat, 382. Centers for Disease Control and Prevention. Defining childhood weight status
intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a ran- BMI for children and teens. Accessed December 17, 2021. https://www.cdc.
domized, controlled trial. Diabetes. 2012;61(11):2787e2795. gov/obesity/basics/childhood-defining.html?CDC_AA_refVal¼https%3A%2F%2F
375. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin www.cdc.gov%2Fobesity%2Fchildhood%2Fdefining.html
for treatment of nonalcoholic fatty liver disease in children and adolescents: 383. Armstrong S, Lazorick S, Hampl S, et al. Physical examination findings among
the tonic randomized controlled trial. JAMA. 2011;305(16):1659e1668. children and adolescents with obesity: an evidence-based review. Pediatrics.
376. Mann JP, Tang GY, Nobili V, Armstrong MJ. Evaluations of lifestyle, 2016;137(2), e20151766.
dietary, and pharmacologic treatments for pediatric nonalcoholic fatty liver 384. Inge TH, Courcoulas AP, Jenkins TM, et al. Five-year outcomes of gastric
disease: a systematic review. Clin Gastroenterol Hepatol. 2019;17(8): bypass in adolescents as compared with adults. N Engl J Med. 2019;380(22):
1457e1476.e7. 2136e2145.
377. Mastrandrea LD, Witten L, Carlsson Petri KC, Hale PM, Hedman HK, 385. Manco M, Mosca A, De Peppo F, et al. The benefit of sleeve gastrectomy in
Riesenberg RA. Liraglutide effects in a paediatric (7-11 y) population with obese adolescents on nonalcoholic steatohepatitis and hepatic fibrosis.
obesity: a randomized, double-blind, placebo-controlled, short-term trial to J Pediatr. 2017;180:31e37.e2.
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Endocrine Practice 28 (2022) 528e562

Contents lists available at ScienceDirect

Clinical Practice Guidelines

American Association of Clinical Endocrinology Clinical Practice

Feature Deﬁnition Score or code

Steatosis grade Low- to medium-power evaluation of parenchymal involvement by steatosis <5% ¼ 0

Abbreviation: NAS ¼ nonalcoholic fatty liver disease activity score.

Methods journal citation, study design and population, limitations, com-

2. Diagnosis of NAFLD in adults

Q2.5 When should an adult be referred to a gastroenterologist/hepatologist for management?

3. Management of NAFLD in adults

(continued on next page)

4. Diagnosis and management of children with NAFLD

Q4.2 What tests can be used to diagnose pediatric NAFLD?

Recommendations with Evidence Base Table 4

Table 5 common comorbidities in NAFLD.116-121 As reported in a couple of

Medication Liver fat Disease activity (steatohepatitis/NAS) Studies

Metformin Unchanged Neutral (298-302)

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