Endocrine Practice 28 (2022) 528e562
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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).
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,K. Cusi, S. Isaacs, D. Barb et al. Endocrine Practice 28 (2022) 528e562
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
, K. Cusi, S. Isaacs, D. Barb et al. Endocrine Practice 28 (2022) 528e562
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
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