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2162 Diabetes Care Volume 44, September 2021
1 2
Preparing for the NASH Fasiha Kanwal, Jay H. Shubrook,
3 4
Zobair Younossi, Yamini Natarajan,
5 6
Epidemic: A Call to Action Elisabetta Bugianesi, Mary E. Rinella,
7
Stephen A. Harrison,
Diabetes Care 2021;44:2162–2172 | https://doi.org/10.2337/dci21-0020 8 9
Christos Mantzoros, Kim Pfotenhauer,
10 11
Samuel Klein, Robert H. Eckel,
12 13
Davida Kruger, Hashem El-Serag, and
14
Kenneth Cusi
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are
commonconditions with a rising burden.Yet there are significant management gaps
between clinical guidelines and practice in patients with NAFLD and NASH. Further,
REPORT there is no single global guiding strategy for the management of NAFLD and NASH.
The American Gastroenterological Association, in collaboration with 7 professional
associations, convened an international conference comprising 32 experts in gastro- 1Baylor College of Medicine, Veterans Affairs
SPECIAL enterology, hepatology, endocrinology, and primary care providers from the United Health Services Research and Development
States, Europe, Asia, and Australia. Conference content was informed by the results Service, Center for Innovations in Quality,
of a national NASH Needs Assessment Survey. The participants reviewed and dis- Effectiveness and Safety, and Michael E. DeBakey
Veterans Affairs Medical Center, Houston,TX
cussed published literature on global burden, screening, risk stratification, diagnosis, 2Touro University California, College of Osteopathic
and management of individuals with NAFLD, including those with NASH. Participants Medicine,Vallejo, CA
identified promising approaches for clinical practice and prepared a comprehensive, 3Inova Health System, Falls Church,VA
4Baylor College of Medicine, Houston,TX
unified strategy for primary care providers and relevant specialists encompassing the 5University of Turin,Turin, Italy
full spectrum of NAFLD/NASH care.They also identified specifichigh-yieldtargetsfor 6Northwestern University, Chicago, IL
clinical research and called for a unified, international public health response to 7Pinnacle Clinical Research, San Antonio,TX
NAFLDandNASH. 8Harvard Medical School, Boston, MA
9MichiganState University, East Lansing, MI
10Washington University School of Medicine,
St. Louis, MO
Nonalcoholic fatty liver disease (NAFLD)—hepatic steatosis on imaging or histology 11University of Colorado Anschutz Medical
in the absence of known causes—is rapidly becoming the most common cause of Campus,Aurora,CO
12Henry Ford Health System, Detroit, MI
chronic liver disease worldwide (1). NAFL is histologically defined as the presence 13Baylor College of Medicine, Houston,TX
of $5% hepatic steatosis without evidence of hepatocellular injury, and nonalco- 14University of Florida and Malcom Randall
holic steatohepatitis (NASH) is defined as the presence of $5% hepatic steatosis Veterans Affairs Medical Center, Gainesville, FL
and inflammation with hepatocyte injury (e.g., ballooning), with or without fibrosis Corresponding author: Kenneth Cusi, kenneth.
(2). At least 20%–30% of patients with NAFLD develop NASH, which can lead to cir- cusi@medicine.ufl.edu
rhosis and associated complications, including hepatocellular cancer (HCC) (2). Received 22 April 2021 and accepted 23 June
NASH is also associated with an increased risk of cardiovascular disease (3) and 2021
increased cardiovascular and liver-related mortality (4–6). This article contains supplementary material online
Although most patients with NAFLD and NASH have traditionally been diagnosed at https://doi.org/10.2337/figshare.14932179.
and managed by hepatologists, the recent availability of noninvasive diagnostic proce- This article is being published jointly in Diabetes
dures is expanding the role of other health care professionals likely to see patients with Care, Gastroenterology, Metabolism: Clinical
and Experimental, and Obesity: The Journal of
these conditions, particularly gastroenterologists, endocrinologists, obesity medicine the Obesity Society.
specialists, and primary care providers (PCPs). Previous research has suggested that This article is featured in a podcast available at
effectively treating NASH will require more education about both NAFLD and NASH https://www.diabetesjournals.org/content/diabetes-
among specialists and PCPs (7). Some published data also showed significant manage- core-update-podcasts.
ment gaps between published guidance and clinical practice in patients with NAFLD © 2021 by the American Diabetes Association,
and NASH (8,9). Much of this disparity could come from a lack of recognition of the theAGAInstitute,Elsevier,andTheObesity
importance of NAFLD/NASH and an absence of a unified strategy that encompasses all Society. Readers may use this article as long as
disciplines involved in managing these patients across the full disease spectrum. the work is properly cited, the use is educational
To address this need, the American Gastroenterological Association (AGA) con- and not for profit, and the work is not altered.
More information is available at https://www.
ducted a needs assessment survey of health professionals likely to be engaged in diabetesjournals.org/content/license.
care.diabetesjournals.org Kanwal and Associates 2163
managing adult patients with NAFLD/ obesity are likely to have NAFLD. Only Supplementary Material for the names
NASH, followed by a virtual conference of 49% of endocrinologists and 45% of and affiliations of all participants.
international experts representing 7 pro- PCPs recognized that NAFLD is very In a series of preconference meetings
fessional societies to review the current common in patients with type 2 dia- conducted over 2 months (May and June
research and outline the future agenda for betes (T2D) (Table 1). 2020), these key opinion leaders met and
clinical practice, research, and policy. The Most participants reported that they discussed the most important and poten-
overarching goal was to call for a unified, screen patients with abnormal liver tially controversial aspects of the current
international public health response to chemistries (96%), those with T2D (87%), NAFLD/NASH landscape, including epide-
NAFLD and NASH. This report summarizes and those who are older than 50 years miology, risk factors, screening, diagnosis,
the results from the survey and the virtual with hypertension and hyperlipidemia and management issues. Formal presen-
conference, “Preparing for a NASH Epi- (70%) for the presence of NAFLD. Most tations by each participant followed dur-
demic: A Call for Action.” Although NAFLD were also aware of the best practices in ing the 1-day conference, which included
is an important and growing problem in the initial evaluation of patients with sus- the best-available evidence about their
children, the current effort was limited to pected NAFLD, including the need to topic. Subsequent to the meeting, work-
adults with NAFLD and NASH. Therefore, exclude competing etiologies (96%) and groups (predefined by subject) reviewed,
we do not cover pediatric NAFLD in this evaluation for commonly associated com- discussed, and collated a summary from
report. orbidities, such as T2D, obesity, and dysli- all presentations in their respective sec-
pidemia (96%). However, only 41% recog- tions, followed by an internal review of
NONALCOHOLIC nized that initial evaluation of patients the summary from all workgroup mem-
STEATOHEPATITIS NEEDS with suspected NAFLD should not include bers. The final manuscript (including sum-
ASSESSMENT SURVEY cross-sectional abdominal imaging (e.g., maries from each workgroup) was then
The NASH Needs Assessment Survey contrast-enhanced computed tomogra- submitted to the full group for a second
was conducted in May 2020.The survey phy) to screen for HCC. There were no round of input and approval. The sections
sought to assess participants’ knowl- significant differences in the responses here detail the discussion, conclusions,
edge related to screening, diagnosis, among gastroenterologists/hepatologists, and recommendations for clinical practice
and management of NAFLD and NASH; endocrinologists, and PCPs. and future research that emerged from
compare current diagnostic and treat- More than 80% of participants were this process.
ment patterns with the most recent prac- aware that noninvasive tests, including
tice guidance on NAFLD/NASH; and the NAFLD fibrosis score, Fibrosis-4 BURDENOFNONALCOHOLIC
identify the educational needs that could Index, and imaging-based tests, such as FATTY LIVER DISEASE AND
serve as targets to improve implementa- vibration-controlled transient elastogra- NONALCOHOLIC
tion of guideline-based treatment of phy or magnetic resonance elastography, STEATOHEPATITIS
NAFLD and NASH.The survey included 24 are clinically useful tools for identifying The clinical burden of both NAFLD over-
questions regarding screening, diagnosing, NAFLD/NASH patients with a high likeli- all and NASH specifically has increased
and managing NASH (see Supplementary hood of advanced liver fibrosis. However, steadily since the 1980s. NAFLD cur-
Material for the full survey). In total, 751 78% also thought that abdominal ultra- rently affects 25% of the global popula-
gastroenterologists, hepatologists, endo- sound can identify NAFLD patients with tion and >60% of patients with T2D
crinologists, and PCPs from 46 states NASH. (10). Studies evaluating the prevalence
across the United States completed the Most participants were aware that of NASH suggest that it may involve an
survey. More than 50% of survey partici- 7%–10% weight loss is recommended for estimated 1.5%–6.5% of the general
pants were PCPs. Respondents had spent patients with NAFLD, but fewer than half population and as many as 37% of peo-
an average of 19.5 years in practice of the participants were aware that piogli- ple with T2D (10). Prevalence of NASH
(range, 2–35 years). tazone or vitamin E can be recommended is expected to increase by 63% between
The survey revealed significant gaps in as treatment in select patients with NASH. 2015 and 2030 (11). Although these
knowledgeaboutwhotoscreenandhow Most respondents (>80%) wanted more numbers seem substantially lower than
to diagnose and treat patients at high risk education about screening, diagnosis, and those for NAFLD overall, they still trans-
for NASH, including disparities between treatment of NAFLD/NASH. late to 4.9 million to 21 million Americans
published practice guidance and clinical and more than 100 million individuals
practice (Table 1). Most respondents A CALL-TO-ACTION CONFERENCE worldwide. Modeling data estimate that
(67%) from all practice types were aware the number of patients with NASH-
that up to one-quarter of the general To address these knowledge gaps, the related advanced fibrosis will likely double
population may have NAFLD. However, AGA convened a virtual conference of by 2030, resulting in 800,000 liver-related
there were shortfalls in the knowledge international experts in gastroenterol- deaths (11).
about prevalence in several high-risk ogy, hepatology, endocrinology, obesity NASH is already the number 1 indica-
groups. For example, only 35% of all management, and primary care on 10 tion for liver transplantation in women,
respondents—including 28% of endocri- July 2020. Participants represented key patients older than 54 years, and Medicare
nologists, 32% of PCPS, and 46% of gas- opinion leaders from 8 professional soci- recipients (12). Beyond the significant
troenterologists/hepatologists—recognized eties, and practiced in the United States, impairment of quality of life experienced
that almost all patients with severe Europe, Australia, and Asia. See the by individuals with NASH and advanced
2164 Preparing for the NASH Epidemic Diabetes Care Volume 44, September 2021
Table 1—Key results from the Nonalcoholic Steatohepatitis Needs Assessment Survey
All participants Gastroenterologists/ Endocrinologists Primary care
Variable (n = 751) hepatologists (n = 175) (n = 175) (n = 401)
Proportions of the key patient groups likely to have
NAFLD
Patients with severe obesity 35 46 28 32
With T2D 50 62 49 45
With dyslipidemia 40 47 41 36
General population 67 79 65 62
Patient groups that should be screened for NAFLD
Patients with abnormal liver chemistry 96 97 97 85
Patients with T2D 87 88 94 83
Patients older than 50 y who have hypertension 70 81 73 67
and hyperlipidemia
Approaches to the initial evaluation of the patient
with suspected NAFLD
Exclude competing etiologies for steatosis and 96 95 95 97
coexisting common chronic liver disease
Consider the presence of commonly associated 95 97 93 95
comorbidities, such as obesity, dyslipidemia,
insulin resistance, or diabetes
Cross-sectional abdominal imaging (such as 41 50 39 38
contrast-enhanced CT scan) to screen for HCC
Knowledge about strategies for noninvasive
diagnosis of steatohepatitis and advanced
fibrosis in NAFLD
NAFLD fibrosis score or Fibrosis-4 Index are 82 94 86 75
useful tools for identifying NAFLD patients
with high likelihood of advanced fibrosis
VCTE (FibroScan) or MRE (imaging) are useful 81 93 85 74
tools for identifying advanced fibrosis in
patients with NAFLD
Abdominal ultrasound is a useful tool for 16 29 18 9
identifying NAFLD patients with steatohepatitis
Appropriateness of treatments for NASH
GLP-1 agonists 16 21 15 15
Metformin 17 33 17 11
Obeticholic acid 15 33 13 9
Omega-3 fatty acids 23 37 23 16
Pioglitazonea 53 53 77 42
Ursodeoxycholic acid 22 49 17 12
Vitamin E for nondiabetic adultsa 40 71 51 38
NOTE. Data represent percentages of participants who answered the item correctly. CT, computed tomography; MRE, magnetic resonance
elastography; VCTE, vibration-controlled transient elastography. aThe estimates for pioglitazone and vitamin E indicate percentages of partici-
pants who would consider treatment overall (with or without liver biopsy).
fibrosis (10,13), Younossi et al. (14) esti- are at an increased risk of T2D (17). In patients with NAFLD, the strongest
mated in 2017 that the overall lifetime NAFLD and especially NASH are indepen- histologic determinant of hepatic and
direct costs of NASH in the United States dently associated with several liver- overall outcomes is the presence and
would be $222.6 billion, and approximately related complications, including cirrhosis, stage of fibrosis, although the presence
$95.4 billion over the next 2 decades, sug- HCC, and liver-related mortality. Patients of NASH is the driving force for fibrosis
gesting a substantial economic burden. withNAFLDalsohaveatwofoldincrease development. Patients with histologic
in risk of cardiovascular disease (18,19). evidence of fibrosis higher than stage 2
RISK FACTORS FOR Indeed, individuals with NAFLD/NASH are are at higher risk for adverse outcomes
NONALCOHOLICFATTYLIVER twice as likely to die of cardiovascular dis- (hepatic decompensation, HCC, and
DISEASE, NONALCOHOLIC ease as liver disease (17). The risk of car- liver-related mortality), and this risk
STEATOHEPATITIS, AND RELATED diovascular disease in NAFLD is not increases as fibrosis advances to cirrho-
COMPLICATIONS completely explained by the shared risk sis (5). Specifically, a recent meta-analy-
Patients with obesity or T2D are at a factors, and might be related in part to sis found that, compared with NAFLD
higher risk of developing NAFLD/NASH abnormalities of cardiac structure and patients with no fibrosis (stage 0),
(15,16). Conversely, patients with NAFLD function (17). patients with fibrosis were at an increased
care.diabetesjournals.org Kanwal and Associates 2165
risk for all-cause mortality, and this risk 1. NAFLD is the one of the most common coexisting causes of liver disease, such as
increased with the stage of fibrosis: stage causes of abnormal liver enzymes, but viral hepatitis or significant alcohol intake,
1: risk ratio (RR) vs. stage 0, 1.58 (95% serum alanine aminotransferase (ALT) through history and laboratory testing
confidence interval [CI], 1.19–2.11); stage and aspartate aminotransferase (AST) (Table 2). The accuracy of ultrasound for
2: RR, 2.52 (95% CI, 1.85–3.42); stage 3: can be normal in many cases of the detection of moderate and severe
RR,3.48(95%CI,2.51–4.83); and stage 4: NAFLD/NASH at all stages, including in steatosis is quite high, >80% in a meta-
RR,6.40(95%CI,4.11–9.95). The results patients with advanced fibrosis (27). analysis compared with that of liver
were more pronounced for risk of liver- 2. Liver fibrosis has been linked to mor- biopsy. However, ultrasound has subopti-
related mortality, which increased expo- bidity and reduced overall patient sur- mal sensitivity for mild steatosis (32,33).
nentially with each increase in fibrosis vival (28). Among patients with a high pretest prob-
stage, from an RR of 1.41 (95% CI, 3. NAFLD and fibrosis are reversible ability of NAFLD, moving directly to risk
0.17–11.95) for stage 1 to an RR of 9.57 with weight loss (29). stratification without an ultrasound to
(95% CI, 1.67–54.93) for stage 2, and an 4. Alcohol causes fatty liver disease with confirm steatosis may be appropriate.
RR of 42.30 (95% CI, 3.51–510.34) for many histologic features of NAFLD. Although an optimal strategy for risk
stage 4 fibrosis (5). Although good clinical history is stratification of individuals with NAFLD/
Notably, fibrogenesis does not pro- extremely important, one way to NASHin primary care and specialist clin-
ceed linearly from simple fatty liver to differentiate alcoholic from nonalco- ics remains undefined, the guiding prin-
NASH to cirrhosis, but progresses and holic fatty liver is the AST/ALT ratio, ciple is to rule out advanced fibrosis by
regresses in up to 30% of patients dur- which is generally $2inpatientswith simple, noninvasive fibrosis scores (such
ing a mean period of 5 years (20). Fur- alcohol as the underlying cause. In as NAFLD fibrosis score or Fibrosis-4
thermore, many patients with isolated certain patients, selective testing for Index). Patients at intermediate or high
hepatic steatosis, previously thought to alcohol metabolites may also be risk may require further assessment with
be benign, are likely to progress to appropriate. a second-line test—elastography, or a
NASH (20). On average, patients with serummarkertestwithdirectmeasures
Clinical practice guidelines do not rec- of fibrogenesis (such as enhanced liver
NASH and NAFLD progress 1 stage of ommendscreening for NAFLD in the gen- fibrosis (34) or fragments of propeptide
fibrosis every 7 and 14 years, respec- eral population, but case finding for of type III procollagen (35), and may
tively (21). Older age, visceral obesity, NASH and significant fibrosis is advised require referral to a hepatology clinic (Fig.
T2D, and hypertension are associated for key high-risk groups, such as those 1). Of note, the enhanced liver fibrosis
with fibrosis progression (21,22). T2D with moderate to severe obesity (BMI and propeptide of type III procollagen
and number of metabolic comorbidities 2
>35 kg/m ), T2D of more than 10 years’ tests are not approved in the United
are also associated with an increased duration or in people older than 50 years, States, limiting their use in clinical prac-
risk of liver-related mortality and HCC or metabolic syndrome (30). The Ameri- tice. In contrast, elastography-based tests
(23,24). The severity of steatosis, how- can Diabetes Association’s 2020 Stand- are available and can be used for risk
ever, has a modest (if any) correlation ards of Medical Care in Diabetes also stratification. Several recent studies show
with the severity of liver histology (25), recommend evaluating patients with pre- that this sequential use of noninvasive
and the relationship between severity diabetes or T2D with steatosis or ele- tests reduces unnecessary referrals to
of steatosis and cardiovascular disease vated ALT for NASH and fibrosis (31). specialists, increases the detection of
remains unclear. Diagnosing NAFLD/NASH begins with advanced fibrosis and cirrhosis, and
evaluating patients for alternative or hence may be cost-effective (36,37).
Screening and Diagnosis
Effectively screening for and timely diag-
nosis of NAFLD may prevent progression Table 2—Initial evaluation in patients with suspected nonalcoholic fatty liver
to NASH and associated complications. disease
Because PCPs are on the front lines of History and medical review Investigations
managing individuals with NAFLD, screen- Obesity Liver biochemistries (ALT, AST)
ing patients at risk, stratifying patients T2D Exclude/identify other liver diseasesa
based on their risk for advanced fibrosis,
and positioning themselves to provide Metabolic syndrome HBV and HCV serology (and viral load)
effective management and referrals are Alcohol intake Auto antibodies (ANA, AMA, ASMA)
important. A recent study showed that <14 drinks/wk for women Serum ferritin, A1AT
screening for NAFLD followed by inten- <21 drinks/wk for men Liver ultrasound: increased echogenicity
sive lifestyle interventions or pioglitazone No known pre-existing liver disease —
was cost-effective in patients with T2D A1AT, a1 antitrypsin; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA,
diagnosed with clinically significant fibro- anti–smooth muscle antibody; HBV, hepatitis B virus; HCV, hepatitis C virus. aNAFLD can
sis, providing support for these recom- coexist with other chronic liver diseases. Of note, 21% of patients with NAFLD may have
mendations (26). elevations in autoantibodies in the absence of autoimmune hepatitis (85), and 20% may
To recognize NAFLD, the PCP must be have high serum ferritin (>300 ng/mL in women and >450 ng/mL in men). Elevated serum
ferritin is associated with advanced hepatic fibrosis (86) in patients with NAFLD.
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