Gastroenterology 2020;158:1851–1864

Nonalcoholic Fatty Liver Disease 2020: The State of the Disease

Thomas G. Cotter1 Mary Rinella2

1
Division of Gastroenterology and Hepatology, The University of Chicago Medicine; and 2Division of Gastroenterology and
Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Nonalcoholic fatty liver disease (NAFLD) is the most com- steatosis or NAFL to NASH and NASH cirrhosis, in addition
mon liver disease, with a worldwide prevalence of 25%. In to the development of diagnostic criteria.7,8 Over time, the
the United States, NAFLD and its subtype, nonalcoholic incidence and prevalence of NAFLD has increased dramati-
steatohepatitis, affect 30% and 5% of the population, cally, in parallel with the global epidemic of obesity.9 With
respectively. Considering the ongoing obesity epidemic more robust understanding of the natural history of NAFLD,
beginning in childhood, the rise in diabetes, and other it has become increasingly evident that even this nomen-
factors, the prevalence of NAFLD along with the proportion clature is inherently problematic, largely due to the het-
of those with advanced liver disease is projected to erogeneity of NAFLD and primary driving forces between
continue to increase. This will have an important impact individuals. For this reason, and in order to better charac-
on public health reflected in health care costs, including terize the disease, an alternate name that better reflects the
impact on the need for liver transplantation, for which
underlying pathophysiology is needed. The rationale for this
nonalcoholic steatohepatitis is already close to becoming
will be discussed in depth in another article from this
the most common indication. NAFLD patients with evi-
Special Issue. Revised nomenclature in conjunction with the
dence of nonalcoholic steatohepatitis and advanced
anticipated ability to sub-stratify the disease into different
fibrosis are at markedly increased risk of adverse out-
comes, including overall mortality, and liver-specific phenotypes will ultimately facilitate a more precise under-
morbidity and mortality, respectively. Identification of standing of the natural history of NAFLD, disease variability,
this cohort of NAFLD patients is paramount, given the and promote a more individualized approach to treatment
associated poorer outcomes, in order to target resources to interventions. This review on NAFLD will explore its current
those who need it most. Various noninvasive tools have epidemiologic patterns, established clinical and prognostic
been developed in this regard. This review provides an features, and diagnostic nuances, and should serve as a
update on the epidemiology, clinical and prognostic fea- foundation ahead of the subsequent reviews of NAFLD in
tures, and diagnostic approach to patients with NAFLD. this issue of Gastroenterology.

I n 1849, the Austrian pathologist, Carl von Rokitansky,

hypothesized that cirrhosis can result from fat accu-
mulation1; however, since then, only sporadic descriptions
Epidemiology
In 2016, the World Health Organization estimated that
of the relationship between fatty liver and both caloric more than 1.9 billion adults (39% of the adult population)
intake and diabetes mellitus have been described in the were overweight and 650 million (13% of the adult popu-
literature more than a century later.1–3 Hepatitis of the fatty lation) were obese.10 In the United States, data from the
liver was first described by Heribert Thaler in 1962,4 before
Jurgen Ludwig and his colleagues at Mayo Clinic added the Abbreviations used in this paper: AUROC, area under the receiver
phrase nonalcoholic steatohepatitis (NASH) to the lexicon in operating curve; BMI, body mass index; CAP, controlled attenuation
parameter; CI, confidence interval; CPR, clinical prediction tool; FIB-4,
1980, with their landmark case series.5 At that point in time, Fibrosis-4; HCC, hepatocellular carcinoma; HSD17B13, hydroxysteroid
it was generally believed that nonalcoholic fatty liver 17b-dehydrogenase 13; LSM, liver stiffness measurement; MetS, meta-
(NAFL) was a benign condition, and that patients with bolic syndrome; MRE, magnetic resonance elastography; NAFLD, nonal-
coholic fatty liver disease; NAS, NAFLD Activity Score; NASH,
obesity-related comorbidities had more pressing medical nonalcoholic steatohepatitis; NASH CRN, Nonalcoholic Steatohepatitis
issues to address. It was not until the 1990s that it became Clinical Research Network; NFS, NAFLD Fibrosis Score; NPV, negative
predictive value; PPV, positive predictive value; T2DM, type 2 diabetes
increasingly recognized that NASH was a serious medical mellitus; VCTE, vibration-controlled transient elastography.
condition in its own right, with associated morbidity and Most current article
mortality.6 The broader term of nonalcoholic fatty liver dis-
© 2020 by the AGA Institute
ease (NAFLD) started to be used in 2002, and encompassed 0016-5085/$36.00
the full spectrum of fatty liver disease from isolated hepatic https://doi.org/10.1053/j.gastro.2020.01.052
1852 Cotter and Rinella Gastroenterology Vol. 158, No. 7

National Health and Nutrition Examination Survey for 2015 28.01 per 1000 person-years (95% CI, 19.34–40.57) in Israel
to 2016 estimated that 39.8% of adults were obese.11 In to 52.34 per 1000 person-years (95% CI, 28.31–96.77) in
parallel with the obesity epidemic, there has been a rise in Asia.12,17 The incidence of NAFLD has been increasing
obesity-related complications, NAFLD notwithstanding. dramatically over time. A population-based study from Olms-
NAFLD is the most common liver disease worldwide,12,13 ted County, Minnesota, revealed a 5-fold increase in NAFLD
and is now the second leading indication for liver trans- incidence since 1997, as identified by diagnostic coding, most
plantation in the United States, narrowly behind only dramatically in younger adults aged 18–39 years old.23
alcohol-related liver disease.14 Moreover, the proportion of Given that NASH requires histologic confirmation via
NASH as an underlying etiology for hepatocellular carci- biopsy, the prevalence of NASH in the general population
noma (HCC) in patients being listed for liver transplantation can only be estimated from a small number of biopsy series.
has increased 7.7-fold (from 2.1% to 16.2%) in the United Based on these inherently incomplete data, the prevalence
States.15 Data from the European Liver Transplant Registry of NASH ranges between 1.5% and 6.45% in the general
database show similar trends, with 8.4% of all liver trans- population.12,17 Among those with NAFLD, the prevalence of
plantations due to NASH, representing a 7-fold increase NASH ranges from 7% to 30%, with an estimated 16.5
between 2002 and 2016.16 million individuals affected in the United States alone in
Currently, it is estimated that the global prevalence of 2015.17,22 The pooled prevalence of NASH in Asia, ascer-
NAFLD is approximately 25%, with more than 80 million tained from biopsy-proven NAFLD patients, was not sur-
individuals affected in the United States alone.17 There are prisingly higher at 63.5% (95% CI, 47.7%–76.8%), given the
similar rates in Asia, with an estimated pooled prevalence selection bias of examining patients who warranted bi-
rate of 27.4% (95% confidence interval [CI], 23.3%–31.9%) opsy.17 Cirrhosis due to NASH is quite common, with 3.3
observed.17 Both the prevalence of NAFLD and stage of liver million individuals estimated to have advanced fibrosis in
disease appear to increase with age.18,19 The overall prev- the United States in 2015.22 Rates of decompensated NASH
alence of NAFLD appears to be higher in men, however, the cirrhosis are projected to increase by 168%, liver-related
prevalence of NASH with more advanced stages of fibrosis deaths by 178%, and incident HCC by 137% between
appears to be somewhat enriched in women.20 Differential 2015 and 2030.22 Although these projected increases might
rates of disease progression resulting in an increased risk of appear dramatic, given the lack of approved therapies for
severe fibrosis in postmenopausal women compared to men NAFLD and the unabating obesity epidemic, these projected
is possibly attributed to loss of the protective effects of figures may in fact underestimate the future burden of liver
estrogen against fibrogenesis.21 Given the projected disease related to NASH.
increasing rates of obesity and type 2 diabetes mellitus There is a noticeable variable prevalence of NAFLD
(T2DM), compounded by an aging population, NAFLD is among populations and phenotypic expression of severity.
projected to increase to 100 million people in the United These differences are attributable to numerous factors,
States by 2030.22 The data on incidence of NAFLD in the including metabolic comorbidities, microbiome, and envi-
general population are less reliable. In this context, the ronmental and genetic/epigenetic factors24 (Figure 1). As an
incidence estimates of NAFLD vary worldwide, ranging from example, some of these variables likely explain the

Figure 1. Modifiers of NAFLD. Factors influencing the course of NAFLD are outlined here and can be broadly divided into
comorbid illness, genetic factors, microbial products, and nutritional/behavioral factors. Factors with an established associ-
ation with NAFLD and NASH progression are bolded in red; factors clearly associated with NAFLD but for which no established
link with disease progression has been established are noted in red; and disease factors with an appreciated association, but
evolving evidence are noted in black. Green denotes a protective factor.
May 2020 NAFLD 2020 1853

increased risk for NASH and related increased prevalence of disease progression and this is likely reflective of relative
fibrosis among Hispanic Americans. Although previously all differences in the predominant mechanism of injury in a
Hispanics were thought to be at risk, more recent data given individual (Figure 1). Alcohol use is pervasive and a
suggest that origin also plays a role (ie, indigenous native confounding factor in many (possibly the majority) of pa-
Americans vs Africa), wherein Hispanics of Mexican origin tients with NAFLD. Furthermore, it is challenging to mea-
have a prevalence rate of 33% and those of Puerto Rican sure the extent to which alcohol intake impacts an
and Dominican descent have prevalence rates of 18% and individual due to inaccurate reporting and genetic differ-
16%, respectively.25 These differences are attributable, in ences in susceptibility to alcohol-induced liver injury.
part, to the difference in carriage of a single polymorphism Increasing alcohol consumption patterns in the US popula-
in the PNPLA3 gene, which has a higher relative frequency tion have been observed in recent years, with per-capita
in Mexico. Other countries such as Japan and South Korea annual consumption of ethanol from all alcoholic bever-
have a higher relative frequency of the PNPLA3 risk allele,26 ages in the United States increasing to 2.35 gallons in 2016,
just as other genetic polymorphisms differ in prevalence from 1995’s 33-year nadir of 2.17 gallons.33 In 2015, the
across different regions.26,27 Although African Americans prevalence of binge drinking within 30 days of the study
have high rates of metabolic syndrome, NAFLD, particularly was 17% in the United States, with some states having a
NASH, is less common in African Americans compared with prevalence as high as 25%, and an average of more than 7
Caucasian and Hispanic populations. This is attributable, in drinks was consumed per occasion, with males having
part, to lower carriage rates of PNPLA3, however, differ- higher alcohol consumption then females.34 It is difficult to
ences in adipose tissue distribution also play a role.28,29 In know what amount of alcohol is “safe” in a given patient,
African Americans, body type tends to be predominantly considering the absence of a consistent and precise defini-
gynoid rather than android, as it typically is in Caucasians or tion of what constitutes significant amounts of alcohol
Hispanics with NASH, and dyslipidemia in African Ameri- consumption in the medical literature.35 In the context of
cans is less likely to be high triglycerides/low high-density NASH clinical trials, significant alcohol consumption
lipoprotein, which are the typical features of the metabolic (defined as more than 21 standard drinks per week in men
syndrome (MetS).30 These observations are suggestive of a and more than 14 standard drinks per week in women) is
complex interplay between genetic and environmental fac- exclusionary during a 2-year period preceding baseline liver
tors that can dictate severity of NAFLD among different histology,36 with a standard alcoholic drink being any drink
patient populations. that contains about 14 g of pure alcohol.37 These arbitrary
Until recently, our understanding of the natural history thresholds are based on levels above which the risk of
of NAFLD was based largely on retrospective data or fairly cirrhosis is higher (20 g of ethanol for women daily, 30 g
small case series unable to control for key confounders. The daily for men),38,39 however, these thresholds have not been
first glimpse of the short-term natural history began to studied in the context of NASH specifically. Alcohol signifi-
emerge from phase 2b/3 clinical trials31 and, over time, will cantly impacts disease progression in other forms of liver
continue to provide prospective insight into the natural disease, including NASH.40 Furthermore, patients with
history of NASH with established fibrosis, although these are moderate alcohol consumption have decreased improve-
a highly selected cohort, which can limit generalizability. ment in steatosis or resolution of NASH.41 The role of
Recently published data from the largest prospective cohort alcohol in altering the disease course in NAFLD requires
of NASH patients encompassing the full spectrum of disease further elucidation and, as a field, we should be emphasizing
confirmed the dynamic nature of NAFLD, with respect to that there is no specific innocuous amount of alcohol in the
both the development and progression of NASH, as well as context of NASH rather than asserting that intake below the
fibrosis. Among other important findings, this study thresholds used in NASH clinical trials is safe or does not
demonstrated that a larger number of those with NAFL are alter disease progression significantly.
likely to progress to NASH (46.9%) than previously thought,
and confirmed that fibrosis improves or progresses in
approximately 30% during a mean period of 4.9 years.32 Concomitant Liver Disease
Given its high prevalence, other causes of liver disease
can coexist with NAFLD and these should be excluded, such
Drivers of Disease Progression as chronic viral hepatitis, autoimmune liver disease, and
The diagnosis of NAFLD requires evidence of hepatic hemochromatosis.12 Some indicators of other forms of liver
steatosis, either by imaging or histology, and absence of disease can modify the course of disease (a serum ferritin
secondary etiologies of hepatic fat accumulation, such as level of >1.5 upper limit of normal, which generally reflects
significant alcohol consumption, long-term use of a steato- hepatic steatosis or secondary hemosiderosis rather than
genic medications (eg, corticosteroids, methotrexate, amio- another form of liver disease, and a-1 antitrypsin hetero-
darone, and tamoxifen), hepatitis C virus infection zygosity are both associated with more advanced
(particularly genotype 3), monogenic hereditary disorders, fibrosis),42–44 while others, such as low titers of autoim-
severe malnutrition, and Wilson disease.12 However, even mune antibodies (in the absence of concomitant autoim-
after exclusion of other causes of steatosis, NASH, as it is mune hepatitis) are common and of no apparent clinical
currently defined, represents a very heterogeneous popu- consequence.45 The presence of commonly associated
lation. A number of factors have been proposed to accelerate comorbidities, such as obesity, hypertension, dyslipidemia,
1854 Cotter and Rinella Gastroenterology Vol. 158, No. 7

diabetes or insulin resistance, hypothyroidism, polycystic ubiquitous among patients with NAFLD, as up to 75% of
ovary syndrome, and obstructive sleep apnea should also be patients who are overweight and 90%–95% of patients with
documented, as they can increase the risk of advanced morbid obesity have NAFLD.70–72 The distribution of
disease, worsen outcomes, and, in some, have a bidirectional adiposity, specifically the presence of truncal obesity, is a
association (Figure 1). The majority of what was previously more important determinant of NAFLD risk than body mass
considered cryptogenic cirrhosis is now recognized as index (BMI).73–75 Moreover, the extent of visceral adipose
“burned out” NASH, as such patients have a disproportion- tissue area is associated with incident NAFLD in a dose-
ately high prevalence of metabolic risk factors despite the dependent manner (adjusted hazard ratio of 1.36 (95% CI,
absence of NASH or even steatosis in the presence of 1.16–1.59, per SD increase),76 and is independently associ-
cirrhosis.46 ated with increased risks of NASH and advanced fibrosis.77
This contributes to the increased disease burden in Asians
Nonalcoholic Steatohepatitis and Advanced with a lower BMI who are more sensitive to increased
visceral adipose tissue prompting adoption of different
Fibrosis
criteria for the diagnosis of the MetS in Asians.78 While
Importantly, those with histologic evidence of NASH and
visceral adipose tissue only accounts for 7%–15% of the
pronounced fibrosis (stage 2 or higher),47–49 are at an even
total body fat, it is much more metabolically active than
higher risk for adverse hepatic outcomes (hepatic decom-
subcutaneous fat and is a dominant source of adipocyto-
pensation, HCC, and liver-related mortality) and this risk
kines and free fatty acids received by the liver via portal
increases in an exponential manner as fibrosis stage ad-
venous blood, which are instrumental in the development of
vances to cirrhosis.12,47,49–57 Specifically, liver-specific and
insulin resistance and the activation of inflammatory
overall mortality rates among NAFLD and NASH patients are
pathways.79
0.77 (range, 0.33–1.77) per 1000 and 11.77 (range, 7.10–
The presence of insulin resistance is a nearly universal
19.53) per 1000 person-years and 15.44 (range, 11.72–
feature of NASH,64,80 while the prevalence of T2DM in those
20.34) per 1000 and 25.56 (range, 6.29–103.80) per 1000
with NAFLD is less consistent across studies with rates as
person-years, respectively.17 Although acknowledging that
low as 15% in the population-based Dallas Heart Study and
fibrosis stage is the clearest histologic determinant of out-
as high as 33%–66% in others.81–84 The presence of NAFLD
comes and NASH has a less clear independent association
increases the risk of incident T2DM, with a relative risk of
with poor outcomes, this is likely due to the high co-linearity
1.86 (95% CI, 1.76–1.95),69 however, some studies have
between NASH and fibrosis severity.58 Specifically, NASH is
shown an almost 4-fold increased risk, especially among
present in 94% of patients with stage 4 fibrosis compared
patients with more advanced disease.85,86 Patients with
with only 35% of those with stage 0 fibrosis.58 Evidently,
NAFLD have demonstrably impaired ability of insulin to
the identification of this subset of patients is of paramount
suppress glucose production, causing hyperglycemia and
importance to appropriate interventions, given their prox-
resulting in hyperinsulinemia, and inappropriate peripheral
imity to clinically relevant liver events.
lipolysis that ensues.87 NASH is also associated with meta-
bolic dyslipidemia, characterized by high triglycerides and
The Influence of Metabolic Syndrome and Type 2 low high-density lipoprotein cholesterol. In a cross-sectional
Diabetes analysis of 9560 apparently healthy Chinese adults who
There are a number of medical comorbidities that have underwent comprehensive health checkups including
varying degrees of association with disease progression abdominal ultrasonography, 23% of patients with NAFLD
among NAFLD patients (Figure 1). The clustering of disease had isolated hypertriglyceridemia, 10% had isolated low
comorbidities manifesting as MetS is by far the most char- high-density lipoprotein cholesterol, and 18% had both
acteristic feature of NAFLD, present in 36%–67% of abnormalities.88
patients,17,59–65 and is a unifying contributor to disease NAFLD patients and/or patients with MetS have an
progression.17,59–65 In one study, 88% of patients with increased rate of fatty acid and triglyceride-rich very low-
NASH met the criteria for MetS, compared with 53% of density lipoprotein secretion into the plasma driven by
patients with NAFLD.59 Similarly, in the Nonalcoholic Stea- increased fatty acid delivery to the liver, as well as increased
tohepatitis Clinical Research Network (NASH CRN) data, the rates of de novo lipogenesis, both mediated my insulin
presence of the MetS increased the likelihood of histologi- resistance.89–92 These free fatty adds are central to the
cally confirmed NASH by 40%,66 and is independently pathogenesis of NASH, resulting in the formation of lipotoxic
associated with increased overall mortality among NAFLD species that lead to endoplasmic reticulum and oxidant
patients in the National Health and Nutrition Examination stress, and inflammasome activation, which are thought to
Survey database.67 Within the context of the MetS, strength underpin the hepatocellular injury, inflammation, stellate
of association varies and there is clear bidirectionality with cell activation, and progressive accumulation of excess
respect to disease with some, particularly with T2DM and extracellular matrix that characterizes the phenotype of
hypertension,68 although definitive causation has not been NASH.68 NAFLD at baseline or incident NAFLD is associated
proven. In a meta-analysis of 81,411, there was a signifi- with an increased risk of incident hypertension,93,94 thought
cantly increased incidence of MetS during a 5-year follow-up to be related to increased renal sodium reabsorption due to
period among NAFLD patients, with a relative risk of 3.22 hyperinsulinemia, enhanced stimulation of the sympathetic
for ultrasonography-diagnosed patients.69 Obesity is nearly nervous system, and impaired vasodilation secondary to
May 2020 NAFLD 2020 1855

insulin stimulation.95,96 Some conditions also have emerging cardiovascular disease in patients with NASH appears to be
associations with NAFLD and include hypothyroidism, beyond that conferred by the shared risk factors, likely
obstructive sleep apnea, hypogonadism, osteoporosis and related to systemic vascular endothelial dysfunction, pro-
psoriasis63,97 (Figure 1). Hypopituitarism and growth hor- atherogenic dyslipidemia, myocardial remodeling, and
mone deficiency are frequently associated with more pro- heart failure.90,117 A meta-analysis of 34,000 patients with
gressive NASH with advanced fibrosis.98 Higher rates of NAFLD revealed a 65% increased risk of developing both
chronic kidney disease are also increasingly recognized in fatal and nonfatal cardiovascular events.118 Cancer-related
patients with NAFLD.99,100 Moreover, the frequency of mortality is the second leading cause of death in NAFLD
simultaneous liver-kidney transplantation is disproportion- patients, ahead of liver-specific mortality, which is far higher
ally increasing in NASH cirrhosis.101 than the general population.119 NAFLD is now the third
most common cause of HCC in the United States, however,
Genetic Influence NAFLD is also associated with an increased risk of non-
There has been vast research undertaken exploring the hepatic malignancies, particularly colon cancers.120–125
genetic drivers of disease in NAFLD, beyond MetS and in-
sulin resistance. A classic example is the single rs738409
C>G polymorphism of PNPLA3, which encodes I148M Diagnosis of Nonalcoholic
regulating lipolysis of hepatocyte lipid droplets, and is Steatohepatitis
strongly associated with NAFLD, steatosis extent, and his- As alluded to in the previous section, evidence of hepatic
tologic severity.102,103 Furthermore, homozygous carriers of steatosis either by imaging or histology is required for the
the p.148M mutation carry a 12-fold increased HCC risk, diagnosis of NAFLD. Liver biopsy is required for NASH but not
arguing for the potential for monogenic inheritance.104,105 for NAFLD, and remains the gold standard for characterizing
The risk-associated PNPLA3-I148M variant is resistant to liver histologic alterations in patients with NAFLD.12 The
normal proteasomal degradation and accumulates on lipid current pathologic standard is to report grade (necroin-
droplets, which interferes with lipolysis. The mutation oc- flammatory “activity”) separately from stage, which ascertains
curs with the greatest frequency in Hispanics, followed by the location of abnormal collagen deposition and architectural
non-Hispanic whites, and the least in African Americans.106 remodeling (ie, “fibrosis”). NAFL is defined as the presence of
These associations are independent of the presence of
5% hepatic steatosis without evidence of hepatocellular
T2DM and obesity.107–109 The PNPLA3 rs738409 GG allele is injury in the form of hepatocyte ballooning.126 NASH is
more common in Asians with lean NAFLD without MetS, distinguished from isolated hepatic steatosis or NAFL by the
which could account for the observation that Asian and presence of hepatocellular injury characterized by the pres-
Caucasian populations have a similar prevalence of NAFLD, ence of lobular inflammation and hepatocellular ballooning
but Asians have a lower metabolic burden.110 Another independent of the presence of absence of fibrosis.12
example is the enzyme hydroxysteroid 17b-dehydrogenase There are 2 accepted scoring systems for the diagnosis
13 (HSD17B13), from a large family of enzymes primarily of NASH—the NAFLD Activity Score (NAS) from the NASH
involved in sex hormone metabolism, which is a novel liver- CRN126 and the Steatosis Activity Fibrosis from the Euro-
specific lipid droplet–associated protein in mouse and pean Fatty Liver Inhibition of Progression Consortium.127
humans. HSD17B13 expression is markedly up-regulated in Both are used to standardize clinical trial outcomes and
patients and mice with NAFLD. Hepatic overexpression of clinicians involved in managing NAFLD patients would
HSD17B13 promotes lipid accumulation in the liver, sup- benefit from familiarity in order to systematically interpret
porting the pathogenic role of HSD17B13 in NAFLD.111 A the efficacy of interventions. The basic histologic lesions
recent study showed a loss-of-function variant in HSD17B13 focused on and evaluated by both are the same (steatosis,
was associated with a reduced risk of chronic liver disease lobular inflammation, hepatocellular ballooning). However,
and of progression from steatosis to steatohepatitis, high- they differ in that the NAS does not include fibrosis stage
lighting it as a potential therapeutic target.112 While these within it, while Steatosis Activity Fibrosis does.128,129 The
genetic advancements have increased our understanding of NAS (plus fibrosis stage) was created as a way to compare
the pathogenesis of NAFLD, and may account in some part liver histology after therapeutic interventions but was not
for the so-called “lean” NAFLD patients, routine testing for intended to replace the pathologist’s separately reported
these genetic variants is currently not advocated. A more diagnostic classification of the overall disease process
comprehensive discussion on NAFLD genetics, including (presence of NASH) reported as a single numeric value, the
TM6SF2 and MBOAT7 gene variants,113 can be found later unweighted sum of steatosis, lobular inflammation, and
in this Special Issue of Gastroenterology. ballooning (0–8). The Steatosis Activity Fibrosis numeric
values were created to more holistically differentiate NAFL
Cardiovascular and Malignancy Risk and NASH, and is reported with subscripts for each
Patients with NAFLD, largely driven by those with component, that is, S (0–3), A (0–4), and F (0–4). Both grade
NASH,57 have an overall higher rate of mortality compared steatosis based on percentage of the parenchyma involved
with matched non-NAFLD controls.114,115 The most common (<5%; 5%–33%; 34%–66%; >66%).129 A major limitation
cause of death among NAFLD patients is cardiovascular common to both scoring systems is the assessment of
disease,116 with patients twice as likely to die of cardio- response to treatment, with NASH resolution or loss of
vascular disease than liver disease. The increased risk of disease activity not completely validated.129
1856 Cotter and Rinella Gastroenterology Vol. 158, No. 7

Figure 2. Risk stratification

of patients with NAFLD. A
pragmatic risk stratifica-
tion approach is important
to identify patients at risk
of advanced fibrosis in a
cost-effective fashion. In
this algorithm, patients are
divided into low- or high-
risk for advanced disease
based on their clinical
profile and clinical predic-
tion rules. Patients who are
identified as low risk of
NASH or advanced
fibrosis can be managed in
primary care with periodic
assessment of new risk
factors. Patients who are
intermediate or high risk
should be considered for
specialist evaluation, with
further evaluation
continuing with liver stiff-
ness assessment.

There are a number of drawbacks to liver biopsy, not for hepatic steatosis and the presence and/or severity of
least the associated morbidity and very rare mortality, coexisting chronic liver diseases cannot be excluded without
expense, and requirement for expert interpretation. Sam- a liver biopsy (Figure 2).
pling “error” remains an issue, with studies showing that
35% of patients with bridging fibrosis on 1 sample may
have only mild or no fibrosis on the other sample.130 Noninvasive Assessment of
Furthermore, the diagnosis of NASH is not uniform among
pathologists. This significant interobserver variability is Nonalcoholic Steatohepatitis and Liver
illustrated by k scores of 0.35–0.56 and 0.33–0.45 for Fibrosis
ballooning and lobular inflammation, respectively. Another The ideal biomarker is a characteristic that can be
issue with the interpretation of liver pathology is fibrosis. measured in an objective manner that recapitulates normal
Although k scores for fibrosis are significantly better (0.61– physiologic or pathogenic processes and changes in parallel
0.84), the current scoring systems do not account for with disease improvement or worsening. In the context of
accumulating fibrosis burden as accurately or as optimally NAFLD, biomarkers can be used for the diagnosis
as they should, given the nonlinear increase in collagen and quantification of steatosis, to determine the presence
burden, especially at later stages of fibrosis.126,131,132 This is and extent of NASH-related liver injury, and to identify and
particularly relevant in the context of assessing response to quantify fibrosis. Ideally, a biomarker is also predictive of
therapy. It is also important to recognize that the interob- outcomes. The diagnosis of hepatic steatosis can be made
server agreements of the aggregate pathologic diagnostic using various imaging modalities—ultrasound, computed
criteria for NASH are also very weak.48 In general, liver bi- tomography, vibration-controlled transient elastography
opsy should be strongly considered in patients with NAFLD (VCTE) (Fibroscan) controlled attenuation parameter (CAP),
who are at increased risk of having NASH and/or advanced and magnetic resonance imaging. Ultrasound and computed
fibrosis on the basis of clinical evaluation, or in those pa- tomography are fairly reliable when there is >30% mac-
tients with suspected NAFLD, in whom competing etiologies rovesicular fat,133,134 with CAP providing less favorable
May 2020 NAFLD 2020 1857

reliability,134 although a notable strength is its ability to but is not available for clinical use in the United States. In
detect significant steatosis when reading is >300 dB/m. addition, Enhanced Liver Fibrosis will need to be validated in
CAP cutoffs from 281–310 dB/m have a sensitivity of 64%– a real-world population with a lower prevalence of advanced
100% and a specificity of 53%–92% for the detection of fibrosis in order to determine its true performance
biopsy-proven S3 (
66% hepatocytes with fat).135 The characteristics.
assessment of dynamic change with either ultrasound, The biggest unmet need in the NASH field is the devel-
computed tomography, or CAP is not reliable. In contrast, opment of a biomarker that can diagnose NASH and deter-
magnetic resonance imaging–derived proton density fat mine disease severity accurately. Multiple approaches have
fraction is currently the gold standard for the diagnosis and been explored or are under development that may hold
quantification of hepatic steatosis and has excellent accu- promise, such as metabolomics or transcriptomic ap-
racy in detecting dynamic change. Given its cost and lack of proaches.145,146 However, the modest performance of any
point-of-care access, its use is most relevant in the context biomarker to diagnosis NASH so far is largely a function of
of a clinical trial as a measure of treatment response. the dynamic nature of the disease, wherein disease activity
However, it is the presence and extent of fibrosis, not and even fibrosis stage can vary significantly over fairly
steatosis, that determine liver-related outcomes. Clinical short periods of time and limit its histopathologic inter-
prediction rules (eg, NAFLD Fibrosis Score [NFS], Fibrosis-4 pretation. It is anticipated that the NIMBLE (Non-Invasive
[FIB-4] Index, Aspartate Aminotransferase to Platelet Ratio Biomarkers of Metabolic Liver Disease) and LITMUS (Liver
Index) and others,28,136 use readily available clinical vari- Investigation: Testing Marker Utility in Steatohepatitis)
ables, providing diagnostic and prognostic information in the consortia in the United States and Europe, respectively, will
practice setting at no cost. Their strength is in their ability to provide invaluable information on the performance of bio-
exclude advanced disease with a high degree of accuracy with markers in the context of NASH in the near future.
their relatively robust negative predictive value (NPV).136 The most accurate noninvasive methods to identify
Their limitations are mainly poor positive predictive value advanced fibrosis and to dichotomize NAFLD patients into
(PPV) (ranging from 27% to 79%) and inaccuracy at the ex- advanced vs nonadvanced fibrosis include VCTE (FibroScan)
tremes of age. Disease severity is overestimated in older pa- and magnetic resonance elastography (MRE).140,147
tients and diabetics, which has prompted the development of Ultrasound-based acoustic force impulse elastography and
age-adjusted lower cutoffs (NFS < 0.12 and FIB-4 < 2) that supersonic shear-wave elastography are additional recog-
maintain the high NPV and thus help exclude advanced nized modalities. VCTE, uses pulsed-echo ultrasonography to
fibrosis in patients older than 65 years. In younger patients, provide a liver stiffness measurement (LSM) as a surrogate
the clinical prediction tools (CPRs) have very poor accu- marker of fibrosis,148 and is approved by the US Food and
racy.136,137 Furthermore, approximately one-third of patients Drug Administration for use in both adults and children with
will be classified as “intermediate” in the case of NFS and FIB- liver disease. VCTE has an AUROC of 0.83 with an NPV of
4, which has considerably lower diagnostic accuracy.138,139 90%, and has a diagnostic accuracy of 80.8% in categorizing
Recent data using a cohort from phase 3 NASH trials nicely patients into subgroups with differing prognoses.149 It is
illustrated the ability of NFS and FIB-4 in discriminating those noteworthy that the cutoff values for different fibrosis stages
patients with advanced fibrosis, with an area under the can vary by both etiology of disease and population. The first
receiver operating curve (AUROC) ranging from 0.75 to study to evaluate the performance of VCTE in a US popula-
0.80.140 However, in sum, CPRs lack sufficient PPV alone to tion (median BMI, 32.2 kg/m2) found the optimal LSM cutoff
diagnose NASH and fibrosis in isolation. Diagnostic perfor- to be 9.9 kPa, which yielded a 95% sensitivity and 77%
mance can be enhanced by the incorporation of VCTE values specificity, with AUROC of 0.93 for detecting advanced
as in the FAST Score (VCTEþCAPþaspartate aminotrans- fibrosis in NASH. An important limitation of this study was
ferase)141 or other fibrosis markers such PRO-C3 (FIB-C3 the fact that more than one-quarter of the 164 patients
score).142 Other proprietary predictive biomarkers, such as assessed had unreliable results, largely related to the lack of
NIS4, that incorporate miR-34a, a2-macroglobulin, YKL-40, XL probe use when indicated.150 The VCTE with M probe
and hemoglobin A1c to predict the presence of NASH and performed similarly in a Japanese cohort of 142 patients
F2 or higher fibrosis or pro-C hold some promise, but require who had a noticeably lower median BMI (28.1 kg/m2) and a
larger-scale validation.143 The most promising thus far to lower failure rate of 10.5%.151 Recently, the NASH CRN
predict disease progression and outcomes is the Enhanced published its VCTE multicenter experience in 992 patients
Liver Fibrosis panel.31 The Enhanced Liver Fibrosis panel with biopsy-proven NAFLD (mean BMI, 33.6 kg/m2) in the
consists of plasma levels of 3 matrix turnover proteins (hy- United States using a machine-guided protocol with either an
aluronic acid, tissue inhibitor of metalloproteinase 1, and N- M 1 or XL 1 probe.152 The results were reassuring, with a low
terminal procollagen III-peptide) and performs marginally failure (3.2%) and high reliability (>95%) rates and repro-
better than the NFS for diagnosing moderate fibrosis (AUROC, ducibility.152 In this cohort, the XLþ probe was used in
0.90 vs 0.86) and severe fibrosis (AUROC, 0.93 vs 0.89), with >60% of the “obese (BMI 30–34.9)” and in almost 90% of
the combination of the 2 tests yielding an AUROC of 0.93 for the “extremely obese (BMI
35)” populations, highlighting
moderate fibrosis and 0.98 for severe fibrosis.144 This the improved diagnostic accuracy when the XLþ probe is
promising biomarker panel has been approved for commer- used in patients with BMI
30 kg/m2. A more recent study
cial use in Europe and was shown to be a useful adjunct in confirmed that the same LSM cutoffs can be used without
differentiating patients with indeterminate CPR scores,122 further adjustment for steatosis for both M and XL probes, as
1858 Cotter and Rinella Gastroenterology Vol. 158, No. 7

long these probes are used according to the appropriate with liver stiffness assessment, with further stepwise evalu-
BMI.153 Further results from a subset of the NASH CRN ation as outlined in Figure 2, which is intended to be used in
cohort showed that at a fixed sensitivity, a cutoff LSM of 6.5 the context of a Gastroenterology and Hepatology practice. It
kPa excluded advanced fibrosis with an NPV of 0.91, and a is challenging to propose a diagnostic algorithm that would
cutoff LSM of 12.1 kPa excluded cirrhosis with an NPV of apply to all clinical scenarios or practice settings including
0.99.154 An important caveat to consider when interpreting endocrinology and primary care. The proposed algorithm is
VCTE results is that, while liver stiffness typically represents deliberately conservative with a low threshold for LSM in
the extent of fibrosis, several other factors (eg, congestive order to not to miss any patients with advanced fibrosis given
hepatopathy, inflammation) can impact liver stiffness, as the implications of a missed diagnosis for patients. As LSM
illustrated by its modest PPV.155 modalities continue to become widely available, we hope that
MRE has a sensitivity of 0.86 (95% CI, 0.65–0.97), speci- this algorithm will be able to be applied more widely across
ficity of 0.91 (95% CI, 0.83–0.96), PPV of 0.68, and NPV of 0.97, all relevant specialties and primary care. AST has been
with an AUROC of 0.924 for diagnosing advanced fibrosis, incorporated given recent published evidence of its prog-
using a stiffness cutoff of 3.63 kPa, in severely obese patients nostication ability with more validating research anticipated
(mean BMI, 40.3 kg/m2) with biopsy-proven advanced shortly.141,160 While ELF has been omitted as we await evi-
fibrosis.156 Furthermore, the use of 3-dimensional MRE has dence of its performance at a general population level. It is
shown at 40 Hz and a stiffness cutoff of 2.43 kPa to have an important to consider that the incorporation of any
AUROC of 0.962 for diagnosing advanced fibrosis.157 MRE is biomarker into medical decision making, it is critical to
better for identifying varying degrees of fibrosis in patients consider the context of use when applying set cutoffs, as well
with NAFLD,158 and performs better than VCTE for identifying as the population from which such cutoffs were derived, to
fibrosis stage 2 or higher, but they both perform equally well most accurately apply on an individual patient level. Tailored
in identifying fibrosis stage 3 or higher with AUROCs for TE interventions for patients with NAFLD are discussed in more
and MRE of 0.88 and 0.89, respectively.151 detail in this Special Issue on NAFLD.
There are a number of factors to be considered when
using these imaging modalities. While VCTE is more acces-
sible and easier to use, its use is limited in patients with
Conclusions
The NAFLD epidemic continues unabated in parallel
severe obesity, ascites, or acute inflammation.159 MRE can
with the ongoing rise in obesity. The impact of the rise in
overcome many of these barriers, except for iron overload
patients with NAFLD and an increasing proportion with
and acute inflammation; however, MRE is limited by
advanced stage disease will be reflected in higher rates of
restricted availability at many centers, cost, required exper-
HCC, the need for liver transplantation, and liver-related
tise for interpretation, presence of metal implants, patient
death, which will heavily burden the health care system.
size, and history of claustrophobia.151 Importantly, neither of
Impactful change in these trajectories will require a
these modalities have shown significant promise in corre-
concerted effort to educate primary care providers on the
lating with treatment response in clinical trials, which may be
prevention and treatment of obesity and the implementa-
due to a number of factors, including the lack of granularity
tion of governmental initiatives to curb the obesity
in the identification of individual stages, the limitations of the
epidemic. Until then, we will be managing increasing
histologic reference standard, the absence of a highly effec-
numbers of patients diagnosed with NASH. The biggest
tive drug, or possibly that liver stiffness may not change in
unmet need in the field is an accurate biomarker that can
real time with histologic fibrosis improvement.
diagnose and stage NASH to supplant the need for liver
Given the magnitude of the NAFLD epidemic, a logical
biopsy. Such a biomarker, when it is available, will expand
algorithmic approach is essential in the initial evaluation of
the ability to identify patients at risk, monitor disease pro-
patients with NAFLD. The majority of patients have mild
gression, and response to therapeutic intervention.
disease, however, patients with severe disease, either NASH
Emerging data sets from phase 3 clinical trials will deter-
or advanced fibrosis need to be identified in order to mitigate
mine the performance characteristics of various biomarkers,
the associated complications. With the current lack of a
as well as provide invaluable insight into how we may begin
simple, widely available, highly accurate biomarker for NASH,
to phenotype patients with NASH. Once this is achieved,
a pragmatic risk-stratification approach is important to
treatment can be individualized to better target the pre-
disseminate “best practice” for the diagnosis of NASH, when
dominant driver of disease in a given patient and more
patients are evaluated by both gastroenterology and hep-
robustly improve NASH-related liver injury.
atology providers. A reasonable approach is to divide patients
into low-risk or high-risk for advanced disease based on their
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nonalcoholic fatty liver disease: a prospective study.

Received September 9, 2019. Accepted January 11, 2020.
Hepatology 2014;60:1920–1928.
159. Srinivasa Babu A, Wells ML, Teytelboym OM, et al. Correspondence
Elastography in chronic liver disease: modalities, tech- Address correspondence to: Mary Rinella, MD, Northwestern University
Feinberg School of Medicine, Chicago, IL 60611. e-mail: mary.rinella@nm.org.
niques, limitations, and future directions. Radiographics
2016;36:1987–2006. Conflicts of interest
This author discloses the following: M. Rinella consults for Intercept, Gilead,
160. Harrison SA, Alkhouri N, Davison BA, et al. Insulin Genfit, Enanta, Bristol-Myers Squibb, Novartis, NGM, Immuron, CymaBay,
sensitizer MSDC-0602K in non-alcoholic steatohepatitis: Merck, Viking, Gelesis, Metacrine, Allergan, Thetis, 3vBio, Madrigal,
A randomized, double-blind, placebo-controlled phase Boehringer Ingelheim, Terns, Genentech, and Fractyl, and has independent
research funding from Novartis. The remaining author discloses no conflicts.
IIb study. J Hepatol 2020;72:613–626.