A MERICAN A SSOCIATION FOR

T HE STUDY OF LIVER D I S E ASES

COMMENTS FROM THE EDITORS | HEPATOLOGY, VOL. 67, NO. 6, 2018

Time to Step-Up the Fight

O
ver the past century, disease spectrums have billion people worldwide.(1) Most recently, prominent
undergone a world-wide epidemiological journals, including New England Journal of Medicine,
transition. Whereas many once-fatal infec- Nature, Nature Reviews, Nature Medicine, Gastroenter-
tious diseases (e.g., malaria, smallpox, and polio) have ology, and HEPATOLOGY, have published serial outlook
been eradicated in most countries benefiting from and perspective articles calling for more attention to
medical advances and new therapeutic developments, the management of NAFLD.
the incidence of metabolic disorders have sharply NAFLD occurs in individuals with more than 5%
increased with the remarkable prevalence of overnutri- hepatic steatosis (HS) that is not attributable to excess
tion, and this sharp increase is threatening modern life. alcohol consumption or to other causes such as viral
One apparent contributor to the epidemiological shift hepatitis or medications. Up to 30% of subjects
is the change of liver disease spectrum. The success of with simple steatosis (nonalcoholic fatty liver; NAFL)
vaccines or therapeutic approaches make it possible to progress to nonalcoholic steatohepatitis (NASH), as
effectively cure or control the progression of chronic reflected by inflammation, hepatocyte ballooning, and,
hepatitis B and C, which were the leading cause of cir- in its later stage, fibrosis.(1) All fatty liver disease was,
rhosis worldwide; there has, however, been a tremen- at one time, thought to be induced by excessive alcohol
dous increase in the prevalence of nonalcoholic fatty intake, and the term NASH was only coined in 1980
liver disease (NAFLD), which has become the leading by Ludwig et al. at the Mayo Clinic.(2) This report
cause of chronic liver disease afflicting more than 1 failed to attract sufficient attention at that time, and
the concept of “NASH as a benign condition” endured
until both clinical and epidemiological studies con-
firmed that NASH can be progressive and lead to
Abbreviations: HCC, hepatocellular carcinoma; HS, hepatic steato-
sis; HSCs, hepatic stellate cells; IR, insulin resistance; MetS, meta-
liver-related morbidity and mortality after 10 years
bolic syndrome; MetS-predisposed, predisposed to metabolic syndrome; later.(3) Up to 20% of NASH patients may further pro-
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic gress to cirrhosis, resulting in a markedly increased risk
steatohepatitis.
for hepatocellular carcinoma (HCC) and liver fail-
Received February 8, 2018; accepted February 8, 2018.
ure.(4) Notably, NASH is correlated with a 10-fold
Supported by grants from the National Science Fund for Distin-
guished Young Scholars (no. 81425005), the Key Project of the National increased risk of cirrhosis and HCC occurrence and
Natural Science Foundation (nos. 81330005 and 81630011), the contributes to a doubling of cardiovascular disease
National Science and Technology Support Project (nos. 2014BAI02B01 events. Moreover, NAFLD-related cirrhosis is cur-
and 2015BAI08B01), the National Key Research and Development
Program (no. 2013YQ030923-05), and the Key Collaborative Project rently the most rapidly increasing cause and second
of the National Natural Science Foundation (no. 91639304). among indications for liver transplantation of adults in
Copyright VC 2018 by the American Association for the Study of
United States.(1) Now, more than ever, NAFLD has
Liver Diseases.
View this article online at wileyonlinelibrary.com. become a significant clinical and economic burden,
DOI 10.1002/hep.29845 and cutting-edge research is urgently needed to dis-
Potential conflict of interest: Nothing to report. cover effective therapies for NAFLD.
The prevalence of NAFLD is still on the rise and,
ADDRESS CORRESPONDENCE AND more alarmingly, the burden of NAFLD may, in fact,
REPRINT REQUESTS TO: be much higher than is appreciated attributed to lack
Hongliang Li, M.D., Ph.D. of recognition of the condition in broader medical
Renmin Hospital of Wuhan University community, as well as challenges in diagnosing this
Zhang ZhiDong Streat,
Wuchang Wuhan, 430060, China
condition. Liver biopsy and blood aminotransferase
E-mail: [email protected] levels are the most commonly applied diagnostic pro-
Tel: 186-27-68759302 cedures for NAFLD, and biopsy-based pathology
remains the only reliable standard to diagnose NASH.

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HEPATOLOGY, Vol. 67, No. 6, 2018 ZHANG, SHE, AND LI

However, liver biopsy is invasive and has important subsequent transforming growth factor beta release from
limitations.(4) Clinicians also use transient elastography Kupffer cells, recruitment of macrophages, and their
(TE) to evaluate liver stiffness as a metric of fibrosis or interaction with hepatocytes are key driving events in
cirrhosis in advanced NASH. While it may be useful HSC activation and extracellular matrix deposition.(1)
in detecting cirrhosis, TE yields unreliable results in IR and lipid accumulation also contribute to fibrogene-
many NAFLD subjects. In recent years, the noninva- sis by incompletely characterized mechanisms. How-
sive ultrasound, magnetic resonance imaging and elas- ever, these understandings of fibrogenesis have been
tography, have emerged as preferred approaches, with challenged by the evidence that fibrosis may have
significantly greater accuracy. However, these imaging occurred at a very early stage of NAFLD without severe
technologies are not routinely available and are unable steatosis, inflammation, or IR. The complex pathogene-
to differentiate NAFL from NASH. The development sis of, and multiple mechanisms for, the progression of
of new noninvasive diagnostic approaches with reliable NAFLD makes it clinically important to clarify the fun-
correlations to disease progression will largely facilitate damental events that may be targeted for NAFLD
both timely lifestyle interventions in subjects with mild treatment. Indeed, systematic biological or “omics”
or moderate NAFLD, as well as the development of approaches should help to delineate rational determi-
new drugs to treat this common disease. nants of NAFLD and offer the hope of applying the
The lack of timely diagnosis of, and intervention precision medicine in clinical practice.
against, NAFLD enables its sustained progression. Application of animal models facilitates our under-
NAFLD is a dynamic disease process with a complex standing of the pathogenesis of NAFLD. An ideal
pathogenesis, where HS, insulin resistance (IR), and NAFLD animal model should closely mimic clinical
inflammation interconnect in a vicious cycle.(5) How- pathologies, including HS accompanied by inflamma-
ever, the fundamental molecular etiology of NAFLD tion, hepatocyte cell death, and fibrosis in the context
remains obscure and controversial. The traditional of IR and a metabolic syndrome (MetS)-like disorder.
“two-hit” hypothesis suggests that HS, resulting from These features should also be achieved within a reason-
an imbalance in lipid flux, is the original driver of sub- able time frame in an animal that is facile to breed and
sequent liver dysfunction, and that lipotoxicity contrib- maintain in a laboratory environment. Currently,
utes to the impaired responses to endogenous insulin, mouse models are most commonly used, with NAFLD
leading to inflammation, oxidative stress, and fibrosis. being achieved by excess nutrition, selective nutri-
IR has also been considered as a primary contributor to ent deficiency, or genetic modifications. The methio-
NAFLD, leading to excess lipid synthesis and glucose nine choline–deficient, conjugated linoleic acid, and
production, which, in turn, promote chronic inflam- choline-deficient L-AA diets have been used to induce
mation. However, this traditional concept of NAFLD liver fibrosis (LF). These diets induce NASH histo-
pathogenesis has been challenged by the concept that pathological features in relatively short periods of time
“multiple parallel hits” may promote NAFLD and its (i.e., several weeks), but they are complicated by weight
progression. This concept is largely based on the het- loss and improved insulin sensitivity. These models
erogeneity of subjects.(1) For instance, a minority of thus fail to faithfully recapitulate the most common
subjects can go on to develop HCC from NASH with- obesity-associated NAFLD in humans. In contrast to
out obvious cirrhosis whereas others may not progress dietary deficiency, the high-fat diet (HFD) and the
at all and instead remain stable without suffering any high-fat with high-cholesterol diet are more widely
liver sequelae. Moreover, different individuals may accepted because they induce obesity, HS, and IR.
respond differently to identical interventions. The However, mice with excess nutrition do not readily
occurrence and progression of NAFLD are also influ- develop hepatic fibrosis and the severity of established
enced by age, sex, genetic susceptibility, smoking and LF does not readily approach that which is observed in
dietary habits, which highlights the clinical importance the advanced stages of human NASH. Mice with defi-
of personalized and precision medicine. ciencies in leptin (ob/ob) or the leptin receptor (db/db)
Fibrosis is the most important predictor of the pro- spontaneously develop HS, but are resistant to fibrosis
gression of NAFLD to more-severe liver injury and because the activation of HSCs is dependent upon lep-
end-stage liver disease. The generation and activation tin. Overall, it is generally appreciated that existing
of myofibroblasts that are proposed to be differentiated murine NAFLD models inadequately represent the
from hepatic stellate cells (HSCs) appears to be a path- complex heterogeneity of NAFLD phenotypes that are
ogenic mechanism.(1) Inflammatory response and the observed in patients.

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ZHANG, SHE, AND LI HEPATOLOGY, June 2018

Another major limitation of murine NAFLD mod- around the world. The considerable risk of NAFLD
els for basic research and clinical translation is the in- progression to advanced liver disease, along with meta-
herent differences in genetic profiling, anatomical bolic impairments and cardiovascular disease, the un-
structure, organ size, and pathophysiological character- satisfactory and invasive diagnostic procedures, and the
istics between mice and human beings. Large animals lack of pharmacological approaches are important
with closer genetic relationships to humans may thus roadblocks for treating NAFLD. More than 1.7 billion
represent a more faithful model of human NAFLD. people now have NAFLD, and the progression from
Ossabaw miniature swine, which harbor a “thrifty NAFLD to cirrhosis or HCC occurs regularly. Yet, no
gene” that allows them to adapt to seasonal limitations drugs for the treatment of NAFLD are available in the
in food, develop liver dysfunction and a MetS with clinic. It is estimated that major pharmaceutical com-
close resemblance to human NASH in response to panies, including Merck, Novartis, Gilead, and Aller-
chronic food excess. Nonhuman primates may also gan, have invested more than $5 billion to develop new
naturally develop metabolic disorders. Monkeys predis- drugs for NAFLD treatment. The market for NASH
posed to MetS (MetS-predisposed) have recently been drugs has been predicted to rise to over $30 billion a
used as a NASH model. These MetS-predisposed year by 2025. The NAFLD-derived annual health care
monkeys exhibit higher blood pressure and body resource and economic burdens are more enormous—
weight than healthy controls. Importantly, moderate $103 billion in the United States alone.(4) These con-
steatosis and inflammation developed in MetS- siderations establish reducing the incidence of
predisposed monkeys fed a normal chow diet, and they NAFLD as well as early diagnosis and intervention as
also exhibit clear increases in the hepatic expression of important priorities.
profibrotic genes.(5-8) When fed an HFD or even a NAFLD now commands widespread attention from
simple high-carbohydrate diet, MetS-predisposed researchers and industry, but its alarming increase in
monkeys rapidly become obese and insulin resistant prevalence demands still more attention from clini-
and develop hepatic inflammation with fibrosis.(5,9,10) cians, society, and governments. It is indeed time to
The similarities between the pathophysiology, anat- step-up the fight against NAFLD.
omy, and histopathological disease spectrum in nonhu-
man primate and humans suggest that the MetS-
predisposed monkey is more representatively faithful to Xiao-Jing Zhang, Ph.D.,1-3
the clinical situation than murine models, and thus Zhi-Gang She, M.D., Ph.D.,1-3
enable much more relevant studies of molecular mech- Hongliang Li, M.D., Ph.D.1-3
anisms of NASH. However, large animal models have 1
Department of Cardiology
not been extensively applied in NAFLD research Renmin Hospital of Wuhan University
because of challenges in breeding and maintaining Wuhan, China
these animals in the laboratory setting. Moreover, these 2
Institute of Model Animal of Wuhan University
models do not lend themselves to the sophisticated Wuhan, China
genetic approaches that can be applied to rodents. 3
Basic Medical School
Clearly, more work is required to develop animal mod- Wuhan University
els that will facilitate in-depth insights into NAFLD Wuhan, China
pathologies and identify molecular targets for therapy.
Lifestyle interventions consisting of diet, exercise,
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Author names in bold designate shared co-first authorship.

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