NEwS & VIEwS

LIVER There remain many challenges for the

MAFLD field, as outlined in these two excel-

From NAFLD to MAFLD: when

lent papers. One of these issues is MAFLD
heterogeneity as different disease subtypes
might exist and both natural history and

pathophysiology succeeds interindividual disease courses are highly

variable. Another challenge is the topic of
metabolically healthy obesity (MHO), which
Herbert Tilg   and Maria Effenberger affects potentially up to 45% of people with
obesity8. It is debated whether MHO is really
Two new position papers convincingly propose that nonalcoholic fatty liver a benign disease as it is associated with neg-
disease needs a new name — metabolic associated fatty liver disease ative cardiovascular outcomes and causes
(MAFLD). A new name for this disease affecting nearly one billion people MAFLD-related fibrosis8. One of the ques-
tions remaining is what does metabolic health
globally is overdue, as knowledge gained from the past decades has mean and how could it be defined. Could it
assuringly demonstrated that MAFLD is a purely metabolic disorder. be sufficient in the future to define metabolic
health by excluding hepatic steatosis, as liver
Refers to Eslam, M. et al. A new definition for metabolic associated fatty liver disease: an international expert con-
sensus statement. J. Hepatol. https://doi.org/10.1016/j.jhep.2020.03.039 (2020) | Eslam, M., Sanyal, A. J., George, J. & fat accumulation is probably one of the most
International Consensus Panel MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver sensitive parameters indicating metabolic dys­
disease. Gastroenterology, https://doi.org/10.1053/j.gastro.2019.11.312 (2020). function? Importantly, besides metabolic
dys­func­tion, many other diseases result in
In the early 1980s, a disease was named into the game when they described that hepatic steatosis, alcohol and drug-induced
nonalco­holic fatty liver disease (NAFLD) NAFLD is associated with insulin resistance liver injury reflecting the most common exam-
or nonalcoholic steatohepatitis (NASH) when in almost all 46 tested patients (including lean ples. What hepatologists now have to learn and
clinicians and pathologists observed that individuals) using homeostasis model assess- become familiar with are the criteria defining
many histopathological features in this dis- ment (HOMA)5. In a follow-up study, they metabolic risk factors7: this list includes waist
ease were reminiscent of alcohol-associated reported that patients with NAFLD demon- circumference, blood pressure, plasma triglyc-
liver disease (ALD)1,2. But the only features strate hepatic insulin resistance, claiming for erides, HDL cholesterol, prediabetes, HOMA
NAFLD and ALD had in common, even in the first time that NAFLD should be consid- score and plasma high-sensitive C-reactive
the early days, were probably certain histo- ered a feature of the metabolic syndrome6. protein levels (Fig. 1). These two reports7,8 have
logical features such as steatosis, steatohep- These investigators were perfectly right, but important implications for the whole field of
atitis, fibrosis and Mallory bodies as clinical ‘NAFLD’ as a name continued for another hepatology as this new view into this disease
and laboratory aspects differed substantially. two decades. will have a major effect on clinical trial design
First descriptions of a fatty liver in associa- NAFLD reflects a progressive condition in the future. This new definition might also
tion with type 2 diabetes mellitus (T2DM) in many instances and its prevalence paral- promote the establishment of MAFLD clin-
occurred at least 50 years ago in the 1970s. lels trends in obesity and diabetes. Based on ics run by hepatologists and diabetologists
Beringer and Thaler described liver histo­ the initial observations of Marchesini et al., together to improve patient care. As discussed
pathology in 465 patients with T2DM claim- numerous studies from the past 20 years have by Eslam et al.7,8, an update on the nomencla-
ing that a fatty liver appeared in 75% of clearly illustrated that NAFLD is a metabolic ture can only be a first step and should build
individuals with T2DM and liver cirrhosis in disease representing the hepatic manifesta- the basis for new research directions to follow.
2.6% versus 0.84% in the general popu­lation3. tion of a systemic metabolic disorder. Based What could be the next steps? If we accept
When Ludwig and colleagues first used the on insights gained from the past two decades, ‘MAFLD’ as standard terminology, we also
term NASH, they demonstrated that most two new position papers have taken the initi- have to accept what has been learned already
of their 20 studied patients were moderately ative to propose a new name for NAFLD — in metabolic disorders, and one of the most
obese and several were confirmed to have that is, metabolic associated fatty liver disease important clinical concepts is the associa-
T2DM1. These early descriptions of associ- (MAFLD)7,8. In these two articles, a highly tion of metabolic disorders with low-grade
ations of NAFLD with T2DM were ignored distinguished group of experts convincingly inflammation. Obesity-related disorders
in the following years and the term ‘nonalco- described why a change of name is overdue. such as metabolic syndrome and T2DM are
holic’ became established. Researchers were Indeed, their new definition clearly establishes characterized in many instances by low-grade
struggling as to how inflammation in NASH this disease as a metabolic disorder7 as crite- systemic inflammation including adipose
might evolve until Day and James proposed ria now require evidence of hepatic steatosis tissue inflammation9. Interestingly, Eslam
a two-hits model, suggesting that oxidative accompanied by one of three features: that is, and colleagues have included high-sensitive
stress irrespective of origin is a driver of either overweight or obesity, T2DM, or lean C-reactive protein levels as one of the met-
liver inflammation4. The landmark paper by or normal weight with evidence of metabolic abolic risk factors as it is well established
Marchesini et al. brought insulin resistance dysregulation (for definition see Fig. 1). that this biomarker is relevant in metabolic

Nature Reviews | Gastroenterology & Hepatology

News & Views

disorders in general7. Inflammation has been
somewhat ignored by the liver community in
MAFLD as histology outcome studies focused
on correlation of disease with fibrosis10. But
this correlation could simply be because liver
biopsy is a snapshot taken at a single moment
in a long-lasting chronic disease. The nature of
inflammation in MAFLD might be chronic–
relapsing or intermittent as in many other
chronic inflammatory and liver disorders
and could simply be missed by liver biopsy. In
gastroenterology, this concept is familiar; for
example, in Crohn’s disease, chronic–relapsing
inflammation is typical and long-term seque-
lae include development of fibrosis, strictures
and stenosis. In many diseases inside and out-
side the gastrointestinal tract there is no doubt
Obesity,
ethnicity, sex,
age, genetic
predisposition
Prediabetes
that inflammation drives fibrosis. Why should
it be different in MAFLD? Such a concept is
also supported by the fact that patients with
MAFLD can fluctuate between steatosis and
steatohepatitis over rather short timeframes,
and steatohepatitis might slowly or rapidly
progress towards fibrosis and fibrosis can even
spontaneously regress, all reflecting a highly
dynamic disease process. MAFLD exerts a tre-
mendous plasticity regarding disease course,
and classification of patients as with or without
NASH has not proven useful and needs to be
reconsidered. New concepts of inflammation
are important in MAFLD as treatment strate-
gies might need anti-inflammatory approaches
to target this disease successfully in the future.
To achieve a better understanding of the
HOMA
natural disease course and recognize timely
requirement for therapy, there exists an urgent
need for noninvasive techniques either in the
sense of biomarkers or imaging to enable
the detection of liver inflammation and fibro-
sis over the disease course. Development of
such techniques should be a high priority in
‘metabolic’ medicine.
To conclude, renaming NAFLD as MAFLD
brings this disease back to reality and closer not
only to its pathophysiology but to T2DM. This
step means that diabetologists and hepatolo-
gists have to intensify their collaborative actions
as only a very close interaction of those two
specialities with support from epidemiologists
and basic scientists will enable progress and
answer the burning issues of this ‘pandemic’
disease. From now on let us call it MAFLD,
though we might miss “MASH” in the future!
Herbert Tilg    ✉ and Maria Effenberger
Department of Internal Medicine I, Gastroenterology,
Hepatology, Endocrinology & Metabolism, Medical
University Innsbruck, Innsbruck, Austria.
✉e-mail: herbert.tilg@i-med.ac.at

https://doi.org/10.1038/s41575-020-0316-6

Type 2 diabetes 1. Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J.

mellitus Nonalcoholic steatohepatitis: Mayo Clinic experiences
with a hitherto unnamed disease. Mayo Clin. Proc. 55,
434–438 (1980).
2. Fleming, K. A. et al. Mallory bodies in alcoholic and
non-alcoholic liver disease contain a common antigenic
determinant. Gut 22, 341–344 (1981).
HDL 3. Beringer, A. & Thaler, H. Relationships between
Inflammation cholesterol diabetes mellitus and fatty liver [German]. Dtsch.
Med. Wochenschr. 95, 836–838 (1970).
4. Day, C. P. & James, O. F. Steatohepatitis: a tale of two
MAFLD “hits”? Gastroenterology 114, 842–845 (1998).
Triglycerides 5. Marchesini, G. et al. Association of nonalcoholic fatty
liver disease with insulin resistance. Am. J. Med. 107,
450–455 (1999).
Gut 6. Marchesini, G. et al. Nonalcoholic fatty liver disease:
Blood a feature of the metabolic syndrome. Diabetes 50,
pressure microbiota 1844–1850 (2001).
7. Eslam, M. et al. A new definition for metabolic
associated fatty liver disease: an international expert
consensus statement. J. Hepatol. https://doi.org/
10.1016/j.jhep.2020.03.039 (2020).
8. Eslam, M., Sanyal, A. J. & George, J. International
Consensus Panel MAFLD: A consensus-driven
Fig. 1 | MaFlD: an ‘old’ new disease. Metabolic associated fatty liver disease (MAFLD) is present proposed nomenclature for metabolic associated
fatty liver disease. Gastroenterology https://doi.org/
if hepatic steatosis is accompanied by either obesity or overweight (BMI >25 kg/m2 in white and 10.1053/j.gastro.2019.11.312 (2020).
>23 kg/m2 in Asian individuals), type 2 diabetes mellitus or evidence of metabolic dysregulation. 9. Tilg, H., Zmora, N., Adolph, T. E. & Elinav, E. The
At least two metabolic risk factors should be present for definition of metabolic dysregulation: intestinal microbiota fuelling metabolic inflammation.
Nat. Rev. Immunol. 20, 40–54 (2020).
waist circumference ≥102/88 cm in white men and women or ≥90/80 cm in Asian men and women; 10. Angulo, P. et al. Liver fibrosis, but no other histologic
prediabetes; inflammation with elevated high-sensitive serum C-reactive protein level; elevated features, is associated with long-term outcomes of
blood pressure or specific drug treatment; decreased HDL-cholesterol levels; increased plasma patients with nonalcoholic fatty liver dmetaisease.
Gastroenterology 149, 389–397 (2015).
triglycerides levels; and homeostasis model assessment (HOMA)-insulin resistance score ≥2.5.
Heterogenous factors lead to MAFLD, including ethnicity , sex, dietary habits, genetic predisposition, Competing interests
age, gut microbiota and metabolic status. The authors declare no competing interests.

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