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Page 2 of 18 Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90

INTRODUCTION
[1]
Fatty liver disease is the most common liver disease worldwide . The realization that liver steatosis may
progress to cirrhosis is credited to the Austrian pathologist Carl von Rokitansky in mid-nineteenth century.
[2]
Rokitansky also acknowledged that alcohol might not explain all types of fatty liver . The link with
obesity was well-established one century after, with the description of liver biopsies from 20 obese men by
[3]
Zelman . The designation “nonalcoholic steatohepatitis” (NASH) was first proposed by Ludwig 40 years
[5,6]
[4]
ago , and the more general “nonalcoholic fatty liver disease (NAFLD)” roughly 20 years ago . In 2020,
an international group of experts changed the designation to “metabolic dysfunction-associated fatty liver
disease” (MAFLD), focusing on the positive association with the metabolic syndrome (MS) rather than
the negative association with alcohol, while acknowledging the possible concomitance of metabolic and
alcohol-associated liver disease, in the same patient .
[7]
NAFLD goes hand-in-hand with obesity and its associated co-morbidities, particularly the MS and its
[8]
components . The prevalence of both NAFLD and obesity are rising. Data from the Fifth National Health
and Nutrition Examination Survey (NHANES), in the US, showed that in the late 1980s, the prevalence of
[9]
obesity was 22% and of NAFLD 20%, whereas currently, it is 39% and 32%, respectively . In fact, obesity
increases the risk for NAFLD by 10-fold .
[9]

Not all patients with NAFLD are overweight or obese. In those patients, liver steatosis has been called
[10]
“lean-NAFLD” Lean-NAFLD was first recognized in studies from Asia , but it has gained relevance in
[11]
Western populations as well .
New diagnostic criteria for MAFLD in lean persons were proposed , in which alcohol consumption is
[7]
not an exclusion criteria, but requires, evidence of hepatic steatosis and the presence of at least 2 of the
following metabolic abnormalities:
(1) Waist circumference (WC) ≥ 102 and 88 cm in Caucasian men and women, respectively (or ≥ 90 and 80 cm
in Asian men and women, respectively);
(2) Blood pressure ≥ 130/85 mmHg or specific drug treatment;
(3) Plasma triglycerides ≥ 150 mg/dL or specific drug treatment;
(4) Plasma high-density lipoprotein (HDL)-cholesterol < 40 mg/dL for men and < 50 mg/dL for women or
specific drug treatment;
(5) Prediabetes (i.e., fasting glucose levels 100-125 mg/dL, or 2-h post-load glucose levels 140-199 mg/dL
or HbA1c 5.7%-6.4%);
(6) Homeostasis model assessment (HOMA) of insulin resistance score ≥ 2.5;
(7) Plasma high-sensitivity C-reactive protein level > 2 mg/L.

Research on lean-NAFLD is flourishing; however, many gaps in knowledge still subside: Does lean-NAFLD
always associate with metabolic dysfunction and hence can be classified as MAFLD? Does lean-NAFLD
follow the same fate as obesity-associated MAFLD? How should lean-NAFLD patients be managed? This
article is a comprehensive review of the pathogenesis and clinical relevance of lean-NAFLD that aims to
help clinicians in their daily practice.

EPIDEMIOLOGY
Roughly 20% of patients with hepatic steatosis present with normal body mass index (BMI) and 40% are
not obese [12,13] . As such, lean-NAFLD represents a significant burden on the daily practice of hepatologists.

Epidemiological studies on lean-NAFLD present very heterogeneous data, which result from: (1) different
populations with different adipose tissue compartmentalization; (2) different definitions of lean (some