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Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90 Page 3 of 18

studies consider normal weight, others non-obese, while studies in rural populations in Asia include a high
[14]
proportion of patients underweight ); and (3) different tools to diagnose liver steatosis. Most studies rely
on ultrasound to diagnose NAFLD, which has very low sensitivity for mild steatosis; others take advantage
of non-invasive scores such as fatty liver index, some quantify liver triglycerides content through magnetic
resonance spectroscopy, and several rely on liver biopsies. Those different diagnostic tools have known
[15]
variations in accuracies for detecting liver steatosis .
Notably, epidemiological studies were performed before the new designation of MAFLD; as such, alcohol
intake was excluded, and patients may not fulfill the diagnostic criteria of MAFLD. Because of this, the
designation “lean NAFLD” is used in this review.

The definition of normal weight using BMI varies depending on the racial background of the individual.
2
Caucasians are considered as having normal weight when BMI is 18.5-25 kg/m with overweight being 25-
2
30 kg/m and obese being > 30 kg/m [2,16] . However, lower BMI cutoffs are applied to Asians because a specific
[17]
BMI reflects a higher percentage of body fat and higher health risk compared to Caucasians . Accordingly,
2
2
in Asians, normal weight is considered when BMI is < 23 kg/m , with overweight being 23-25 kg/m
and obese being > 25 kg/m [2,16] .
Although studies have shown a wide range of prevalence of NAFLD in lean individuals (from as low as
5% to as high as 26%), two recent meta-analysis showed that roughly 10% of lean adults have NAFLD.
The prevalence rises to 16% in non-obese adults [12,18] . Interestingly, the prevalence of lean-NAFLD
gradually increased from 5.6% (95%CI: 3.6-8.8) in studies before 2000 to 12.6% (95%CI: 8.8-17.9) in
[18]
studies after 2011 . The prevalence of NAFLD is around 4 times lower in the lean population compared
to the overweight/obese population [11,19-24] . Asians seem to have a higher prevalence of lean-NAFLD,
and African Americans lower [12,25] , which might be explained, at least to some extent, with different
compartmentalization of fat depots and intrinsic differences in adipose tissue structure/function in
[26]
individuals with different racial backgrounds .

Regarding the association with metabolic features, lean patients with NAFLD seem to have an intermediate
phenotype between healthy subjects and obese patients with MAFLD [12,18,27,28] , regarding glucose intolerance
and insulin resistance (IR), type-2 diabetes mellitus (T2DM), hypertension, and hyperuricemia. The
lipid profile, however, appears to be similar between lean and obese patients with NAFLD, with similar
levels of total cholesterol and triglycerides, although lean patients tend to present higher levels of HDL
cholesterol [20,27,29,30] .

On the other hand, a risk factor for NAFLD in lean subjects seems to be - besides older age - the presence
[31]
of MS components (which seems to have an even stronger impact than in obese) . In particular,
hypertriglyceridemia associates with a 2-fold increased risk for hepatic steatosis in lean [10,27,32] . Furthermore,
baseline hypertriglyceridemia or T2DM were predictors of incident lean-NAFLD in longitudinal
studies [33-35] .

Even though they are in the normal weight range, history of weight gain over 10 kg since early adulthood
[21]
increased the risk for NAFLD 2.5-fold in lean individuals . Furthermore, patients with lean-NAFLD tend
[30]
to present higher BMI as compared to lean subjects without NAFLD . Interestingly, a Japanese study
2
showed a linear increase on the prevalence of NAFLD with increasing BMI, starting at 18 kg/m until
28 kg/m [2,21,36] . Similarly, two longitudinal community-based studies in non-obese subjects, from South
Korea and Sri-Lanka, showed that body weight changes were indicators for the development or regression
of ultrasound-defined NAFLD [33,35] . Apparently, the lower the body fat (excluding underweight), the lower
is the susceptibility for developing NAFLD.