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Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90 Page 11 of 18

Hypobetalipoproteinemia is a common autosomal dominant disease that is characterized by defective
transport of triglycerides from the liver, causing intrahepatic accumulation. Mutations in ApoB and
microsomal triglyceride transfer protein can induce hepatic steatosis [155] . Hypobetalipoproteinemia
associates with hypotriglyceridemia, absence of cardiometabolic dysfunction/IR [156] , severe forms of
NAFLD, and even hepatocellular carcinoma [157] .

CLINICAL FEATURES AND PROGNOSIS
Patients with lean-NAFLD may present the whole spectrum of liver disease, from isolated steatosis to liver
cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Most epidemiological studies suggest that
liver histology might be less severe in lean patients as compared to overweight/obese patients with NAFLD/
MAFLD [12,117,118,158-160] . This finding, however, may be biased as clinicians might have a lower threshold to
perform liver biopsy in lean patients with hepatic steatosis, in whom it may be clinically relevant to exclude
other diseases. As such, liver biopsy may be performed in patients with milder forms of liver injury.
In a community-based Hong Kong cohort, non-obese NAFLD presented lower liver stiffness (4.6 kPa
vs. 5.6 kPa) despite similar intrahepatic triglycerides content. However, the percentage of advanced
[22]
fibrosis, defined by liver stiffness > 9.6 kPa, was similar . Indian studies also showed similar prevalence
of steatohepatitis and advanced fibrosis in lean and overweight/obese NAFLD patients [30,161] . An Austrian
study of 466 liver biopsies, on the contrary, found worse liver injury with more severe fibrosis and more
prevalent cirrhosis in lean patients [162] .

Central obesity/VAT expansion was the most transversal risk factor for advanced fibrosis in different
2
epidemiological studies on lean-NAFLD [118] . In fact, each 10-cm increase in VAT is associated with a
20% increased risk for significant fibrosis . Other risk factors seem to be T2DM, hypertriglyceridemia,
[63]
hypertension [118] , and higher levels of hemoglobin (suggesting mild iron overload and hence increased
oxidative stress) [163,164] .

Lean subjects with NAFLD have a 3-fold increased risk for incident T2DM, even in the absence of MS. The
risk for de novo T2DM seems similar to overweight/obese NAFLD patients [23,24,165] .

An analysis of the Third NHANES, showed that compared to healthy lean subjects, lean patients with
ultrasound-diagnosed NAFLD had a 50% increase in all-cause mortality and over a two-fold increase in
cardiovascular mortality [166] .

Three long-term follow-up studies evaluated the outcome of patients with biopsy-confirmed lean-
NAFLD [117,160] , one of them was presented as a poster [158] . A recent meta-analysis including the 2 published
studies suggested that lean-NAFLD patients had 28% and 78% lower odds of overall mortality and liver-
related mortality, respectively. However, the cardiovascular death rate was similar, compared to obese
[12]
patients with MAFLD . The Asian published study followed 307 NAFLD patients for up to 5 years and
did not find a difference in clinical events between lean and non-lean. The majority of the events were
cardiovascular. Only 6 deaths occurred, all of them in obese patients. Furthermore, relevant liver events
were limited to 2 cases of hepatocellular carcinoma and one of liver failure, again all obese patients [117] . The
European published study followed 646 patients for up to 20 years [160] . They found no difference on overall
mortality in lean versus non-lean NAFLD patients, but lean patients presented an increased risk for severe
liver disease compared to overweight and similar to risk compared to obese patients. Of note, 58% of lean
patients who developed severe liver disease had no or mild fibrosis (F0-2) at baseline [160] . The unpublished
study is an international cohort of 1,900 patients and found that even though lean-NAFLD patients had
milder histology at baseline, they had lower liver-transplant free survival than non-lean patients.