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Page 10 of 18 Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90

as compared to healthy matched controls [147,148] . Interestingly, the risk of hepatic steatosis in non-obese
celiac disease patients was almost 6 times higher than in weight-matched controls [147] . It seems that the
more severe the malabsorption the higher the risk of hepatic steatosis. Indeed, patients with IBD that are
underweight have 4 times higher prevalence of hepatic steatosis (up to 85%) than the ones with normal
[41]
weight. Hepatomegaly, severity of steatosis, and elevation of aminotransferases are also more severe .

One important mechanistic link between bowel diseases and NAFLD is gut dysbiosis and increased
intestinal permeability that may promote steatosis and inflammation in the liver [149] . Furthermore,
malnutrition might lead to an impaired function of liver mitochondria and a loss of peroxisomes, which
are important to maintain the normal liver function [150] .

Lastly, intestinal failure/parenteral nutrition-associated fatty liver disease is a different entity, in which liver
histology is characterized by steatosis (often microsteatosis) in association with cholestasis. This form of
fatty liver disease is associated with rapid and frequent progression to steatohepatitis and end-stage liver
failure. Mechanistically, it associates with choline deficiency, which impairs lipid metabolism resulting in
[42]
reduced synthesis of phospholipids and reduced export of hepatic lipids .
Hepatic steatosis as a manifestation of other liver diseases
NAFLD is more frequent in overweight/obese subjects as compared to lean subjects. Hence, other liver
diseases that increase liver fat should be actively excluded in lean subjects who present with hepatic
steatosis. Chronic viral hepatitis (particularly hepatitis C virus genotype 3 [151] ) and Wilson’s disease can
present with liver steatosis. Celiac disease should be systematically excluded since the prevalence of celiac
disease in lean-NAFLD can reach up to 15% [144] . Cystic fibrosis should also be investigated, particularly in
young patients with history of recurrent infections.

Inborn errors of metabolism should be suspected in young patients with atypical facial appearance, low
stature, severe metabolic derangements (such as severe hyper- or hypolipidemia, hypoglycemia, and
metabolic acidosis), and other organs involvement, with particular attention for muscle abnormalities,
[44]
kidney disease (particularly tubulopathy), cardiovascular, and neurological symptoms .
Lysosomal acid lipase (LAL)-deficiency is a rare autosomal recessive lysosomal disease that can present
in the adulthood. It manifests by hepatosplenomegaly, dyslipidemia, and hepatic steatosis [152] . Its clinical
course is characterized by early onset atherosclerosis with severe cardiovascular disease, and rapidly
progressive liver disease. Indeed, liver cirrhosis and end-stage liver disease may develop within 3 years of
the clinical onset. Liver biopsy presents mixed macro- and microvesicular steatosis, and the presence of
birefringent cholesteryl ester crystals is pathognomonic. Diagnosis can be made with determination of
LAL activity in dry blood sample. Albeit a rare disease (estimated prevalence of 1:40000 to 1:300000), an
enzyme replacement therapy (sebelipase-alpha) is available. As such, it is worthwhile to investigate LAL-
deficiency in young lean-NAFLD patients with severe hypercholesterolemia (LDL higher than 160 mg/dL
or 130 mg/dL in patients taking lipid-lowering drugs; and HDL lower than 40 mg/dL in men and 50 mg/dL
in women), with cryptogenic cirrhosis, or with liver biopsy that shows microvesicular steatosis [152] . In fact,
one third of patients with microvesicular steatosis or cryptogenic cirrhosis may have LAL-deficiency [153] .

Glycogen storage diseases might be misdiagnosed as lean-NAFLD because glycogen and fat accumulation
in the liver may be undistinguishable by ultrasonography [154] . Some types of glycogen storage diseases may
present a milder phenotype that can manifest only in adulthood, particularly types I, III, VI and IX. Besides
symptoms related to hypoglycemia, these diseases may present with hepatosplenomegaly, that can progress
to liver cirrhosis, hyperlipidemia (particularly hypertriglyceridemia), recurrent infections, myopathy, and
[44]
kidney affection with tubular dysfunction and Fanconi-Bickel syndrome .