Page 988 - Read Online

Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90 Page 9 of 18

modulation and anti-inflammatory properties that have already been implicated in the pathogenesis of
NAFLD [134] .

A Japanese study also found that lean-NAFLD patients more frequently carry an HLA haplotype
(HLA-B*54:01) that modulates gut microbiota towards an impoverishment of bacteria potentially protective
against progression to cirrhosis, such as the phylum Vernucomicrobia and the genus Akkermansia [134,135] .

Another way gut dysbiosis can promote hepatic steatosis is through the enrichment of bacteria, such as
Weissella confusa that can produce ethanol through the fermentation of glucose and fructose [136,137] . A first
pass effect of ethanol in the liver would abrogate systemic metabolic effects in patients harboring ethanol-
producing microorganisms in the gut.

Studies regarding the use of probiotics on NAFLD do not specifically evaluate lean patients, are small sized,
use different combinations of probiotic agents, and do not evaluate hard outcomes such as liver biopsy.
However, a recent meta-analysis suggests a benefit of probiotics in the treatment of patients with NAFLD,
inducing an improvement in liver enzymes [138] .

Lifestyle
A South Korean study evaluated a cohort of patients from the KNHANES, and found a high carbohydrate
energy ratio and lower than moderate-level physical activity to be predictors of lean-NAFLD [139] .
Carbohydrates are known to downregulate PNPLA3, which may partially explain its steatogenic
effect [111,112] . A caveat of this finding is that the type of carbohydrates consumed in Asia, where rice is the
major carbohydrate, is likely not the same as in Western populations, hence it is difficult to extrapolate
these findings to non-Asians [139] . High fructose intake has also been associated with lean-NAFLD [140] . Lean
patients that develop NAFLD consume more than double added sugar than lean subjects without NAFLD.
Of note, most of the added sugar, in lean-NAFLD patients, comes from soft drinks and juices. Indeed, the
prevalence of excessive soft drink consumers is 4 times as higher in lean-NAFLD patients than healthy lean
subjects [140] .

Lean-NAFLD patients tend to eat high-cholesterol diets. Both European and Asian cohorts showed
lean-NAFLD patients to consume more cholesterol and less polyunsaturated fatty acids, as compared to
healthy lean subjects, even without an excessive caloric intake [68,141] . Cholesterol has steatogenic effects,
since it promotes fatty acids synthesis and de novo lipogenesis through activation of SREBP-1c and liver
[68]
X-receptor-a .

Even though lean-NAFLD patients by definition have normal weight, they tend to adopt an intermediate
obesogenic lifestyle. In fact, lean subjects that gain weight, over 10 kg, in their adulthood have a 2.5 fold
[21]
increased risk of developing NAFLD, even when maintaining a normal BMI . Probably in patients that
[52]
develop NAFLD, those 10 extra kilograms surpass their “personal fat threshold” inducing adiposopathy
and its associated comorbidities.

Malabsorption
NAFLD is the most frequent hepatic manifestation of small bowel diseases with malabsorption such as
inflammatory bowel disease (IBD) and celiac disease. We must consider these diagnoses in patients with
lean-NAFLD, since 3% of patients with NAFLD have underlying celiac disease, which is 3 times the overall
prevalence of celiac disease [142-145] . If we consider lean-NAFLD, the prevalence of celiac disease raises to up
to 15% [144] .

Overall, the reported prevalence of hepatic steatosis in patients with IBD is roughly 40% [146] . Also celiac
disease patients, even when in a gluten-free diet, present 3 times higher prevalence of hepatic steatosis