Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Abstract

Background and Aims Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. Approach and Results We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin‐like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy‐proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium‐dependent BA transporter inhibitor (SC‐435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. Conclusions Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.

Letter to the Editor: Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease

“…[13] In MAFLD patients, particularly those with obesity, increased inflammatory activity in the liver and visceral fat is independently correlated with increased levels of IL-6, [14] which might have an additive/synergistic role in promoting greater severity of COVID-19. It is conceivable that the secretion of hepatokines for example, reduced adiponectin or the altered secretion of inflammatory lipid mediators in obese patients with MAFLD, [15] may also contribute to the current observations. While this is the first multi-center study to investigate obesity as a possible risk factor for severe COVID-19 illness in patients with MAFLD, some limitations should be recognized.…”

Prevalence and Risk Factors of Metabolic Associated Fatty Liver Disease in Xinxiang, China

“…Previous studies have shown that fecal and blood microbiota profiles showed different patterns between subjects with obese and lean MAFLD [42]. Increased visceral obesity (as opposed to general obesity), characteristic fat intake [43], and genetic risk factors [44], including congenital defects of metabolism, might be associated with lean MAFLD [9]. Further studies are needed to prove mechanisms of lean MAFLD.…”

Hepatic Steatosis in Lean Patients: Risk Factors and Impact on Mortality

“…These data further suggest that the gut-liver axis is of major pathophysiological importance in NAFLD and NASH. Similarly, a recent multicenter study addressed the interplay between bile acids, fibrosis, and gut microbiota composition and demonstrated that bile acid levels, which can alter the microbiome, were significantly higher in patients with NAFLD and additional fibrosis than in patients without fibrosis [22]. These data underline that fibrosis severity has to be considered in NAFLD/NASH studies as a major confounding factor.…”