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‘Lean NAFLD’ displays altered pathophysiology, gut microbiome

Researchers found that patients with “lean” nonalcoholic fatty liver disease had altered gut microbiota profiles along with higher bile acid and fibroblast growth factor 19, or FGF19, levels compared with patients with overweight or obesity.

Fei Chen, MD, from the Westmead Hospital and University of Sydney, Australia, and colleagues wrote that although insulin resistance is the core of both lean NAFLD and NAFLD associated with obesity, accumulating evidence suggests that lean NAFLD may have a distinct pathophysiology.

“The pathogenesis and mechanisms for their favorable metabolic profile compared to obese NAFLD are puzzling and poorly understood, and therapeutic options for lean NAFLD remain undefined,” they wrote. “We provide a testable hypothesis for the pathophysiological distinction between lean and non-lean NAFLD that can be examined in other cohorts.”

Among the 538 patients recruited with NAFLD, the researchers considered 99 patients to be “lean,” with BMI less than 25 kg/m². The patients with lean NAFLD had higher total, primary and secondary bile acid levels, which was significant for secondary levels (P = .01).

Patients with lean NAFLD also had significantly higher FGF19 levels compared with non-lean NAFLD patients (P = .028), which was more profound in those with mild fibrosis, including fibrosis stage 0 or stage 1 (P = .005)

Regarding the gut microbiome, the researchers observed differences at the genus level. Patients with lean NAFLD had enrichments in Erysipelotrichaceae UCG-003 and several bacterial genera within the Clostridiales order, including Ruminococcus, Clostridium sensu stricto 1, Romboutsia, and Ruminococcaceae UCG-008, whereas patients with NAFLD and obesity had in Ruminiclostridium and Streptococcus (P < .05).

These changes remained significant for Ruminococcaceae UCG-008 when corrected for multiple comparison testing (false discovery rate, P = .01).

“We suggest that the onset of disease occurs at a lower BMI set point (with lower measures of insulin resistance and dyslipidemia) and is shaped by the genetics background and early alterations in the [bile acid] and gut microbiota profile,” Chen and colleagues wrote.

The researchers hypothesized that such changes may reflect altered dietary composition and cholesterol metabolism or differences in mucosal immunology.

“This hypothesis does not negate the possibility that there are overweight/obese NAFLD patients with a similar pattern of compensatory mechanisms but suggests that lean patients have a preponderance of a gut-mediated phenotype,” they wrote. “Our hypothesis would suggest that these individuals will have more severe and progressive liver disease, as it has been suggested before, but this hypothesis needs further confirmation.” – by Talitha Bennett

Disclosures: The authors report no relevant financial disclosures.