Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: A prospective observational study

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) may be associated with changes in bile acid (BA) metabolism. Hepatic BA production, measured by serum levels of the precursor 7α-hydroxy-4-cholesten-3-one (C4), is regulated by the farnesoid-X-receptor (FXR)-dependent ileal hormone fibroblast growth factor 19 (FGF19). Low FGF19 and high C4 are features of chronic BA diarrhea. Obeticholic acid, an FXR agonist, stimulates FGF19 and has shown therapeutic potential in both BA diarrhea and in NAFLD. We hypothesized there are associations of FGF19, C4 and BA diarrhea with NAFLD.

Methods and findings: 127 patients with known NAFLD were recruited prospectively. Clinical features, including metformin use, markers of NAFLD severity and BA synthesis were analyzed. The overall incidence of chronic diarrhea was 25%, with features of BA diarrhea in 12%. FGF19 negatively correlated with C4 (rs = -0.43, p = 0.001) and with alanine aminotransferase (rs = -0.22, p = 0.03), but not with either NAFLD fibrosis or Fibroscan scores. High C4 was associated with a higher NAFLD fibrosis score (p < 0.05), and with diarrhea (p = 0.001). The median NAFLD fibrosis score was higher in those with diarrhea (p = 0.002). Metformin use, in 44% overall, was particularly associated with diarrhea (in 36% vs 17%, p = 0.02), and a lower median FGF19 (74 vs 105 pg/mL, p < 0.05).

Conclusions: Increased hepatic BA production and diarrhea, but not low FGF19, were associated with increased NAFLD fibrosis score, indicating dysregulation of the FXR-FGF19 axis and suggesting hepatic FGF19 resistance. Metformin use was an important factor in a subgroup, lowering FGF19, and resulting in bile acid diarrhea.

Fig 1. NAFLD fibrosis scores in different groups, and FGF19 and C4 by liver biopsy findings.

Median (IQR) NAFLD fibrosis score by FGF19 (A), C4 (B), presence of chronic diarrhea (C) or bile acid diarrhea (D). Median (IQR) FGF19 (E) and C4 (F) by liver biopsy findings. NASH: Non-alcoholic steatohepatitis. *p<0.05 **P<0.01.

Fig 2. Effects of metformin use in NAFLD patients.

Odds ratios (95%CI) of chronic diarrhea (A) and dysregulated FGF19 axis (B) by subgroup including metformin use, diabetes (DM), body mass index (BMI) >25 and >30, female gender and ethnicity. Median (IQR) FGF19 (C), C4 (D), NAFLD fibrosis score (E) and FibroScan score (F) by metformin use. *p<0.05, **p<0.01, ****p<0.00001.