Date Published: January 25, 2019
Publisher: Public Library of Science
Author(s): Richard N. Appleby, Iman Moghul, Shahid Khan, Michael Yee, Pinelope Manousou, Tracy Dew Neal, Julian R. F. Walters, Pavel Strnad.
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.
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). 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.
Non-alcoholic fatty liver disease (NAFLD) affects 30–40% of the Western population. It comprises a spectrum from benign hepatic steatosis, with 30% progressing to inflammatory non-alcoholic steatohepatitis (NASH), and 3% progressing to fibrosis and cirrhosis. Insulin resistance, dyslipidemia and obesity are important risk factors for the development of NAFLD and are part of the metabolic syndrome. Many NAFLD patients are on treatment for these conditions, including anti-diabetics such as metformin, statins or other medications.
A total of 127 patients were enrolled into the study. Blood tests for FGF19 and C4 were obtained on 96 patients as 31 patients did not provide a fasting sample. Fibroscan was performed on 78 patients, and 50 had a liver biopsy. Diarrhea was reported in 32 subjects (25%), 25 of whom had blood tests for FGF19 and C4, 25 had Fibroscan and 18 had liver biopsy.
In this prospective study of patients with NAFLD, we found a higher than expected incidence of chronic diarrhea, associated with increased bile acid production, as shown by raised C4 production. Lower FGF19 alone was not associated with NALFD severity in this cohort, but C4 was significantly associated with higher NAFLD fibrosis score, suggesting that dysregulation of the FGF19 axis is involved in NAFLD. We did not find that this effect was significantly reflected in more advanced disease, as shown by Fibroscan or liver biopsy results. However, metformin use in almost half of this cohort, and the presence of diabetes, were important contributing factors, and were associated with the presence of diarrhea and with more advanced disease.