Division of Digestive Diseases, Imperial College London, London, United Kingdom.
Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom.
PLoS One. 2019 Jan 25;14(1):e0211348. doi: 10.1371/journal.pone.0211348. eCollection 2019.
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.
非酒精性脂肪性肝病（NAFLD）可能与胆汁酸（BA）代谢的变化有关。通过血清 7α-羟基-4-胆甾烯-3-酮（C4）前体水平测量的肝 BA 产生受法尼醇 X 受体（FXR）依赖性回肠激素成纤维细胞生长因子 19（FGF19）调节。低 FGF19 和高 C4 是慢性 BA 腹泻的特征。奥贝胆酸是一种 FXR 激动剂，可刺激 FGF19，在 BA 腹泻和 NAFLD 中均显示出治疗潜力。我们假设 FGF19、C4 和 BA 腹泻与 NAFLD 有关。
前瞻性招募了 127 名已知患有 NAFLD 的患者。分析了临床特征，包括二甲双胍的使用、NAFLD 严重程度和 BA 合成的标志物。慢性腹泻的总发生率为 25%，其中 BA 腹泻的特征为 12%。FGF19 与 C4 呈负相关（rs=-0.43，p=0.001）和丙氨酸氨基转移酶（rs=-0.22，p=0.03），但与 NAFLD 纤维化或 Fibroscan 评分无关。高 C4 与较高的 NAFLD 纤维化评分相关（p<0.05），与腹泻相关（p=0.001）。腹泻患者的中位 NAFLD 纤维化评分较高（p=0.002）。二甲双胍的使用（总体占 44%）尤其与腹泻相关（分别为 36%和 17%，p=0.02），且 FGF19 中位数较低（74 与 105 pg/mL，p<0.05）。
肝 BA 产生增加和腹泻，但不是低 FGF19，与增加的 NAFLD 纤维化评分相关，表明 FXR-FGF19 轴失调，并提示肝 FGF19 抵抗。二甲双胍的使用是一个重要因素，降低了 FGF19，并导致 BA 腹泻。
