Obeticholic acid may increase the risk of gallstone formation in susceptible patients

JOURNAL OF HEPATOLOGY

卷:71

Article

Al-Dury, Samer¹  Wahlstrom, Annika¹  Panzitt, Katrin²  Thorell, Anders^3,4  Stahlman, Marcus¹  Trauner, Michael⁵  Fickert, Peter²  Backhed, Fredrik¹  Fandriks, Lars⁶  Wagner, Martin²  Marschall, Hanns-Ulrich¹ 

[1] Univ Gothenburg, Sahlgrenska Acad, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden

[2] Med Univ Graz, Dept Gastroenterol & Hepatol, Graz, Austria

[3] Ersta Hosp, Karolinska Inst, Dept Clin Sci, Danderyd Hosp, Stockholm, Sweden

[4] Ersta Hosp, Dept Surg, Stockholm, Sweden

[5] Med Univ Vienna, Div Gastroenterol & Hepatol, Vienna, Austria

[6] Univ Gothenburg, Sahlgrenska Acad, Dept Gastrosurg Res & Educ, Gothenburg, Sweden

关键词: Obeticholic acid;    Farnesoid X receptor;    FGF19;    Cholesterol saturation index;    Hydrophobicity index;    Gallstones;   

DOI  :  10.1016/j.jhep.2019.06.011

来源: Elsevier

【 摘 要 】

Background & Aims: The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has been developed for the treatment of liver diseases. We aimed to determine whether OCA treatment increases the risk of gallstone formation. Methods: Twenty patients awaiting laparoscopic cholecystectomy were randomized to treatment with OCA (25 mg/day) or placebo for 3 weeks until the day before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7 alpha-hydroxy-4-cholesten-3-one), and fibroblast growth factor 19 (FGF19) were measured before and after treatment. During surgery, biopsies from the liver and the whole bile-filled gallbladder were collected for analyses of gene expression, biliary lipids and FGF19. Results: In serum, OCA increased FGF19 (from 95.0 +/- 8.5 to 234.4 +/- 35.6 ng/L) and decreased C4 (from 31.4 +/- 22.8 to 2.8 +/- 4.0 nmol/L) and endogenous BAs (from 1,312.2 +/- 236.2 to 517.7 +/- 178.9 nmol/L; all p <0.05). At surgery, BAs in gallbladder bile were lower in patients that received OCA than in controls (OCA, 77.9 +/- 53.6 mmol/L; placebo, 196.4 +/- 99.3 mmol/L; p <0.01), resulting in a higher cholesterol saturation index (OCA, 2.8 +/- 1.1; placebo, 1.8 +/- 0.8; p <0.05). In addition, hydrophobic OCA conjugates accounted for 13.6 +/- 5.0% of gallbladder BAs after OCA treatment, resulting in a higher hydrophobicity index (OCA, 0.43 +/- 0.09; placebo, 0.34 +/- 0.07, p <0.05). Gallbladder FGF19 levels were 3-fold higher in OCA patients than in controls (OCA, 40.3 +/- 16.5 ng/L; placebo, 13.5 +/- 13.1 ng/ml; p <0.005). Gene expression analysis indicated that FGF19 mainly originated from the gallbladder epithelium. Conclusions: Our results show for the first time an enrichment of FGF19 in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF19 might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk of gallstone development. Lay summary: Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary levels of fibroblast growth factor 19, our findings suggest that pharmacological activation of the farnesoid X receptor increases the risk of gallstone formation. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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