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Al-Dury, S; Wahlström, A; Panzitt, K; Thorell, A; Ståhlman, M; Trauner, M; Fickert, P; Bäckhed, F; Fändriks, L; Wagner, M; Marschall, HU.
Obeticholic acid may increase the risk of gallstone formation in susceptible patients.
J Hepatol. 2019; 71(5):986-991 Doi: 10.1016/j.jhep.2019.06.011
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Co-Autor*innen der Med Uni Graz
Fickert Peter
Panzitt Katrin
Trauner Michael
Wagner Martin
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Abstract:
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. 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 (7α-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. 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. 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. 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. Clinical trial number: NCT01625026. Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Adult -
Bile Acids and Salts - blood
Bile Acids and Salts - genetics
Biopsy -
Carrier Proteins - genetics
Chenodeoxycholic Acid - adverse effects
Chenodeoxycholic Acid - analogs & derivatives
Chenodeoxycholic Acid - pharmacology
Cholestenones - blood
Double-Blind Method -
Female -
Fibroblast Growth Factors - blood
Gallbladder - pathology
Gallbladder - surgery
Gallstones - blood
Gallstones - chemically induced
Gallstones - surgery
Gene Expression -
Humans -
Liver - pathology
Liver Diseases - blood
Liver Diseases - drug therapy
Male -
Middle Aged -
Receptors, Cytoplasmic and Nuclear - agonists
Treatment Outcome -

Find related publications in this database (Keywords)
Obeticholic acid
Farnesoid X receptor
FGF19
Cholesterol saturation index
Hydrophobicity index
Gallstones
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