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

Artikel i vetenskaplig tidskrift
Författare Samer Al-Dury
Annika Wahlström
Katrin Panzitt
Anders Thorell
Marcus Ståhlman
Michael Trauner
Peter Fickert
Fredrik Bäckhed
Lars Fändriks
Martin Wagner
Hanns-Ulrich Marschall
Publicerad i Journal of hepatology
Volym 71
Nummer/häfte 5
Sidor 986-991
ISSN 1600-0641
Publiceringsår 2019
Publicerad vid Wallenberglaboratoriet
Institutionen för kliniska vetenskaper, Avdelningen för gastrokirurgisk forskning och utbildning
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 986-991
Språk en
Länkar dx.doi.org/10.1016/j.jhep.2019.06.0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Gastroenterologi

Sammanfattning

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 three weeks before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7α-hydroxy-cholest-4-ene-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 1312.2±236.2 to 517.7±178.9 nmol/L; all p<0.05). At surgery, BAs in gallbladder bile were lower in OCA patients than 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 was three-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 a mainly gallbladder epithelial origin of FGF19.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 for gallstone development.Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary FGF19, our findings suggest that pharmacological FXR activation increases the risk of gallstone formation.

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