A physico-chemical explanation for the litho-protective effects of obeticholic acid in low phospholipid-associated...

Patients with low phospholipid-associated cholelithiasis may suffer from recurrent biliary symptoms and complications despite cholecystectomy and ursodeoxycholic acid therapy. Recently, beneficial clinical effects of treatment with the potent Farnesoid X receptor (i.e. bile salt receptor) agonist obeticholic acid in combination with ursodeoxycholic acid were reported in this patient group. In contrast, other studies reported more gallstone-related events and increased cholesterol saturation indices in gallbladder biles during obeticholic acid monotherapy. We here provide an in-depth review on solubilization and crystallization of cholesterol in bile, including all relevant physico-chemical aspects of cholesterol gallstone pathogenesis. We offer an explanation that reconciles seemingly contradictory data in previous publications. We propose that, due to the well-known inhibition of intra-hepatic bile salt synthesis from cholesterol by Farnesoid X receptor stimulation, biliary bile salt concentrations decrease during obeticholic acid therapy. As a result, biliary cholesterol solubilization shifts from mixed micelles into cholesterol-phospholipid vesicles, with inhibited cholesterol crystallization despite increased cholesterol saturation index (the latter takes only micellar cholesterol solubilization into account). We suggest that obeticholic acid has a lithoprotective effect, provided that increased bile salt hydrophobicity from obeticholic acid (a quite hydrophobic bile salt that is secreted into bile) is prevented by concomitant ursodeoxycholic acid therapy. We also suggest future directions for research into the role of obeticholic acid and other Farnesoid X receptor agonists to improve the prospects of low phospholipid-associated cholelithiasis patients and other gallstone patients with persisting biliary problems after cholecystectomy. In conclusion, obeticholic acid may enhance lithoprotective effects of ursodeoxycholic acid.