Liver disease associated with canalicular transport defects: Current and future therapies

Bile formation at the canalicular membrane is a delicate process. This is illustrated by inherited liver diseases due to mutations in ATP8B1, ABCB11, ABCB4, ABCC2 and ABCG5/8, all encoding hepatocanalicular transporters. Effective treatment of these canalicular transport defects is a clinical and scientific challenge that is still ongoing. Current evidence indicates that ursodeoxycholic acid (UDCA) can be effective in selected patients with PFIC3 (ABCB4 deficiency), while rifampicin reduces pruritus in patients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 deficiency), and might abort cholestatic episodes in BRIC (mild ATP8B1 or ABCB11 deficiency). Cholestyramine is essential in the treatment of sitosterolemia (ABCG5/8 deficiency). Most patients with PFIC1 and PFIC2 will benefit from partial biliary drainage. Nevertheless liver transplantation is needed in a substantial proportion of these patients, as it is in PFIC3 patients. New developments in the treatment of canalicular transport defects by using nuclear receptors as a target, enhancing the expression of the mutated transporter protein by employing chaperones, or by mutation specific therapy show substantial promise. This review will focus on the therapy that is currently available as well as on those developments that are likely to influence clinical practice in the near future.

Abbreviations: ABC, adenosine triphosphate-binding-cassette, PC, phosphatidylcholine, PS, phosphatidylserine, PFIC, progressive familial intrahepatic cholestasis, BRIC, benign recurrent intrahepatic cholestasis, GGT, gamma-glutamyl transpeptidase, ICP, intrahepatic cholestasis of pregnancy, LPAC, low-phospholipid associated cholelithiasis syndrome, DJS, Dubin Johnson syndrome, UDCA, ursodeoxycholic acid, PXR, pregnane X receptor, MARS, extracorporal albumin dialysis, PBD, partial biliary diversion, IB, ileal bypass, PEBD, partial external biliary diversion, PIBD, partial internal biliary diversion, NBD, nasobiliary drainage, FXR, farnesoid X receptor, 6-ECDCA, 6-ethyl chenodeoxycholic acid, PPAR, peroxisome proliferator activator receptor, CAR, constitutive androstane receptor, CF, cystic fibrosis, 4-PBA, 4-phenylbutyrate acid, CFTR, cystic fibrosis transmembrane conductance regulator

Keywords: PFIC, Therapy, Canalicular transport, Hereditary cholestasis