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

Abstract

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.

An Update on Drug-induced Liver Injury

“…UDCA due its membrane stabilizing action protects the hepatocytes and cholangiocytes by replacing the endogenous, cytotoxic bile salts and also by enhancing the function of transporters. 104 Anecdotal reports of UDCA in drug-induced cholestasis in particular vanishing bile duct syndrome attests to its usefulness, albeit in select cases. 105 Cholestyramine may be attempted in those with cholestasis and pruritus.…”

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 2

“…In some patients, biliary diversion may decrease cholestasis. 15 Nasobiliary drainage may help to select potential responders to biliary diversion. So far, clear genotype-phenotype correlation data are missing and remain to be defined in order to identify those PFIC2 patients who could benefit from UDCA or biliary diversion.…”

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 1

“…In some patients, biliary diversion may decrease cholestasis. 17 Nasobiliary drainage may help to select potential responders to biliary diversion. Treatment with 4-phenylbutyrate as chaperone drug might restore in vitro the aberrant folding caused by some missense mutations.…”