Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults.

Abstract

The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.

• Authors: Albert Friedrich Stättermayer, Emina Halilbasic, Fritz Wrba, Peter Ferenci, Michael Trauner
• Journal: Journal of hepatology (J Hepatol) Vol. 73 Issue 3 Pg. 651-663 (09 2020) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 32376413 (Publication Type: Case Reports, Journal Article, Review)
• Copyright: Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Ursodeoxycholic Acid
• multidrug resistance protein 3

Topics

• ATP Binding Cassette Transporter, Subfamily B (deficiency, genetics)
• Adult
• Bile Duct Neoplasms (diagnosis, drug therapy, genetics, surgery)
• Chemical and Drug Induced Liver Injury (diagnosis, drug therapy, genetics, surgery)
• Cholelithiasis (diagnosis, drug therapy, genetics, surgery)
• Cholestasis, Intrahepatic (diagnosis, drug therapy, genetics, surgery)
• Female
• Gallbladder Neoplasms (diagnosis, drug therapy, genetics, surgery)
• Humans
• Liver Cirrhosis (diagnosis, drug therapy, genetics, surgery)
• Liver Transplantation (methods)
• Male
• Polymorphism, Single Nucleotide
• Pregnancy
• Pregnancy Complications (diagnosis, drug therapy, genetics, surgery)
• Treatment Outcome
• Ursodeoxycholic Acid (therapeutic use)
• Young Adult