Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults.
The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multi drug resistance 3 protein [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 identified so far that lead to ABCB4 deficiency accounting for a disease spectrum ranging from progressive familial cholestasis type 3 (PFIC-3) to less severe forms presenting as low phospholipid associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP) or drug-induced liver injury (DILI). Furthermore, whole genome sequencing identified ABCB4 variants to be associated with an increased incidence of gallstone disease, gallbladder and cholangiocarcinoma, 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 lacking so far. Ursodeoxycholic acid is the most commonly used medical treatment, but confirmation of its benefit by large controlled clinical studies is still lacking. 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 farnesoid X receptor (FXR) agonists or PPARα-ligands/fibrates. In cirrhotic patients with end stage liver disease or patients with intractable pruritus orthotopic liver transplantation remains the last and often only therapeutic option.