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 genotypephenotype 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 PPARa (peroxisome proliferator-activated receptor-a)-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.

Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities

“…The latter two findings are consistent with the results of genomewide association studies showing close associations between ABCB4 variants and the risk of developing cirrhosis and/or hepato-biliary malignancies [19,20]. They are also in line with the longterm risk of cirrhosis or cholangitis reported in women with ICP [7,21]. In the present study, most of the cancers diagnosed in index cases or their relatives were cholangiocarcinomas, but a few cases of hepatocellular carcinoma developed on cholestatic or idiopathic cirrhosis were reported in relatives.…”

“…This condition has causally been linked to a defect of phospholipid canalicular secretion into bile leading to impaired solubilization of biliary cholesterol that precipitates in the form of crystals in canaliculi and intrahepatic bile ducts. Germline mutations in the sequence of the ATP-binding cassette subfamily B member 4 (ABCB4) gene, which encodes the phospholipid floppase multi-drug resistance type 3 (MDR3), have been reported in 30% to 50% of patients with this condition [2][3][4][5][6], thus including LPAC syndrome in the different disease manifestations associated with ABCB4 variants [7].…”

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

“…This variant is of low frequency in AA (MAF=1.2%) but virtually absent in EA and ASN. ABCB4, also known as multidrug resistance protein 3 (MDR3), is a compelling candidate gene, as it has been previously implicated in cholestasis, gallbladder disease, and adult biliary fibrosis/cirrhosis [40][41][42] . Finally, for a number of variant gene-pairs, the observed effect on NAFLD risk and the impact of gene expression in the liver was consistent with our understanding of the expected effect given what is known about gene function, suggesting possible relevance as therapeutic targets.…”

Reply to: “Challenges in understanding the consequences of variants in ABCB4 gene”

“…We thank Dr. Nayagam and his colleagues for their insightful comment on our recently published review on genetic variants in ABCB4 in adult patients with cholestatic liver disease. 1 In fact, the index patient presented in the clinical vignette within this review showed a comparably mild disease course as his homozygous frameshift variant (p.R1256fs*39) would have suggested. He became symptomatic in early adulthood and showed progression of his cholestatic liver disease with portal fibrosis to decompensated liver cirrhosis within almost 2 decades.…”