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 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.

Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma.

BACKGROUND AND AIMS: Adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) deficiency may lead to progressive familial intrahepatic cholestasis type 3 (PFIC3), biliary cirrhosis, low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptive-induced cholestasis (CIC) or may remain asymptomatic. The long-term course, quality of life and histology were investigated in ABCB4 deficiency. METHODS: Adult carriers of ABCB4 gene variants from two regional academic centres were analysed by history taking, electronic patient files, physical examination, blood analysis, abdominal ultrasound (US) and liver elastography. Patients completed a 36-Item Short Form Health Survey (SF-36) for quality of life and a Visual Analogue Scale (VAS) for pruritus. Available liver specimens were re-classified according to the Nakanuma scoring system, so far validated for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) only. Quality of life data were compared to published data of patients with PBC, PSC and the general population. RESULTS: Sixty-seven patients were identified, 64 (96%) were alive at the time of analysis and 62 (93%) were (at some time) treated with ursodeoxycholic acid (UDCA). Two patients died of cholangiocarcinoma (CCA), and one of decompensated biliary cirrhosis. Three additional deaths of CCA were reported in first-degree relatives. Transplant-free survival was 91% (median follow-up 14 years). Liver stiffness was normal (<6.3 kPa) in 75%, intrahepatic stones were detected at ultrasound (US) in 33% and microcalcifications in 22% of cases. Quality of life (n = 48) was lower than in the general population particularly in energy/fatigue and general health domains and comparable to that in PSC. Staging according to Nakanuma in 15 specimens reflected the clinical course. CONCLUSIONS: ABCB4 deficiency has a mild clinical course, but impaired quality of life and limited risk of CCA. The Nakanuma scoring system appears feasible for histological evaluation in ABCB4 deficiency.

ABCB4/MDR3 in health and disease - at the crossroads of biochemistry and medicine.

Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30-40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.