The ABCB4 gene (MIM 171060) has www.selleckchem.com/products/Imatinib-Mesylate.html a crucial role as evidenced by cholestatic liver diseases caused by its deficiency.1 ABCB4 is also known as multidrug resistance 3 gene (MDR3), a member of the MDR/TAP subfamily involved in multidrug resistance as well as antigen presentation. The human ABCB4 gene is located on chromosome 7q21.1, contains 27 coding exons, and spans approximately 74kb.2 The pathophysiology of the ABCB4 alterations resides in the lack of phospholipid protection in the bile against the detergent effect of the bile salts, resulting in damage to the biliary epithelium, bile ductular proliferation, and potential progressive portal fibrosis. As biliary cholesterol solubilization depends not only on the concentration of the sterol itself but also on the bile salt and phospholipid concentration, a decreased rate of phospholipid excretion can also be a cause of gallstone formation.
The wide clinical spectrum of the ABCB4 deficiency syndromes in humans covers cholestatic disorders presenting from the neonatal period of life to late adulthood.3, 4, 5 At least three distinct syndromes with variable severity have been clearly identified: progressive familial intrahepatic cholestasis type 3 (PFIC3; MIM 602347), low phospholipid-associated cholelithiasis (LPAC alias gallbladder disease 1, GBD1; MIM 60080), and familial intrahepatic cholestasis of pregnancy (ICP; MIM 147480). Evidences of ABCB4 mutations have also been found in transient neonatal cholestasis,6 or adult idiopathic biliary fibrosis or cirrhosis.4, 7, 8, 9, 10, 11 A recessive inheritance pattern of PFIC3 has been observed.
7, 12 Most ABCB4 mutations in the patients with PFIC3 have been reported to be homozygous or compound heterozygous.3, 7, 9, 12, 13, 14 These mutations include missense and non-sense mutations, and short frameshift deletions or insertions. ABCB4 mutations are associated with an absence or a weak level of the canalicular ABCB4 protein, and with a low level of biliary phospholipids.7, 12, 15 Patients with PFIC3 usually present at a few years of age and suffer from severe chronic and progressive cholestasis. Liver histology often reveals fibrosis with portal inflammation and strong bile duct proliferation in an early stage.16 A characteristic high-serum gamma-glutamyltransferase activity is found in PFIC3. As a consequence of the cirrhosis, the PFIC3 patients are prone to gastrointestinal bleeding.
About 50% of the patients need a liver Cilengitide transplantation. Interestingly, the other half may benefit from treatment with ursodeoxycholic acid (UDCA).7 Mutations in the ABCB4 gene that may reduce but not eliminate or drastically decrease the protein (leaving residual activity of the transporter), have been shown to cause a variety of milder cholestatic phenotypes, including LPAC and ICP.