Primary biliary cirrhosis (PBC) and primary scleros-ing cholangitis (PSC) are chronic cholestatic liver diseases, which often lead to liver cirrhosis and its inherent complications, such as portal hypertension and liver failure. Although major advances in the understanding of the molecular pathomechanisms have been made, more studies are needed to define the immunologic and genetic factors involved in these potentially fatal disorders. 1, 2 Evidence for a genetic susceptibility are the associations of both diseases with alleles of the major histocompatibility complex3, 4 and the raised familial risk. 5 However, family clustering could also be due to shared environmental factors or gene environment interactions. 5 Until recently, no twin studies supporting the genetic component were available, but a preliminary report suggests a concordance rate of 75% for PBC in monozygotic twins, consistent with a significant genetic contribution to disease susceptibility. 6 Because autoimmune mechanisms are thought to be crucial in the pathogenesis of both diseases, investigators have focused on genetic variants (polymorphisms) in non-HLA candidate genes involved in immune regulation. 7–15 In addition, it has been reported that a gene variant of the matrix metalloproteinase 3, which is involved in extracellular matrix degradation and liver fibrogenesis, is associated with susceptibility and disease progression in PSC. 16 These examples indicate that not only genes regulating innate and acquired immune functions play a role in the pathogenesis of PBC and PSC, but that the systematic identification of additional genes modulating disease susceptibility and/or progression can be awaited.

For both diseases it is not yet clear whether immunemediated, toxic and/or vascular impairment of the bilesecretory apparatus represents a prerequisite for liver injury. The secretion of bile normally depends on the integrity of an ensemble of membrane transport systems in hepatocytes and cholangiocytes. 17 Of note, the transport of all three major biliary lipids (ie, bile salts, phosphatidylcholin, and cholesterol) across the canalicular membrane is mediated by ATP-dependent export pumps, known as ATP-binding cassette (ABC) transporters. 18 Two of the major transporters are the “multidrug resistance” P-glycoprotein 3 (MDR 3/ABCB4), which translocates phosphatidylcholine (lecithin), and the “bile salt export pump”(BSEP/ABCB11). Mutations in the genes encoding these hepatobiliary transporters have been identified as causative in progressive familial intrahepatic cholestasis in children. 17 One study reported an association between PSC and functional variants of the cystic fibrosis gene (CFTR/ABCC7), 19 yet another member of the ABC transporter family that is expressed on the apical membrane of biliary epithelial cells. Of note, mice with homozygous disruption of the MDR3 (ABCB4) ortholog (Mdr2) develop liver lesions that are characterized by segmental biliary strictures due to periductal fibrosis and obliteration of bile ducts, thus resembling sclerosing cholangitis. 20, 21 The liver injury in these mice is generally attributed to the phospholipid deficiency of their bile, which does not contain mixed lecithin-cholesterol-bile salt micelles that normally protect the biliary epithelium against the detergent properties of bile salts. 20, 21 In the light of these findings, ABCB4 and ABCB11 represent promising candidate genes, which could also modify the cholestatic injury in PBC and PSC. Therefore, the investigation of the role of BSEP (ABCB11) and MDR3 (ABCB4) gene variants in patients with PBC and PSC by Pauli-Magnus et al. in this issue of HEPATOL-OGY22 is a timely candidate gene …