Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases

Abstract

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR-and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear

A rare missense variant in APC interrupts splicing and causes AFAP in two Danish families

“…Different inheritance patterns and genes have been suggested to be involved in CD, i.e. autosomal recessive inheritance due to PKHD1 mutations [11,12]. In family 1 several family members suffered from cholelithiasis; the family might also have an autosomal dominant genetic predisposition to gall bladder disease, but we have no reason to believe that CD and the APC variant should be linked in any way, which is substantiated by the fact that the APC variant and gall bladder disease did not segregate in the family.…”

The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

“…A common trait of these diseases is the cyst-like enlargement of the intrahepatic bile duct epithelium accompanied by a progressive deposition of fibrotic tissue in the peribiliary region. In the dysgenetic ducts, cholangiocytes present cilium defects and retain features of immaturity reminiscent of a fetal-like behavior (2)(3)(4)19). Worsening fibrosis leads to portal hypertension and related complications, such as variceal bleeding and ascites, and young patients are generally disposed to develop chronic cholangitis (2,68,69).…”

“…Cholangiopathies are a heterogeneous group of liver diseases targeting the biliary epithelium of different etiologies including genetic defects (causing Alagille syndrome, cystic fibrosis-related cholangiopathy, and polycystic and fibropolycystic liver diseases) and immune-mediated attacks (causing primary biliary cholangitis and primary sclerosing cholangitis) (1)(2)(3). Their clinical evolution is generally much slower than liver diseases aimed at the hepatocytes, spanning over years or decades, and depends on the balance between the manifestations related to the bile duct injury such as cholestasis, ductopenia (or conversely, exuberant bile duct expansion), and portal/biliary fibrosis (4).…”

“…These studies have lent support to the notion that biliary fibrogenesis is an intricate process where multiple cell types are actively involved. Following biliary injury, cholangiocytes lining the finest ramifications of the biliary tree, abutting the canals of Hering, become activated in a so-called "ductular reaction" (2,(15)(16)(17). They start to secrete a huge variety of mediators like cytokines, chemokines, and growth factors, and to express a rich repertoire of receptors that enable them to communicate extensively with portal fibroblasts and hepatic stellate cells, the ultimate effectors of the deposition of new extracellular matrix (ECM) components (2,18).…”

“…Following biliary injury, cholangiocytes lining the finest ramifications of the biliary tree, abutting the canals of Hering, become activated in a so-called "ductular reaction" (2,(15)(16)(17). They start to secrete a huge variety of mediators like cytokines, chemokines, and growth factors, and to express a rich repertoire of receptors that enable them to communicate extensively with portal fibroblasts and hepatic stellate cells, the ultimate effectors of the deposition of new extracellular matrix (ECM) components (2,18). Cell interactions between the epithelial and the mesenchymal compartments are molded by the further involvement of inflammatory cell types recruited from the blood such as neutrophils, macrophages, and lymphocytes (19,20).…”