Genetic Contributors and Modifiers of Biliary Atresia

Abstract

To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.

Innate Immunity and Pathogenesis of Biliary Atresia

“…Diverse theories regarding the causes of the disease have been formulated, including embryonic or developmental abnormalities (17,21), exposure to exogenous triggers such as viruses or toxins (16,22), immune immaturity (11,23), immune dysregulation (24,25), and autoimmunity (26)(27)(28)(29). Furthermore, numerous susceptibility factorssuch as genetic predisposition (30), maternal diabetes (17), or microchimerism (31)-have also been implicated in the pathogenesis of the disease. This complex cocktail of variables and factors supports the claim that biliary atresia is not a disease with a single etiology but a combination of different phenotypes that share certain clinical features, such as the obliteration of the biliary tree early in life (32).…”

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

“…Moreover, the establishment of normal left to right (L–R) patterning in vertebrate embryogenesis is dependent on both sensory and motile ciliary functions . Support for the potential contribution of ciliary dysfunction in BA comes from several sources: (1) cholangiocyte cilia in BA livers are significantly shorter, abnormal in their orientation, and less abundant compared with other cholestatic disorders and normal livers; (2) mutations in a small number of ciliopathy and laterality genes, including cripto, FRL‐1, cryptic family 1 ( CFC1 ), nodal growth differentiation factor ( NODAL ), and Zic family member 3 ( ZIC3 ), have been suggested as a possible etiology for BA in some patients; and (3) several well‐characterized mutations in ciliopathy genes lead to developmental biliary tract diseases known as cholangiociliopathies—Caroli syndrome, ductal plate malformations, congenital hepatic fibrosis, and polycystic liver diseases …”

Current strategies to generate mature human induced pluripotent stem cells derived cholangiocytes and future applications

“…Nonetheless, certain susceptibility yet to decipher triggers an exaggerated immune response that induces fibrosis, perhaps related to autoimmunity although patients don't benefit from corticosteroid use. 74,75 Thus, it will be interesting to confirm such an etiological hypothesis with iPSCs cholangiocytes derived from biliary atresia cases, and genetic alteration may define potential therapeutic targets. Primary biliary cholangitis and primary sclerosing cholangitis are similar cholangiopathies in the sense that both are characterized by chronic immune-mediated inflammation and destruction of the bile ducts, although their differences are evident including a female preponderance and distinctive antimitochondrial antibodies in the former, and male preponderance and probable HLA antigen-B locus related susceptibility in the latter.…”