Aetiology

Aetiology is unknown at present. However, several aetiological factors have been suggested, many of which warrant further study:[22][23]​​

  • Viral infection: numerous studies exploring a viral aetiology have focused on reovirus, rotavirus, and other hepatotropic viruses. None have been fully substantiated.[24]​ 

  • Toxin-induced cholangiocyte injury: studies have identified a plant toxin (biliatresone from Dysphania species plants) that causes biliary atresia in newborn lambs.[25] This toxin has been found to damage cholangiocytes in zebrafish, mouse and human cell culture models, and to activate glutathione antioxidant pathways.[26][27] Further studies are necessary to determine the possible contribution of toxin exposure to human biliary atresia.

  • Defects in morphogenesis: potentially caused by an insult at a critical time in embryological development. The strongest evidence for this comes from children with biliary atresia associated with other congenital abnormalities.[4][5][6][7][8][9]

  • Genetic predisposition: the condition is unlikely to be inherited by Mendelian genetics, but genetic factors likely contribute. The increased association with histocompatibility antigen HLA-B12 (haplotypes A9-B5 and A28-B35) and its early onset suggest a genetic susceptibility to an acquired insult.[28][29] Case reports of biliary atresia within families are rare.[21][30][31][32] Genome-wide association studies have implicated the ADD3, EFEMP1 and ARF6 genes as possible susceptibility factors for biliary atresia.[33][34] Exome sequencing of patients with biliary atresia splenic malformation has revealed mutations in the cilia-associated gene PKD1L1.[35][36][37]

  • Defects in antenatal circulation: bile ducts receive their blood supply exclusively from the hepatic arterial circulation. Interruptions of this flow account for bile duct damage in liver transplantation, as well as in a fetal sheep model.[38][39][40]

  • Immune or autoimmune dysregulation: animal models of the condition support the role of autoimmunity. Autoreactive T cells specific to bile duct epithelia are sufficient to produce bile duct inflammation in mice, causing a similar phenotype. Adoptive transfer of liver T cells from a mouse model of the disease can induce bile duct-specific disease in immunodeficient mice.[41][42][43] These concepts are being explored in human tissue.

Pathophysiology

The destructive inflammatory process underlying the condition may involve a short segment of a duct, an entire duct, or the entire system. The hepatic or common bile duct is obliterated or discontinuous for a portion between the porta hepatis and the duodenum. This inflammation is the hallmark of the disease and, even after hepatoportoenterostomy, the inflammatory process can continue to ascend through the intrahepatic biliary tree leading to fibrosis, cirrhosis, portal hypertension, and subsequent nutritional deficits.[44]

Classification

Ohi classification system based on biliary anatomy

The Ohi classification system used by the Japanese Biliary Atresia Registry has been adopted to describe the anatomical variants.[1]

Three types of biliary anatomy are described:

  • Type 1: atresia of the common bile duct (10% of patients)

  • Type II: atresia of the hepatic ducts (2% of patients)

  • Type III: atresia at the porta hepatis (88% of patients).

The first 2 are sometimes referred to as correctable, whereas the third is the so-called non-correctable type of atresia and accounts for the majority of patients.

Classification based on presentation

Biliary atresia may be classified into 2 forms, based on presentation.

  • Isolated biliary atresia accounts for the majority of all cases (80%-90%). Infants' first stools are normally pigmented, and the children are of average birth weight.

  • Biliary atresia associated with other congential anomalies occurs in 10% to 20% of cases.[2] Associated congenital anomalies may be either related to laterality (biliary atresia splenic malformation syndrome) or other anomalies (genitourinary, intestinal, etc.).

One small prospective study suggests that infants with isolated biliary atresia or biliary atresia associated with other congenital anomalies have laboratory evidence of evolving cholestasis in the first days of life.[3]

Classification based on associated malformations

Half of the affected children with associated malformations have a stereotypical pattern of features suggesting a disorder of laterality (characterised by misplacement of 1 or more organs according to the right/left axis).[4][5][6][7][8][9]​ This is referred to as biliary atresia splenic malformation, polysplenia syndrome, or heterotaxy with biliary atresia. The constellation of reported findings includes:

  • Interruption of the suprarenal segment of the inferior vena cava with azygous continuation

  • Preduodenal portal vein

  • Symmetrical liver

  • Intestinal malrotation

  • Situs anomalies (inversus, ambiguous)

  • Bronchial anomalies

  • Polysplenia

  • Cardiac malformations.

The other half of children have a range of associated malformations that do not fit into this group.

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