Biliary Atresia, Extrahepatic

Description

Biliary atresia is a disorder of infants in which there is progressive obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow. Untreated, the resulting cholestasis leads to progressive conjugated hyperbilirubinemia, cirrhosis, and hepatic failure (Bates et al., 1998). Most patients require liver transplantation within the first year of life (Leyva-Vega et al., 2010).

See also Alagille syndrome (118450), which includes biliary atresia as a feature.

Krauss (1964) noted the reports of 5 sibships in which 2 or more sibs had extrahepatic biliary atresia. Renal and cardiac malformations were associated in Krauss's cases. Sweet (1932) found 3 cases in 1 family; 2 of the 3 had right ventricular hypertrophy (one with ventricular septal defect and patent ductus arteriosus). Other familial cases have been reported by Hopkins (1941), Rumber (1961), and Whitten and Adie (1952). Schulte and Lenz (1978) observed extrahepatic biliary atresia in a brother and sister whose parents were related.

Danesino et al. (1999) described a family in which 1 brother had extrahepatic biliary atresia and a second brother had intrahepatic biliary atresia.

Among 251 cases of EHBA, Carmi et al. (1993) found 51 with associated anomalies. Analysis of segregation patterns of these anomalies suggested the existence of 2 major groups: 15 cases (29.4%) had various combinations of anomalies within the laterality sequence; 30 cases (58.8%) had 1 or 2 anomalies mostly involving the cardiac, gastrointestinal, and urinary systems. The latter anomalies did not follow any recognizable pattern. A third group of 6 cases had intestinal malrotation, some with preduodenal portal vein; these cases showed some similarity to the laterality sequence group and may represent a more confined phenotypic expression of faulty determination of situs.

Biliary atresia is likely multifactorial in etiology. A proposed mechanism includes genetic predisposition to the disease with immune dysregulation and environmental factors, such as a virus or toxin, playing variable roles. Genetic factors are believed to contribute to susceptibility to the disease (Leyva-Vega et al., 2010).

The report of biliary atresia that was probably due to ascending cholangitis as part of an intrauterine infection by Listeria monocytogenes indicates a possible basis for familial occurrence of biliary atresia (Becroft, 1972). Listeria infection has been observed in successive pregnancies.

Cunningham and Sybert (1988) identified 11 instances of familial extrahepatic biliary atresia in the literature. They reported 2 further families, each with 2 affected sibs. A number of observations suggest an exogenous basis for EHBA; there was an elevated frequency of antibodies to reovirus 3, and a time-area clustering had been noted in 2 studies. Genetic factors are suggested by the wide variation in the incidence of EHBA among genetically isolated racial groups (Chinese, Filipino, and Caucasian) in Hawaii, although this could have in part or in whole an exogenous explanation. On the whole, a polygenic or multifactorial basis is likely and is supported by the description of discordance in at least 3 sets of monozygotic twins (Hyams et al., 1985; Strickland et al., 1985).

Among 251 cases of EHBA, Carmi et al. (1993) found 51 with associated anomalies, which they divided into 2 main groups; see CLINICAL FEATURES section. Carmi et al. (1993) suggested that EHBA with anomalies of laterality may prove a suitable candidate for a major gene mutation. Teratogenic, infectious, and polygenic multifactorial causes may play a more significant role in EHBA associated with 'nonsyndromic' organ system anomalies.

Leyva-Vega et al. (2010) screened DNA from 35 patients with biliary atresia for genomic copy number variation (CNV), defined in size by 10 or more consecutive SNPs. Only 1 CNV, a heterozygous deletion mapping to chromosome 2q37.3, was found in 2 unrelated male patients and in none of 2,026 controls. The first patient developed symptoms at age 3 weeks and was found to have biliary atresia, hepatomegaly, and an atretic gallbladder. He had a liver transplant at age 8 months, and was healthy without developmental delay at age 17 years. His unaffected father also carried the 2q37.3 deletion. The second patient was diagnosed at age 7 weeks and had liver transplantation at age 10 months. He was doing well at age 16 months, but had some other congenital anomalies, including hypothyroidism, polysplenia, developmental delay, and seizures, as well as dysmorphic facies and digital anomalies. Karyotype analysis revealed a 47,XXY karyotype, consistent with Klinefelter syndrome. The first patient had a 1.76-Mb deletion that was fully encompassed in the second patient's large 5.87-Mb deletion on chromosome 2q27.3. The second patient also had a 2.9-Mb deletion on chromosome 2q33.1. The authors noted that neither patient had the clinical features associated with the 2q37 deletion syndrome (600430). Leyva-Vega et al. (2010) postulated that the common 1.76-Mb deletion in these patients, which encompasses 30 genes including AGXT (604285), may harbor a susceptibility factor for the development of biliary atresia.

For a discussion of a possible association between variation in the XPNPEP1 gene and susceptibility to biliary atresia, see 602443.

Biliary atresia has an incidence of approximately 1 in 10,000 live births worldwide (Bates et al., 1998).

Tiao et al. (2008) reported that the peak incidence of biliary atresia in Taiwan occurred in 2002 (1.90 per 10,000), which accompanied a dengue fever (614371) epidemic in 2002. These findings implicated viral infection outbreaks as a potential cause of biliary atresia.

The incidence of biliary atresia is highest among Asian populations, occurring in 1.46 per 10,000 live births in Taiwan, compared to 0.65 to 0.85 per 10,000 live births in the United States (Leyva-Vega et al., 2010).