Update on investigations pertaining to the pathogenesis of biliary atresia

Kilgore, Alexandra; Mack, Cara L.

doi:10.1007/s00383-017-4172-6

Cited by 51 publications

(51 citation statements)

References 95 publications

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“…Biliary atresia is the most common cause of end stage liver disease in infants and is associated with poor prognosis and high mortality. The etiology of BA is not known, but irrespective of the cause, histological evidence at diagnosis supports the involvement of the immune system in mediating injury to the bile duct epithelium, which is facilitated by adhesion molecules that help recruitment of inflammatory cells [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia

Gawish¹,

El-Monem²,

El-Abd³

et al. 2020

ceh

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Section: Discussionmentioning

confidence: 99%

MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia

Gawish¹,

El-Monem²,

El-Abd³

et al. 2020

ceh

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“…1 Biliary atresia (BA), with the incidence ranges from 1:5,000 to 1:19,000 births, is a disease of unknown etiology and causes significant morbidity in pediatric populations. 2 If affected infants are identified with BA within the first month, they undergo the Kasai hepatoportoenterostomy (8 weeks of age) in an attempt to restore bile flow and delay cirrhosis. If BA is diagnosed later, infants have advanced liver damage; they rarely benefit from the Kasai operation and have to proceed with liver transplantation.…”

Section: Introductionmentioning

confidence: 99%

Can Free Carnitine or Bilirubin in Blood Be Used in Neonatal Screening for Biliary Atresia?

Zheng

Chen

et al. 2019

Eur J Pediatr Surg

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Objective To investigate the efficiency of free carnitine, unconjugated bilirubin (UBIL), bilirubin monoglucuronide (BMG), and bilirubin diglucuronide (BDG) in dry blood spots (DBSs) measured using tandem mass spectrometry (MS/MS) for screening biliary atresia (BA). Materials and Methods All the patients with BA, residing in Shanghai, were collected from four different children's hospitals in Shanghai from January 1, 2015, to June 30, 2017. UBILMS, BMG, BDG, and free carnitine were measured in the DBS samples of 48 patients with BA, 10,008 pediatric patients, and 52,862 newborns using MS/MS. Conjugated bilirubin was measured by MS/MS (CBMS) = BMG + BDG, and total bilirubin was measured by MS/MS (TBMS) = UBILMS + CBMS. Four hundred pediatric patients' direct bilirubin (DB) and total bilirubin (TB), measured by the clinical laboratory and MS/MS, were used as a control. Results The total number of births at the registered permanent residences in Shanghai was 233,000; among them, the occurrence of BA was in 33 patients in 2 years. Therefore, the incidence of BA in Shanghai was 1:7,060. The ratio of DB/TB and CBMS/TBMS of most patients with BA was elevated gradually in the neonatal period and higher than the normal range after 1 month after birth. The area under the receiver operating characteristic curve of DB, DB/TB, CBMS/TBMS, CBMS, and free carnitine for predicting BA was 0.98, 0.95, 0.73, 0.57, and 0.92, respectively. Using the 95% percentile as a cutoff, the sensitivity of DB and free carnitine to predict BA was 100 and 85%, respectively, and the specificity was 52 and 85%, respectively. Conclusion In free carnitine, DB, and CBMS/TBMS tests, blood concentrations are elevated in all infants with BA. However, they may not be elevated while they are newborns. These tests will result in high false negatives or positives. Thus, they should not be used as newborn screening tests for BA due to their lower sensitivity and specificity.

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“…A developmental cause of BA was first proposed in an early case collection, while support for a potential genetic contribution comes not only from prenatal and perinatal evidence of biliary tract dysgenesis in BA but also from several familial case reports of BA . However, given the general lack of heritability of BA within families and reports of twin discordance, recent studies have explored nongenetic etiologies underlying BA, including viral, toxin, and immune‐mediated mechanisms . Nevertheless, the genetic determinants of heterotaxy syndromes often involve mutations in genes essential for ciliary structure or function, providing support to refocus efforts exploring potential roles for variants in key ciliary genes in the pathogenesis of the BASM syndrome …”

mentioning

confidence: 99%

“…(10) However, given the general lack of heritability of BA within families and reports of twin discordance, (11)(12)(13) recent studies have explored nongenetic etiologies underlying BA, including viral, toxin, and immune-mediated mechanisms. (2,14) Nevertheless, the genetic determinants of heterotaxy syndromes often involve mutations in genes essential for ciliary structure or function, (15,16) providing support to refocus efforts exploring potential roles for variants in key ciliary genes in the pathogenesis of the BASM syndrome. (6,7) A growing list of genes involved in bile duct development and function have been implicated in the pathogenesis of biliary tract diseases including BA, several of which cause structural and functional alterations in primary cilia.…”

mentioning

confidence: 99%

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

Berauer¹,

Mezina²,

Okou³

et al. 2019

Hepatology

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Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations—a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole‐exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient–parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases–supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome.

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Update on investigations pertaining to the pathogenesis of biliary atresia

Cited by 51 publications

References 95 publications

MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia

MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia

Can Free Carnitine or Bilirubin in Blood Be Used in Neonatal Screening for Biliary Atresia?

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

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