Aetiology of biliary atresia: what is actually known?

Petersen, Claus; Davenport, Mark

doi:10.1186/1750-1172-8-128

Cited by 110 publications

(80 citation statements)

References 128 publications

(130 reference statements)

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“…59 It is postulated that a prenatal or perinatal viral infection may initiate cholangiocyte apoptosis, which causes the release of antigens that trigger an immune response involving T-helper cell lymphocytes that amplify the ongoing bile duct injury, inflammation, and obstructive fibrosis. 60 Humoral immunity and activation of the innate immune system may also contribute to this process. 61 Recent studies suggest that regulatory T cells and genetic susceptibility factors may activate destructive autoimmune mechanisms in biliary atresia.…”

Section: Biliary Atresiamentioning

confidence: 99%

The Cholangiopathies

Lazaridis

LaRusso

2015

Mayo Clinic Proceedings

178

170

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Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies—primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma—because the latest scientific progress in the field concerns these conditions. We performed a search of the literature in PubMed for published papers using the following terms: cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.

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Section: Biliary Atresiamentioning

confidence: 99%

The Cholangiopathies

Lazaridis

LaRusso

2015

Mayo Clinic Proceedings

178

170

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“…The putative causes of biliary atresia can be separated into a variety of etiologic categories, including toxin-related, viral, immunological, maternal fetal factors, and genetic [29,30,31,32,33]. From Australia, there are intriguing data related to an episodic form of newborn lamb cholangiopathy associated with a change in diet due to harsh weather conditions, whereby ingestion of a plant-derived toxin from the species of Dysphania damages the developing biliary tree [34].…”

Section: Nongenetic Etiologic Theories Of Biliary Atresiamentioning

confidence: 99%

“…Investigations into a viral etiology have yielded mixed results, implicating various strains of rotavirus, reovirus, and cytomegalovirus, among others, but there have been inconsistencies in the detection of viruses in patient samples. Preclinical and animal models have identified intriguing contributions to disease progression from various immunological mediators, viruses, and immune cell types, several of which have been demonstrated in human studies [11,21,30,31,33,35,36,37]. Currently, there is a paucity of support for a single viral or immunological insult in the etiopathogenesis of biliary atresia, though these factors certainly may play modifying roles for disease progression.…”

Section: Nongenetic Etiologic Theories Of Biliary Atresiamentioning

confidence: 99%

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Genetic Contributors and Modifiers of Biliary Atresia

Mezina

Karpen²

2015

Dig Dis

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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.

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“…Increased levels of both CD68 + cells and its circulating markers (tumor necrosis factor-a and IL-18) have been shown [7]. In addition, marked CD68 + macrophage infiltrates in the portal tracts correlated with a worse outcome in BA patients [8].…”

Section: Introductionmentioning

confidence: 98%

Hepatic expression of interferon-γ and CD68 in biliary atresia compared with other neonatal cholestatic disorders

Arafa¹,

Behairy²,

Abdelmotaleb³

et al. 2015

Medical Research Journal

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Objective The diagnosis of biliary atresia (BA) can be challenging as its histopathologic features overlap with those of other pediatric cholestatic liver diseases. We aimed to study the diagnostic value of hepatic interferon-c (IFN-c) and CD68 immunostaining in the differentiation of BA from other causes of neonatal cholestasis (NC).Patients and methods Hepatic IFN-c and CD68 immunostaining were investigated in 69 patients divided on the basis of the diagnosis into the BA group (n = 34) and the non-BA group (n = 35). The semiquantitative assessment included estimating the average of positive staining cells among inflammatory infiltrate in portal tracts of liver biopsy. ResultsThe mean hepatic CD68 and IFN-c immunostaining in patients with BA was significantly higher (41.2 ± 9.2 and 39.3 ± 12.6, respectively) than that in the cholestasis group (20.8 ± 15.2 and 21.5 ± 15.7, respectively). The cutoff values were 24 for CD68 and 22 for IFN-c to differentiate between BA and cholestatic patients, with a sensitivity and specificity of 94.18 and 74.30% for CD68 and 89 and 73.14% for IFN-c, respectively.Conclusion Both IFN-c and CD68 immunostaining of the liver had a diagnostic value in differentiation between BA and other NC disorders and might be useful as an additional stain when investigating infants with NC. Med

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Aetiology of biliary atresia: what is actually known?

Cited by 110 publications

References 128 publications

The Cholangiopathies

The Cholangiopathies

Genetic Contributors and Modifiers of Biliary Atresia

Hepatic expression of interferon-γ and CD68 in biliary atresia compared with other neonatal cholestatic disorders

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