ReviewBiliary atresia and other cholestatic childhood diseases: Advances and future challenges
Section snippets
Key questions
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Which strategies can enhance earlier recognition of neonatal cholestasis, including biliary atresia (BA)?
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What is the value of abdominal ultrasound, nuclear isotope excretion scan, liver biopsy and endoscopic retrograde cholangiopancreatography (ERCP) in the diagnostic work up?
BA prognosis relates to timely surgical correction and therefore early diagnosis is mandatory (ideally before 30 days of age). Various diagnostic algorithms have been proposed [1], [2], [3]. A prompt diagnosis relies on the
Key questions
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To what extent has the prognosis of BA been characterised among different centers and countries? How has this evolved over time?
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What are the major causes and predictors of morbidity and mortality of patients with BA?
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Is centralized care essential for improving prognosis?
Paediatric registries have proven useful for detailing epidemiology of BA and for benchmarking both their short and long-term outcomes [7], [19], [20], [21], [22], [23]. The UK registry was the basis for the first report of a
Key questions
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Which strategies following the Kasai portoenterostomy (KPE) may delay or prevent the need for liver transplantation?
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What are accepted prognostic parameters for long-term success of KPE?
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What can be learned from variance in outcome of BA and KPE among different centers and countries?
The most important advances for the long-term prognosis of BA have been the development of KPE [32] and of paediatric liver transplantation. The development of effective medical treatments following KPE to delay need
Key questions/controversies
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What are the genetic susceptibility factors for BA?
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Which viruses may trigger BA and does viral infection occur prenatally?
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Does immune dysregulation or autoimmunity play a role in the progressive bile duct injury after KPE?
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Do the intestinal microbiome and innate immunity play a role in BA pathogenesis and the rapid progression of fibrosis, even after successful KPE?
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Is there evidence that a toxin or vascular insult causes human BA?
There are several phenotypes of BA, each likely with its own
Key questions
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Does prenatally discovered choledochal malformation (CM) require a different treatment strategy than postnatally diagnosed CM?
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What is the right timing of surgery in patients with asymptomatic CM?
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What is the life-long risk of bile duct malignancy in CM patients?
The diagnosis and treatment of CM has been rather controversial, probably due to the very low incidence and the large variability in clinical and anatomical presentation. CM can be diagnosed pre- or postnatally. The optimal mode of
Key questions/controversies
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Are there effective medical treatments for intractable pruritus?
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What is the spectrum of non-hepatic morbidities in affected patients?
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Which patients benefit from liver transplantation and what is the outcome?
Alagille syndrome (ALGS) is an autosomal dominant multisystem condition [68], [69] that is caused by mutations in JAG1 or NOTCH2 in the Notch signaling pathway. These mutations cause defective bile duct morphogenesis and angiogenesis, and abnormalities in skeletal, ocular, cardiovascular and
Key questions
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What are the genetic and molecular underpinnings of progressive familial intrahepatic cholestasis (PFIC) or PFIC-like diseases?
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What is the mechanism underlying the success of partial biliary diversion strategies and do they prevent the development of end-stage liver disease and hepatocellular carcinoma?
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Do patients respond to strategies to medically reduce the bile acid pool size through inhibition of ASBT?
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What are the mechanisms of increased risk of hepatocellular carcinoma in PFIC type 2?
PFIC
Key questions
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What are the most important medical risks for BA and BA-related diseases patients reaching adulthood with their native livers and what is the optimal timing of listing for liver transplantation?
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How can the transition from paediatric to adult care be facilitated through the acquisition of self-responsibility and self-management?
There is an increasing proportion of patients with BA or another cholestatic childhood disease surviving into adulthood, requiring expertise in these disorders by
Conclusions and perspectives
The prevalence of BA and other cholestatic childhood diseases is rare, which requires collaborative efforts to address the top priorities formulated for these disorders (summarised in Table 2). Dissemination of current research advances in the context of BA has led to a unifying hypothesis (Fig. 1). Isolation of a novel compound, biliatresone, causing natural BA in sheep (and in a zebrafish model) will open up a new research avenue. Areas of controversies that require new data include whether
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Authors’ contributions
Study concept and design: HJV, JAB, MD, RJS, CP; Drafting of the manuscript: HJV, JAB, MD, RAS, GM-V, JBH, RJS, DAK, BU, PFW, MS, CP; Critical revision of the manuscript for important intellectual content: all authors; editing of final draft: HJV, JAB, MD, RJS, CP.
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