Elsevier

Journal of Hepatology

Volume 65, Issue 3, September 2016, Pages 631-642
Journal of Hepatology

Review
Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

https://doi.org/10.1016/j.jhep.2016.04.032Get rights and content

Summary

Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10–19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

Section snippets

Key questions

  • Which strategies can enhance earlier recognition of neonatal cholestasis, including biliary atresia (BA)?

  • 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

  • To what extent has the prognosis of BA been characterised among different centers and countries? How has this evolved over time?

  • What are the major causes and predictors of morbidity and mortality of patients with BA?

  • 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

  • Which strategies following the Kasai portoenterostomy (KPE) may delay or prevent the need for liver transplantation?

  • What are accepted prognostic parameters for long-term success of KPE?

  • 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

  • What are the genetic susceptibility factors for BA?

  • Which viruses may trigger BA and does viral infection occur prenatally?

  • Does immune dysregulation or autoimmunity play a role in the progressive bile duct injury after KPE?

  • Do the intestinal microbiome and innate immunity play a role in BA pathogenesis and the rapid progression of fibrosis, even after successful KPE?

  • 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

  • Does prenatally discovered choledochal malformation (CM) require a different treatment strategy than postnatally diagnosed CM?

  • What is the right timing of surgery in patients with asymptomatic CM?

  • 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

  • Are there effective medical treatments for intractable pruritus?

  • What is the spectrum of non-hepatic morbidities in affected patients?

  • 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

  • What are the genetic and molecular underpinnings of progressive familial intrahepatic cholestasis (PFIC) or PFIC-like diseases?

  • 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?

  • Do patients respond to strategies to medically reduce the bile acid pool size through inhibition of ASBT?

  • What are the mechanisms of increased risk of hepatocellular carcinoma in PFIC type 2?

PFIC

Key questions

  • 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?

  • 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.

References (112)

  • A. Zani et al.

    Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup

    J Pediatr Surg

    (2015)
  • E. Caponcelli et al.

    Cystic biliary atresia: an etiologic and prognostic subgroup

    J Pediatr Surg

    (2008)
  • G. Cheng et al.

    Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

    J Hepatol

    (2013)
  • C. Oetzmann von Sochaczewski et al.

    Rotavirus particles in the extrahepatic bile duct in experimental biliary atresia

    J Pediatr Surg

    (2014)
  • P. Shivakumar et al.

    Perforin and granzymes work in synergy to mediate cholangiocyte injury in experimental biliary atresia

    J Hepatol

    (2014)
  • P. Shivakumar et al.

    Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia

    Gastroenterology

    (2007)
  • B.R. Lu et al.

    Alpha-enolase autoantibodies cross-reactive to viral proteins in a mouse model of biliary atresia

    Gastroenterology

    (2010)
  • R.M. Tucker et al.

    Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia

    J Hepatol

    (2013)
  • R. Hill et al.

    Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome

    J Pediatr Surg

    (2015)
  • J.L. dos Santos et al.

    Medial thickening of hepatic artery branches in biliary atresia. A morphometric study

    J Pediatr Surg

    (2005)
  • S.K. Narayanan et al.

    Hepaticoduodenostomy vs. hepaticojejunostomy after resection of choledochal cyst: a systematic review and meta-analysis

    J Pediatr Surg

    (2013)
  • D. Alagille et al.

    Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur

    J Pediatr

    (1975)
  • E. Jacquemin

    Progressive familial intrahepatic cholestasis

    Clin Res Hepatol Gastroenterol

    (2012)
  • J.C. Emond et al.

    Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease)

    J Pediatr Surg

    (1995)
  • P.F. Whitington et al.

    Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis

    Gastroenterology

    (1988)
  • H. Arnell et al.

    Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis

    J Pediatr Surg

    (2008)
  • K.M. Emerick et al.

    Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome

    Hepatology

    (2002)
  • M.S. Clifton et al.

    Button cholecystostomy for management of progressive familial intrahepatic cholestasis syndromes

    J Pediatr Surg

    (2011)
  • C.M. Hollands et al.

    Ileal exclusion for Byler’s disease: an alternative surgical approach with promising early results for pruritus

    J Pediatr Surg

    (1998)
  • J. Bustorff-Silva et al.

    Partial internal biliary diversion through a cholecystojejunocolonic anastomosis–a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report

    J Pediatr Surg

    (2007)
  • V. Moyer et al.

    Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

    J Pediatr Gastroenterol Nutr

    (2004)
  • American Academy of Pediatrics Subcommittee on Hyperbilirubinemia

    Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation

    Pediatrics

    (2004)
  • S.I. Wadhwani et al.

    Prolonged neonatal jaundice and the diagnosis of biliary atresia: a single-center analysis of trends in age at diagnosis and outcomes

    Pediatrics

    (2008)
  • T.H. Lien et al.

    Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan

    Hepatology

    (2011)
  • B.E. Wildhaber

    Screening for biliary atresia: Swiss stool color card

    Hepatology

    (2011)
  • Y.H. Gu et al.

    Stool color card screening for early detection of biliary atresia and long-term native liver survival: a 19-year cohort study in Japan

    J Pediatr

    (2015)
  • R.A. Schreiber et al.

    Home-based screening for biliary atresia using infant stool colour cards: a large-scale prospective cohort study and cost-effectiveness analysis

    J Med Screen

    (2014)
  • S. Harpavat et al.

    Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth

    Pediatrics

    (2011)
  • R. Keil et al.

    Diagnostic efficacy of ERCP in cholestatic infants and neonates–a retrospective study on a large series

    Endoscopy

    (2010)
  • N.P. Shanmugam et al.

    Selective use of endoscopic retrograde cholangiopancreatography in the diagnosis of biliary atresia in infants younger than 100 days

    J Pediatr Gastroenterol Nutr

    (2009)
  • T.M. Humphrey et al.

    Biliary atresia: US diagnosis

    Radiology

    (2007)
  • P. Farrant et al.

    Improved diagnosis of extraheptic biliary atresia by high frequency ultrasound of the gall bladder

    Br J Radiol

    (2001)
  • R.A. Schreiber et al.

    Biliary atresia: the Canadian experience

    J Pediatr

    (2007)
  • W. de Vries et al.

    Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008

    J Pediatr

    (2012)
  • H. Lampela et al.

    National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes

    Scand J Gastroenterol

    (2012)
  • R.A. Schreiber et al.

    Biliary atresia in Canada: the effect of centre caseload experience on outcome

    J Pediatr Gastroenterol Nutr

    (2010)
  • J.W. McClement et al.

    Results of surgical treatment for extrahepatic biliary atresia in United Kingdom 1980–2. Survey conducted on behalf of the British Paediatric Association Gastroenterology Group and the British Association of Paediatric Surgeons

    Br Med J (Clin Res Ed)

    (1985)
  • B.L. Shneider et al.

    A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000

    J Pediatr

    (2006)
  • E. Livesey et al.

    Epidemiology of biliary atresia in England and Wales (1999–2006)

    Arch Dis Child Fetal Neonatal Ed

    (2009)
  • C. Chardot et al.

    Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996

    Hepatology

    (1999)
  • Cited by (0)

    View full text