Abbreviations:ALGS (Alagille syndrome), BARD (Biliary Atresia and Related Diseases), PFIC (Progressive Familial Intrahepatic Cholestasis), KPE (Kasai hepatoportoenterostomy), NeSBAR (Netherlands Study group for Biliary Atresia Registry), ChiLDReN (Childhood Liver Disease Research Network), ERCP (endoscopic retrograde cholangiopancreatography), START (Steroids in Biliary Atresia Randomised Trial), BASM (Biliary Atresia Splenic Malformation syndrome), ASBT (apical sodium dependent bile acid transporter), CM (choledochal malformation), GGT (gamma glutamyltransferase)
Diagnostic developments for neonatal cholestasis
- •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?
Top priorities for enhancing early diagnosis of neonatal cholestasis
- •We recommend a broader implementation of screening strategies, in particular the stool color card, with implementation that is tailored to country-specific infant care models. Educating parents of newborns is essential to the success of the stool color card program. To minimise diagnostic delay, patients with neonatal cholestasis should be evaluated in (or under guidance of) an experienced center that can complete the evaluation rapidly and, if indicated, can perform an intraoperative cholangiogram and KPE without delay.
Advancing the prognosis of biliary atresia
- •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?
- McClement J.W.
- Howard E.R.
- Mowat A.P.
Top priorities for advancing the prognosis of biliary atresia
- •To study the relationships between clinical and therapeutic interventions and outcomes through expanding the reach and depth of data in databases. Expanded databases in BA will also facilitate collaborative studies to “enable better assessment of disease risk, understanding of disease mechanisms, and prediction of optimal therapy” – as proposed by the National Institute of Health of the USA []. The recently launched online registry “bard-online” (www.bard-online.com) might aid in the collection of multinational data, including from countries without registries.
Treatment of biliary atresia after Kasai portoenterostomy
- •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?
Top priorities for improving the treatment success of biliary atresia after Kasai portoenterostomy
- •Identification of predictors of the responsiveness to medical treatments after KPE, through analysis of clinical, laboratory, genetic and radiological characteristics.
- •Studies of environmental, medical, and surgical approaches that may be linked to the variance in outcomes in different centers and countries.
- •Exploration of new therapeutic strategies (e.g., anti-fibrotic drugs or farnesoid X-receptor agonists) that presently are in development, particularly in adult cholestatic diseases, to assess their ability to improve native liver survival.
Developments in understanding of the pathogenesis of biliary atresia
- •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?
Top priorities to understand the pathogenesis of biliary atresia
- •Identification of genetic variants that are more relevant to pathogenesis of syndromic forms of BA, and if found, characterise their functional significance.
- •Assessment of possible influences of genetic variants on severity of disease and response to surgical treatment.
- •Systematic biological approach to identify if common immunological factors can be identified in the pathogenesis of BA and BA-related liver fibrosis and if they are amenable to therapeutic interventions.
- •Assessment of the role of specific toxins that target bile duct epithelia (e.g., biliatresone) in the pathogenesis of BA in humans.
- •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?
Top priorities to improve diagnosis and treatment of choledochal malformation
- •Development of multicenter/multi-country patient registries, such as “bard-online”, to allow (sub)classification of CM and assessment of treatment results and long-term course of disease. Over time, the data can provide greater insights into variation in disease presentation and clinical course.
- •Defining the optimal surgical procedure, short- and long-term outcome, morbidities, optimal prevention and treatment of cholelithiasis, and the life-long risk of bile duct malignancy.
Alagille syndrome: diagnosis and treatment
- •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?
Top priorities to improve diagnosis and treatment of Alagille Syndrome
- •Clinical practice studies and patient registries to define the long-term natural history of disease (both hepatic and extra-hepatic manifestations) and the effects of interventions. Long-term monitoring of sequelae of ALGS is warranted (renal disease, cardiovascular disease, and in case of cirrhosis, development of hepatocellular carcinoma) using case-control analyses from adolescent and adult ALGS patients enrolled into registries. This will require the involvement of hepatologists treating adult patients.
- •Trials targeting either the pathogenesis of end-stage liver disease or of pruritus (including antifibrotic drugs and inhibitors of ASBT) are indicated. Given the low incidence of ALGS, collaboration across many centers will be mandatory in order to conduct properly powered clinical trials.
- •Develop a better understanding of the mechanisms by which partial biliary diversion may be beneficial, and prediction of which patients can benefit from these surgical interventions.
Progressive familial intrahepatic cholestasis
- •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?
- Bustorff-Silva J.
- Sbraggia Neto L.
- Olimpio H.
- de Alcantara R.V.
- Matsushima E.
- De Tommaso A.M.
- et al.
Top priorities to improve diagnosis and treatment of PFIC
- •Establishing the relationships between PFIC genotype and therapeutic response (i.e., responsiveness to PEBD) is needed to better allow prognostication and personalise specific treatments in individual patients.
- •Determining whether newer surgical procedures to divert bile directly into the colon are effective and safe, and could replace external diversion strategies.
- •Identifying the mechanism underlying the increased risk of hepatocellular carcinoma in patients with PFIC-2. It has recently been shown that the genomic modifications in hepatocellular carcinoma of PFIC-2 patients can be distinguished from those arising in other cholestatic liver diseases [], what could provide a target for elucidation of the mechanism.
- •Assessing the therapeutic value of new pharmacologic agents to interrupt the enterohepatic circulation of bile acids or improve intracellular trafficking of mutant protein.
- •Continue to identify new genetic causes of PFIC in patients negative for current genotypes.
Transition from paediatric to adult care for BA and other cholestatic childhood disease patients
- •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?
Top priorities to improve transition from paediatric to adult care for BA or other cholestatic childhood disease patients
Conclusions and perspectives
Conflict of interest
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