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EBioMedicine Dec 2021Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of... (Review)
Review
Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of liver development with a focus on cholangiocyte differentiation and how use of technical platforms, including rodent, zebrafish and organoid models, advances our understanding of Biliary Atresia. This is followed by a description of potential pathomechanisms, such as autoimmune responses, inflammation, disturbed apical-basal cell polarity, primary cilia dysfunction as well as beta-amyloid accumulation. Finally, we describe current and emerging diagnostic opportunities and recent translation breakthroughs for Biliary Atresia in the area of emerging therapy development, including immunomodulation and organoid-based systems for liver and bile duct repair.
Topics: Animals; Bile Ducts; Biliary Atresia; Cell Differentiation; Disease Models, Animal; Epithelial Cells; Humans; Organoids
PubMed: 34781099
DOI: 10.1016/j.ebiom.2021.103689 -
NeoReviews Dec 2021Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis,... (Review)
Review
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
Topics: Biliary Atresia; Child; Cholestasis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Liver Diseases
PubMed: 34850148
DOI: 10.1542/neo.22-12-e819 -
Clinics in Liver Disease Aug 2022Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow... (Review)
Review
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
Topics: Biliary Atresia; Child; Humans; Infant; Liver Transplantation
PubMed: 35868678
DOI: 10.1016/j.cld.2022.03.001 -
Hepatology (Baltimore, Md.) Sep 2018Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage,... (Review)
Review
Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a prenatal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g., biliatresone) and of viruses (e.g., cytomegalovirus) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate proinflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. (Hepatology 2018; 00:000-000).
Topics: Biliary Atresia; Humans; Infant, Newborn
PubMed: 29604222
DOI: 10.1002/hep.29905 -
Journal of Autoimmunity Sep 2016Biliary atresia presents as an obliterative cholangiopathy with neonatal jaundice and pale stools. The disease exhibits aetiological heterogeneity with a multiplicity of... (Review)
Review
Biliary atresia presents as an obliterative cholangiopathy with neonatal jaundice and pale stools. The disease exhibits aetiological heterogeneity with a multiplicity of potential causative factors, both developmental and environmental. A number of clinical variants making up a minority of all cases can be defined relatively precisely which match suggested aetiology better although in most it still remains speculative. These include the syndromic form (BASM), the cystic form and those associated with CMV IgM antibodies. We review not only the clinical evidence for a developmental or an immune-mediated aetiology perhaps triggered by perinatal viral exposure but also several other recently suggested concepts such as microchimerism, gene susceptibility and environmental toxins.
Topics: Bile Ducts; Biliary Atresia; Biopsy; Chimerism; Cytomegalovirus; Environmental Exposure; Genetic Predisposition to Disease; Humans; Immunity, Humoral; Immunoglobulin M; Incidence; Infant; Liver; Liver Function Tests; T-Lymphocytes; Ultrasonography
PubMed: 27346637
DOI: 10.1016/j.jaut.2016.06.005 -
Pediatric Radiology Apr 2022Biliary atresia is challenging to diagnose because many of the clinical and imaging features of this condition overlap with those of other causes of cholestasis in... (Review)
Review
Biliary atresia is challenging to diagnose because many of the clinical and imaging features of this condition overlap with those of other causes of cholestasis in newborns. When jaundice persists beyond 2 weeks of age, the neonate should be evaluated for cholestasis, and biliary atresia - the most common cause of neonatal cholestasis - should be considered. It is critical to diagnose biliary atresia early because failure to treat can result in hepatic fibrosis and death in less than 1 year. In this paper, we review the current diagnostic imaging methods, differential considerations and treatment options for biliary atresia.
Topics: Biliary Atresia; Cholestasis; Diagnosis, Differential; Humans; Infant; Infant, Newborn
PubMed: 34331566
DOI: 10.1007/s00247-021-05148-y -
Clinical and Translational Medicine Nov 2022Biliary atresia (BA) is a devastating inflammatory and fibrosing cholangiopathy of neonates with unknown aetiology. We aim to investigate the relationship between these...
BACKGROUND
Biliary atresia (BA) is a devastating inflammatory and fibrosing cholangiopathy of neonates with unknown aetiology. We aim to investigate the relationship between these two main characteristics.
METHODS
Single-cell RNA sequencing and spatial transcriptomics were performed on liver samples from a cohort of 14 objects (BA: n = 6; control: n = 8). We conducted data integration and cell-type annotation based on gene expression profiling. Furthermore, we identified fibrosis-related immune cells according to their spatial locations, GO and KEGG analysis. Finally, SPOTlight and CIBERSORTx were used to deconvolute ST data and microarray data of the GSE46960 cohorts, respectively.
RESULTS
Immune subpopulations inhabiting the 'fibrotic niche' (areas of scarring), comprising 'intermediate' CD14 CD16 monocytes, scar-associated macrophages, natural killer T cells, transitional B cells and FCN3 neutrophils were identified. GO and KEGG analyses showed that pathways including 'positive regulation of smooth muscle cell/fibroblast proliferation' and 'positive regulation of/response to VEGFR/VEGF/EGFR/FGF' were enriched in these cell types. Interactions analysis showed that communication among 'FGF_FGFR', 'RPS19-C5AR1', 'CD74_COPA/MIF/APP' and 'TNFRSF1A/B_GRN' was extensive. Finally, the results of deconvolution for ST data and microarray data validated that the proportions of certain identified fibrosis-related cell types we identified were increased in BA.
DISCUSSION
Fibrosis is an important feature of BA, in which the immune system plays an important role. Our work reveals the subpopulations of immune cells enriched in the fibrotic niche of BA liver, as well as key related pathways and molecules; some are highlighted for the first time in liver fibrosis. These newly identified interactions might partly explain why the rate of liver fibrosis occurs much faster in BA than in other liver diseases.
CONCLUSION
Our study revealed the molecular, cellular and spatial immune microenvironment of the fibrotic niche of BA.
Topics: Infant, Newborn; Humans; Biliary Atresia; Transcriptome; Liver Cirrhosis; Liver Diseases
PubMed: 36333281
DOI: 10.1002/ctm2.1070 -
Pediatrics in Review Nov 2022
Topics: Humans; Infant; Biliary Atresia
PubMed: 36316259
DOI: 10.1542/pir.2021-005287 -
JAMA Mar 2020Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is...
IMPORTANCE
Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is difficult to detect during its early stages.
OBJECTIVE
To determine the diagnostic yield of newborn screening for biliary atresia with direct or conjugated bilirubin measurements and to evaluate the association of screening implementation with clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS
A cross-sectional screening study of 124 385 infants born at 14 Texas hospitals between January 2015 and June 2018; and a pre-post study of 43 infants who underwent the Kasai portoenterostomy as treatment for biliary atresia at the region's largest pediatric hepatology center before (January 2008-June 2011) or after (January 2015-June 2018) screening implementation. Final follow-up occurred on July 15, 2019.
EXPOSURES
Two-stage screening with direct or conjugated bilirubin measurements. In stage 1, all newborns were tested within the first 60 hours of life, with a positive screening result defined as bilirubin levels exceeding derived 95th percentile reference intervals. In stage 2, infants who had a positive screening result in stage 1 were retested at or before the 2-week well-child visit, with a positive screening result defined as bilirubin levels greater than the stage 1 result or greater than 1 mg/dL.
MAIN OUTCOMES AND MEASURES
The primary outcomes of the screening study were sensitivity, specificity, positive predictive value, and negative predictive value based on infants testing positive in both stages. The reference standard was biliary atresia diagnosed at the region's pediatric hepatology centers. The primary outcome of the pre-post study was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia.
RESULTS
Of 124 385 newborns in the screening study, 49.2% were female, 87.6% were of term gestational age, 70.0% were white, and 48.1% were Hispanic. Screening identified the 7 known infants with biliary atresia with a sensitivity of 100% (95% CI, 56.1%-100.0%), a specificity of 99.9% (95% CI, 99.9%-99.9%), a positive predictive value of 5.9% (95% CI, 2.6%-12.2%), and a negative predictive value of 100.0% (95% CI, 100.0%-100.0%). In the pre-post study, 24 infants were treated before screening implementation and 19 infants were treated after screening implementation (including 6 of 7 from the screening study, 7 from screening at nonstudy hospitals, and 6 from referrals because of clinical symptoms). The age infants underwent the Kasai portoenterostomy was significantly younger after screening was implemented (mean age, 56 days [SD, 19 days] before screening implementation vs 36 days [SD, 22 days] after screening implementation; between-group difference, 19 days [95% CI, 7-32 days]; P = .004).
CONCLUSIONS AND RELEVANCE
Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population, although the 95% CI around the sensitivity estimate was wide and the study design did not ensure complete ascertainment of false-negative results. Research is needed in larger populations to obtain more precise estimates of diagnostic yield and to better understand the clinical outcomes and cost-effectiveness of this screening approach.
Topics: Age Factors; Biliary Atresia; Bilirubin; Cross-Sectional Studies; Female; Humans; Infant; Infant, Newborn; Liver Transplantation; Male; Neonatal Screening; Portoenterostomy, Hepatic; Predictive Value of Tests; Reference Values; Sensitivity and Specificity; Time-to-Treatment
PubMed: 32207797
DOI: 10.1001/jama.2020.0837 -
Liver Transplantation : Official... May 2022
Topics: Biliary Atresia; Humans; Infant; Liver Transplantation
PubMed: 35189027
DOI: 10.1002/lt.26432