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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 -
Drugs Jan 2022Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the... (Review)
Review
Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
Topics: Humans; Alagille Syndrome; Biliary Atresia; Carrier Proteins; Cholestasis, Intrahepatic; Clinical Trials as Topic; Drug Approval; Membrane Glycoproteins; United States; United States Food and Drug Administration; Benzothiepins
PubMed: 34813049
DOI: 10.1007/s40265-021-01649-0 -
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 -
Cell Dec 2020Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA...
Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
Topics: Animals; Antigens, CD20; B-Lymphocytes; Biliary Atresia; Biopsy; CX3C Chemokine Receptor 1; Cell Death; Cell Line; Cell Proliferation; Cell Transdifferentiation; Child; Child, Preschool; Cohort Studies; Cytotoxicity, Immunologic; Disease Models, Animal; Female; Humans; Immunoglobulin G; Infant; Inflammation; Killer Cells, Natural; Kupffer Cells; Liver; Liver Cirrhosis; Lymphocyte Depletion; Lymphopoiesis; Male; Mice, Inbred BALB C; Phagocytosis; RNA; Rituximab; Rotavirus; Single-Cell Analysis; Th1 Cells; Th17 Cells
PubMed: 33248023
DOI: 10.1016/j.cell.2020.10.048 -
Hepatology (Baltimore, Md.) Jan 2022Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of liver dysfunction. Our aim was to investigate the mechanisms linked to abnormal cholangiocyte development.
APPROACH AND RESULTS
We generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls. Organoids emerged from biliary atresia livers and controls and grew as lumen-containing spheres with an epithelial lining of cytokeratin-19 albumin SOX17 cholangiocyte-like cells. Spheres had similar gross morphology in all three groups and expressed cholangiocyte-enriched genes. In biliary atresia, cholangiocyte-like cells lacked a basal positioning of the nucleus, expressed fewer developmental and functional markers, and displayed misorientation of cilia. They aberrantly expressed F-actin, β-catenin, and Ezrin, had low signals for the tight junction protein zonula occludens-1 (ZO-1), and displayed increased permeability as evidenced by a higher Rhodamine-123 (R123) signal inside organoids after verapamil treatment. Biliary atresia organoids had decreased expression of genes related to EGF signaling and FGF2 signaling. When treated with EGF+FGF2, biliary atresia organoids expressed differentiation (cytokeratin 7 and hepatocyte nuclear factor 1 homeobox B) and functional (somatostatin receptor 2, cystic fibrosis transmembrane conductance regulator [CFTR], aquaporin 1) markers, restored polarity with improved localization of F-actin, β-catenin and ZO-1, increased CFTR function, and decreased uptake of R123.
CONCLUSIONS
Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.
Topics: Adolescent; Bile Ducts; Biliary Atresia; Biopsy; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Cholestasis; Epithelial Cells; Healthy Volunteers; Humans; Infant; Infant, Newborn; Organoids; Primary Cell Culture; Tight Junctions
PubMed: 34392560
DOI: 10.1002/hep.32107 -
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 -
Journal of Hepatology Nov 2022We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the...
BACKGROUND & AIMS
We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA.
METHODS
Immune cells from the livers of mice with rhesus rotavirus-induced BA were analysed. Single-cell RNA-sequencing was performed to specifically analyse Gr-1 (Ly6C/Ly6G) cells in the liver. Gene expression profiles of CD177 cells were analysed using the Smart-Seq RNA-sequencing method, and the pathogenesis of BA was examined in Cd177 mice. Neutrophil extracellular trap (NET) inhibitors were used to determine the role of CD177 cell-derived NETs in BA-associated bile duct damage, and a pilot clinical study evaluated the potential effects of N-acetylcysteine on NET release in BA.
RESULTS
Increased levels of Gr-1 cells were observed in the livers of mice with rhesus rotavirus-induced BA. RNA-sequencing analysis revealed that CD177 cells were the main population of Gr-1 cells and expressed elevated levels of both interferon-stimulated and neutrophil degranulation genes. Cd177 BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality. High numbers of mitochondria were detected in CD177 cells derived from mice with BA; these cells were associated with increased levels of reactive oxygen species and increased NET formation, which induced the apoptosis of biliary epithelial cells in cocultures. In a pilot clinical study, the administration of N-acetylcysteine to patients with BA reduced CD177 cell numbers and reactive oxygen species levels, indicating a potential beneficial effect.
CONCLUSIONS
Our data indicate that CD177 cells play an important role in the initiation of BA pathogenesis via NET formation.
CLINICAL TRIAL REGISTRATION
The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505).
LAY SUMMARY
Neutrophils (a type of innate immune cell, i.e. an immune cell that doesn't target a specific antigen) are thought to play a role in the development of biliary atresia (a rare but potentially lethal condition of the bile ducts that occurs in infants). Herein, we found that neutrophils expressing a particular protein (CD177) played an important role in bile duct damage by releasing a special structure (NET) that can trap and kill pathogens but that can also cause severe tissue damage. A pilot study in patients with biliary atresia showed that inhibiting NETs could have a beneficial effect.
Topics: Acetylcysteine; Animals; Biliary Atresia; Disease Models, Animal; Extracellular Traps; Interferons; Mice; Mice, Inbred BALB C; Pilot Projects; RNA; Reactive Oxygen Species; Rotavirus
PubMed: 35803543
DOI: 10.1016/j.jhep.2022.06.015 -
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