Biliary Atresia

Complex MONDO:0008867 Pathograph 68 Show in embeddings browser Neonatal Cholestasis

Biliary atresia is an infantile fibro-obliterative cholangiopathy that obstructs bile drainage and causes conjugated hyperbilirubinemia, pale stools and progressive liver disease. Injury commonly begins before visible jaundice, and abnormal direct/conjugated bilirubin can be present shortly after birth. Clinical presentations include isolated disease, laterality-associated malformations and cystic biliary remnants. Genetic susceptibility, developmental abnormalities and dysregulated immune responses contribute to mechanistic models, while specific viral or toxin causes remain unproven in humans. Kasai portoenterostomy can restore drainage and prolong native-liver survival, but many patients develop continuing fibrosis, portal hypertension or recurrent cholangitis and require liver transplantation.

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Classifications

Harrison's Part

👪

Inheritance

Non-Mendelian / multifactorial HP:0001426

Usually sporadic and non-Mendelian. A systematic review of 35 reported twin pairs found 34 discordant pairs, but published cases do not provide a population recurrence or penetrance estimate. Common susceptibility alleles and rare candidate variants may contribute. Biallelic PKD1L1 variants in five of 67 broadly defined BASM cases support a candidate recessive contribution in some patients, not an established Mendelian explanation for BASM as a whole.

Non-Mendelian inheritance

Show evidence (2 references)

PMID:32504124 SUPPORT REVIEW SYNTHESIS Human Clinical

"97.1% twins were discordant, among 55.9% of which were monozygotic twin sets, indicating that BA may be related to genetic phenotype or penetrance."

Published-case synthesis, with marked twin discordance; it does not estimate population penetrance or prove a particular environmental or epigenetic cause.

PMID:30664273 SUPPORT DIRECT Human Clinical

"Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans."

Candidate biallelic variants in a minority of the ascertained BASM cohort.

◆

Subtypes

Isolated (non-syndromic) biliary atresia

Biliary atresia without a recognized associated malformation syndrome, comprising most cases. The historical term perinatal form describes presentation, not proof of postnatal acquisition: direct/conjugated bilirubin may already be abnormal in the first days of life.

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the majority of cases, currently termed isolated BA, there are still too few clues as to aetiology or indeed pathogenesis."

Review synthesis of this clinical subgroup; definitions and overlap vary.

Biliary atresia splenic malformation syndrome MONDO:0016577

Biliary atresia with splenic and other laterality-associated malformations, including polysplenia or asplenia, abnormal visceral situs, intestinal malrotation, preduodenal portal vein and interrupted inferior vena cava. Definitions vary between cohorts. It accounts for roughly 10–15% in some Western series but is much less frequent in some Asian series; prognosis depends on associated anatomy and clinical context.

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The commonest of these is the Biliary Atresia Splenic Malformation (BASM) syndrome, which accounts for about 10–15% of European and American series ..., but is distinctly rare in Chinese and Japanese series (<2%) ...."

Review synthesis of this clinical subgroup; definitions and overlap vary.

Cystic biliary atresia

Biliary atresia with cystic dilatation of part of the extrahepatic remnant, sometimes detected prenatally. It must be distinguished from a choledochal cyst. Timely Kasai surgery often gives better jaundice-clearance outcomes than other biliary-atresia variants, although late deterioration can still occur.

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Post-operatively, these infants have >75% chance of clearance of jaundice and native liver preservation, though their prognosis does appear to have a marked relationship with age at surgery ...."

Review synthesis of this clinical subgroup; definitions and overlap vary.

Cytomegalovirus-associated biliary atresia

Clinical subgroup with evidence of CMV infection at presentation, often defined by CMV IgM. Associations with more severe disease and poorer outcomes have been reported, but seropositivity at diagnosis does not establish congenital infection, timing, or viral causation of biliary atresia.

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Therefore, using CMV IgM antibodies as a marker of infection up to 30% of Chinese BA series have been positive ... compared to about 10% in a UK series ...."

Review synthesis of this clinical subgroup; definitions and overlap vary.

Cardiac-associated biliary atresia

A clinical risk subgroup with cardiac anomalies, partly overlapping BASM. The phenotype is heterogeneous and does not establish one common pathogenesis; hemodynamically important heart disease affects operative planning and prognosis.

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Indeed, when we reviewed our experience of biliary atresia-associated cardiac anomalies (n = 37), features indicative of BASM were present in 48% ...."

Review synthesis of this clinical subgroup; definitions and overlap vary.

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Pathophysiology

Cholangiocyte Injury of the Bile Duct Epithelium

Cholangiocyte epithelial damage is a central lesion. RRV infection and biliatresone exposure produce experimentally defined injury in mice and zebrafish, respectively; neither demonstrates the initiating cause in human disease. Immune attack and developmental susceptibility may contribute through distinct, incompletely resolved routes.

extrahepatic cholangiocyte CL:0019020 intrahepatic cholangiocyte CL:0002538

cholangiocyte apoptotic process GO:1902488 ↑ INCREASED

Animal models

Rhesus rotavirus (RRV) neonatal mouse model Mouse partially recapitulates Early infection produces biliary epithelial injury and obstruction.

Biliatresone zebrafish model Zebrafish recapitulates Biliatresone reproduces selective extrahepatic-cholangiocyte injury, modeling the toxin route to the cholangiocyte-injury node.

Low-dose prenatal biliatresone mouse exposure Mouse fails to recapitulate The tested prenatal exposure did not induce the histologic injury phenotype.

Downstream

Immune-Mediated Periductal Inflammation Epithelial injury participates in the fibroinflammatory response; initial human triggers remain uncertain.

Ductular Epithelial Expansion A reactive epithelial response accompanies obstructive injury; lineage origin remains partly inferred.

Show evidence (2 references)

PMID:23844248 SUPPORT DIRECT Model Organism

"the amount of cholangiocyte epithelial damage and bile duct edema was significantly greater in the early infection group"

Histologic epithelial injury in the time-dependent RRV mouse model.

PMID:27102575 SUPPORT Model Organism

"Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae."

The plant toxin biliatresone selectively injures extrahepatic cholangiocytes, demonstrating that a targeted cholangiocyte insult can initiate a BA-like extrahepatic cholangiopathy.

Immune-Mediated Periductal Inflammation

Periductal innate and adaptive immune activation accompanies biliary epithelial injury. Human tissue studies show inflammatory infiltrates and regulatory abnormalities; perturbation studies in neonatal RRV mice support contributions from Th1, Th17, B-cell and macrophage pathways. No single experimental immune mechanism establishes the cause of all human cases.

T-helper 1 cell CL:0000545 cytotoxic T cell CL:0000910 T-helper 17 cell CL:0000899 macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED T cell mediated cytotoxicity GO:0001913 ↑ INCREASED

Downstream

Portal Mesenchymal Cell Activation Immune populations associate spatially with fibrotic tissue; inferred profibrotic signaling requires functional validation.

Show evidence (2 references)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mild lymphocytic inflammation is usually present within portal tracts in BA. Other inflammatory cells, including eosinophils, plasma cells and macrophages, are also present."

Human pathology synthesis describes mixed portal inflammation.

PMID:36333281 SUPPORT DIRECT Human Clinical

"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."

Spatial association of immune populations with scar tissue, not a causal intervention.

Portal Mesenchymal Cell Activation

Sustained inflammation activates portal fibroblasts and transdifferentiates hepatic stellate cells into a myofibroblast-like, matrix-secreting phenotype — the organ-specific mesenchymal activation step of the conserved fibrotic response in the biliary atresia portal tract.

hepatic stellate cell CL:0000632

hepatic stellate cell activation GO:0035733 ↑ INCREASED

Downstream

Fibro-obliteration of the Biliary Tree Activated mesenchymal cells contribute excess matrix to duct scarring.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The transformation and proliferation of hepatic stellate cells (HSCs) from fat-storing cells to myofibroblasts in BA plays an important role in hepatic fibrogenesis. HSCs are responsible for increased extracellular matrix, which leads to progressive scarring"

The pathology review supports mesenchymal activation and matrix production in biliary atresia.

Fibro-obliteration of the Biliary Tree

Activated portal myofibroblasts deposit excess extracellular matrix around and within the injured ducts, producing a fibro-obliterative process that progressively narrows and obliterates the extrahepatic biliary tree and damages the intrahepatic ducts, forming the characteristic fibrous remnant at the porta hepatis. This obliteration is the anatomic substrate that the Kasai portoenterostomy attempts to bypass.

collagen fibril organization GO:0030199 ↑ INCREASED

Downstream

Impaired Bile Drainage Scarring obstructs the biliary lumen.

Show evidence (2 references)

PMID:32518681 SUPPORT REVIEW SYNTHESIS Human Clinical

"Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen."

Portal-tract fibroplasia and ductular reaction on biopsy evidence the fibro-obliterative remodeling of this node.

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The destructive fibroinflammatory process that underlies BA, may involve a short segment of a duct, an entire duct or the entire biliary system."

Fibroinflammatory remodeling of the resected biliary tree.

Impaired Bile Drainage

Obstruction of the biliary tree reduces delivery of bile to the intestine and retains conjugated bilirubin and bile acids. Drainage may remain impaired after Kasai, while ongoing intrahepatic disease contributes to later liver injury.

bile acid secretion GO:0032782 ↓ DECREASED

Downstream

Biliary Cirrhotic Remodeling Persistent obstruction contributes to progressive liver injury and cirrhotic remodeling.

Impaired Intestinal Lipid Absorption Reduced bile delivery impairs nutrient absorption.

Conjugated hyperbilirubinemia Conjugated hyperbilirubinemia is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Prolonged neonatal jaundice Prolonged neonatal jaundice is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Acholic stools Acholic stools is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Dark urine Dark urine is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Hepatomegaly Hepatomegaly is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Pruritus Pruritus is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (1 reference)

PMID:32518681 SUPPORT REVIEW SYNTHESIS Human Clinical

"Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice."

Obstructive bile-flow impairment and neonatal jaundice, distinct from subsequent cirrhotic remodeling.

Embryonic Patterning Disturbance

The combination of biliary atresia with splenic, visceral-situs, vascular and cardiac malformations suggests disturbed embryonic patterning in BASM. CFC1, a NODAL coreceptor, and PKD1L1 are candidate links to left-right signaling in a subset, with supportive animal data; the underlying defect remains unresolved in most patients. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

CFC1 hgnc:18292

CFC1 coreceptor activity GO:0015026

Downstream

Disrupted Biliary Morphogenesis A candidate developmental contribution in BASM; the molecular intermediate is unresolved.

Polysplenia Polysplenia is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Abnormal abdominal situs Abnormal abdominal situs is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Asplenia Asplenia is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Intestinal malrotation Intestinal malrotation is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Congenital heart defects Congenital heart defects is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (2 references)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"As this biliary timeline is shared by the determination of visceral situs, spleen formation, evolution of the portal venous and caval venous system anomalies it is not too much to speculate that BASM is also an embryonic defect."

Developmental interpretation of the BASM phenotype, not a proven single molecular cause.

PMID:18162845 SUPPORT DIRECT Human Clinical

"The heterozygous transition c.433G>A (Ala145Thr) located in exon 5 was identified in 5 patients, with a twice-higher frequency than in control patients."

Small candidate-gene study; no Mendelian penetrance inference.

Disrupted Biliary Morphogenesis

Susceptibility-gene perturbations can impair developing biliary networks. Gpc1, add3a, arf6 and pkd1l1 studies provide distinct experimental routes, but sparse fish ducts are not equivalent to the human fibro-obliterated extrahepatic remnant. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

PKD1L1 hgnc:18053

PKD1L1 calcium channel activity GO:0005262

Animal models

Gpc1 knockdown zebrafish Zebrafish perturbs Knockdown impairs the biliary network; gpc1 mRNA rescue and partial cyclopamine rescue support specificity and Hedgehog involvement.

Add3a dosage perturbation zebrafish Zebrafish perturbs Both increased and decreased add3a dosage perturb biliary development.

Pkd1l1 mutant zebrafish Zebrafish perturbs Mutants have laterality abnormalities, sparse intrahepatic biliary networks and impaired biliary transport; most retain a gallbladder.

Downstream

Impaired Bile Drainage Experimental developmental defects impair transport; their contribution in individual human cases varies.

Show evidence (2 references)

PMID:23336978 SUPPORT DIRECT Model Organism

"Knockdown of gpc1 in zebrafish led to developmental biliary defects."

Experimental biliary developmental phenotype.

PMID:37675454 SUPPORT DIRECT Model Organism

"These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system"

Fish loss-of-function data support developmental plausibility rather than variant-specific human causality.

Altered ADD3 Regulatory Activity

At the human ADD3 susceptibility locus, H69 cholangiocyte reporter assays detect allele-dependent activity in four fragments: risk haplotypes increase activity at E2, E4 and E10 but decrease it at E9. The fragment containing lead marker rs17095355 has no significant allelic difference. These assays concern cloned regulatory elements; they do not establish endogenous expression changes, a causal nucleotide, or chromatin contacts in patient cholangiocytes. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

ADD3 hgnc:245

ADD3 actin binding GO:0003779

Experimental models

H69 ADD3 regulatory-element reporter assays CELL LINE Reports allelic transcriptional activity of cloned DNA fragments.

Downstream

Disrupted Biliary Morphogenesis Reporter effects and fish dosage experiments suggest a susceptibility mechanism; they do not trace one human allele through to disease.

Show evidence (1 reference)

PMID:41589307 SUPPORT DIRECT In Vitro

"four elements (E2, E4, E9 and E10) showed allele-specific reporter activity differences"

Direct reporter measurement in the H69 human cholangiocyte cell line.

Excess Hedgehog Signaling in Developmental Models

Gpc1 or add3a knockdown increases Hedgehog-pathway readouts in zebrafish. Cyclopamine partially rescues the associated biliary defects, supporting a model-specific contribution of excessive signaling. A uniform Hedgehog abnormality caused by each human susceptibility allele has not been demonstrated. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

GPC1 hgnc:4449

smoothened signaling pathway GO:0007224 ↑ INCREASED

GPC1 growth factor binding GO:0019838

Downstream

Disrupted Biliary Morphogenesis Inhibitor rescue supports a Hedgehog contribution in the gpc1 fish model.

Show evidence (2 references)

PMID:23336978 SUPPORT DIRECT Model Organism

"Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype."

Pharmacologic rescue in fish.

PMID:27526058 SUPPORT DIRECT Model Organism

"MO-mediated knockdown of add3a also showed higher mRNA expression of hedgehog (Hh) targets. Inhibition of Hh signaling rescued biliary defects caused by add3a knockdown."

An additional fish perturbation/rescue route.

Reduced EGFR-ARF6 Developmental Signaling

Arf6 knockdown and EGFR inhibition produce sparse intrahepatic biliary networks and impaired bile transport in zebrafish, with arf6 mRNA rescue. The human noncoding association does not directly establish deficient ARF6 expression or this complete pathway in affected infants. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

ARF6 hgnc:659

ARF6 GTPase activity GO:0003924

Animal models

Arf6 knockdown zebrafish Zebrafish perturbs Perturbation and rescue test EGFR–ARF6 involvement in biliary network development.

Downstream

Disrupted Biliary Morphogenesis Developmental perturbation impairs the experimental intrahepatic network.

Show evidence (1 reference)

PMID:26379158 SUPPORT DIRECT Model Organism

"Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA."

Perturbation and rescue support EGFR–ARF6 involvement in fish development.

Impaired Extrahepatic Duct Elastic-Fiber Organization

Adult Efemp1 heterozygous mouse ducts have fewer organized elastic fibers despite preserved total elastin, with altered responses to pressure. This suggests structural susceptibility involving fibulin-3, but neither spontaneous atresia nor the direction of effect of human EFEMP1 risk variants was established. A mechanical contribution to epithelial vulnerability remains a hypothesis without a demonstrated causal edge to injury. The molecular-function annotation identifies the linked protein’s normal activity; it does not establish the functional effect of each human susceptibility allele.

EFEMP1 hgnc:3218

EFEMP1 extracellular matrix structural constituent GO:0005201

Animal models

Efemp1 heterozygous mouse duct mechanics Mouse perturbs Reduced organized elastic fibers accompany altered pressure-dependent duct mechanics.

Show evidence (2 references)

PMID:39717503 SUPPORT DIRECT Model Organism

"in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased by approximately half."

Mouse matrix-organization phenotype.

PMID:39717503 SUPPORT DIRECT Model Organism

"Pressure myography showed that Efemp1 +/- ducts have altered mechanics compared to control ducts"

Measured duct mechanics following heterozygous gene loss.

Reduced Cholangiocyte Glutathione Reserve

In zebrafish, extrahepatic cholangiocytes have a relatively oxidized glutathione state and are susceptible to biliatresone-induced redox stress. Glutathione depletion sensitizes biliary cells, whereas NAC supplementation or Nrf2 activation reduces injury. This is a toxin-model mechanism; intrinsic glutathione deficiency has not been established as a general initiating human defect.

glutathione metabolic process GO:0006749

Animal models

Biliatresone zebrafish model Zebrafish perturbs Glutathione depletion increases toxin susceptibility, while antioxidant manipulations reduce injury.

Downstream

Cholangiocyte Injury of the Bile Duct Epithelium Lower reserve sensitizes fish cholangiocytes to electrophilic toxin injury.

Show evidence (1 reference)

PMID:27102575 SUPPORT DIRECT Model Organism

"GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic cholangiocytes to the toxin"

Manipulating antioxidant reserve changes susceptibility in fish.

Reduced Regulatory T-Cell Restraint

Human BA samples show reduced Treg frequency and inadequate CTLA-4 upregulation, including blood collected at transplantation; these observations do not establish an initiating neonatal defect. Treg augmentation after infection improves survival and biliary injury in the RRV mouse model, supporting a regulatory contribution to ongoing inflammation.

regulatory T cell CL:0000815

Animal models

Treg augmentation in RRV mouse Mouse rescues Treatment after infection expands Tregs, improves survival and reduces biliary inflammation.

Downstream

Immune-Mediated Periductal Inflammation Treg augmentation reduces model inflammation; the human initiating role is unproven.

Show evidence (2 references)

PMID:39131670 SUPPORT DIRECT Human Clinical

"Patients with BA had decreased peripheral blood Treg frequency and lack of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) upregulation despite a highly activated, effector Treg phenotype."

Human clinical sample phenotype, with stage and comparator limitations.

PMID:39131670 SUPPORT DIRECT Model Organism

"Treg augmentation in the murine model led to increased survival, decreased direct bilirubin levels and liver inflammation, and expansion of resident macrophages."

Intervention result in RRV mice, not established human treatment efficacy.

Th1-Associated Cytotoxic Inflammation

T-bet-dependent inflammatory and cytotoxic programs contribute to duct injury in the RRV mouse model. T-bet deletion reduces these programs and preserves duct patency in many mice, but cholestatic symptoms and mortality persist. Duct patency therefore does not establish complete disease rescue.

Animal models

T-bet-deficient RRV mouse Mouse perturbs T-bet loss preserves duct patency despite continued obstructive-cholangiopathy symptoms and unchanged mortality.

Downstream

Cholangiocyte Injury of the Bile Duct Epithelium T-bet perturbation alters biliary injury without rescuing survival.

Show evidence (1 reference)

PMID:34943969 SUPPORT DIRECT Model Organism

"Even though the percentage of T-bet KO mice displaying symptoms of an obstructive cholangiopathy and overall mortality rate was not different compared to wild-type mice, the extrahepatic bile ducts of T-bet KO mice remained patent."

The primary study distinguishes anatomic protection from survival benefit.

Dendritic-Cell-Dependent Th17 Polarization

In the post-obstructive phase of RRV-induced disease, dendritic cells promote Th17 responses. Depletion decreases hepatic IL-17A and intrahepatic injury without preventing the initial extrahepatic obstruction. Human IL-17A-positive-cell and macrophage associations support relevance but do not constitute equivalent intervention evidence.

dendritic cell CL:0000451

Downstream

Cholangiocyte CCL2 Induction Th17-derived IL-17A can stimulate the cholangiocyte chemokine response.

Show evidence (2 references)

PMID:27641439 SUPPORT DIRECT Model Organism

"Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury."

Dendritic-cell perturbation in the RRV model.

PMID:27641439 SUPPORT DIRECT Human Clinical

"Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation."

Cellular cytokine-production finding in human clinical samples.

Cholangiocyte CCL2 Induction

IL-17A induces CCL2 expression in cultured neonatal cholangiocytes. In this assay it does not directly kill the biliary cells; the proposed injury pathway involves recruitment of inflammatory cells.

intrahepatic cholangiocyte CL:0002538

Downstream

CCR2-Dependent Inflammatory Macrophage Recruitment CCL2 signaling recruits CCR2-positive inflammatory macrophages in the model.

Show evidence (1 reference)

PMID:27641439 SUPPORT DIRECT In Vitro

"Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in neonatal cholangiocytes in vitro"

Direct cell-culture response to IL-17A.

CCR2-Dependent Inflammatory Macrophage Recruitment

CCL2/CCR2 signaling recruits inflammatory Ly6C-high macrophages during later RRV-model injury. CCR2 blockade reduces recruitment, and disrupted IL-17 signaling preserves intrahepatic ducts and improves survival. In human tissue, IL-17A-positive cells correlate with CD68-positive infiltration; causal human intervention evidence is lacking.

macrophage CL:0000235

Downstream

Immune-Mediated Periductal Inflammation Recruitment expands the model inflammatory infiltrate.

Show evidence (2 references)

PMID:27641439 SUPPORT DIRECT Model Organism

"blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment of inflammatory macrophages to the liver in vivo."

In vivo perturbation of the recruitment pathway.

PMID:27641439 SUPPORT DIRECT Human Clinical

"the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis."

Human tissue association, not a test of CCR2 blockade.

Macrophage CXCL2-Dependent Neutrophil Chemotaxis

RRV-infected RAW264.7 macrophage conditioned medium recruits neutrophils, and CXCL2/Mip2 depletion abolishes this response. RRV is detected in hepatic macrophages in vivo, but the necessity of this chemotactic pathway for duct injury in vivo was not demonstrated. Infected cholangiocyte conditioned medium did not reproduce the response.

macrophage CL:0000235 neutrophil CL:0000775

Experimental models

RRV-infected macrophage conditioned-medium assay CELL LINE Tests the CXCL2 dependence of conditioned-medium chemotaxis.

Downstream

Immune-Mediated Periductal Inflammation The cell-culture recruitment mechanism may amplify inflammation; its necessity in vivo remains unresolved.

Show evidence (1 reference)

PMID:20234283 SUPPORT DIRECT In Vitro

"addition of anti-Mip2/Cxcl2 antibodies depleted this chemokine in the conditioned media and completely prevented neutrophil chemotaxis."

Conditioned-medium depletion experiment; the causal intervention is in vitro.

B-Cell-Dependent Inflammatory Amplification

B-cell-deficient mice resist RRV-induced biliary obstruction and have reduced Th1 inflammation. Treg depletion does not abolish this protection. Antigen presentation is a proposed explanation; this experiment does not establish that autoantibodies themselves cause human disease.

B cell CL:0000236

Downstream

Immune-Mediated Periductal Inflammation B-cell deficiency limits model inflammatory injury; the responsible B-cell function is incompletely defined.

Show evidence (1 reference)

PMID:23991203 SUPPORT DIRECT Model Organism

"the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction."

Genetic B-cell deficiency protects against model pathology.

Neutrophil Extracellular Trap Formation

CD177-positive neutrophils in the RRV model exhibit increased oxidative activity and NET formation; coculture experiments link NET-associated activity to biliary epithelial apoptosis. Cd177 loss reduces experimental disease severity. Human NAC pilot observations are exploratory and do not establish durable clinical benefit. The 2025 corrigendum corrects duplicated representative flow plots, with the authors reporting unchanged underlying statistics.

neutrophil CL:0000775

Animal models

Cd177-deficient RRV mouse Mouse perturbs Cd177 loss delays onset and reduces model morbidity and mortality.

Downstream

Cholangiocyte Injury of the Bile Duct Epithelium NET-associated coculture activity damages biliary epithelium.

Show evidence (2 references)

PMID:35803543 SUPPORT DIRECT Model Organism

"Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality."

Mouse genetic intervention.

PMID:35803543 SUPPORT DIRECT In Vitro

"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."

The epithelial injury assay is in coculture, distinct from the in vivo mouse outcome.

Ductular Epithelial Expansion

Expanded portal biliary epithelium is a characteristic tissue response. A 2025 human single-cell study found cells coexpressing hepatocyte and cholangiocyte markers; RNA velocity and pseudotime inferred a hepatocyte-to-biliary trajectory. These computational trajectories are not lineage tracing, and their downstream fibrogenic function remains partly inferential.

hepatocyte CL:0000182 intrahepatic cholangiocyte CL:0002538

Show evidence (3 references)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Portal tracts show expansion and demonstrate edematous fibroplasia with bile ductular proliferation"

Histologic epithelial expansion.

PMID:40366121 SUPPORT DIRECT Human Clinical

"the reprogrammed cells expressed both hepatocyte and cholangiocyte markers."

Human tissue-derived single-cell coexpression.

PMID:40366121 SUPPORT INDIRECT Computational

"Pseudotime analysis depicted a differentiation trajectory from hepatocytes across reprogrammed cells to cholangiocytes in BA."

Computational trajectory inference; not direct observation of human cell fate conversion.

Biliary Cirrhotic Remodeling

Persistent biliary injury and matrix deposition distort liver architecture into irregular regenerative nodules and scarring. Progression can continue despite restored extrahepatic drainage.

Downstream

Portal Venous Pressure Elevation Distorted hepatic architecture contributes to increased portal resistance.

Biliary cirrhosis Biliary cirrhosis is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Biliary pattern cirrhosis with irregular nodules are observed on microscopy."

Architectural endpoint seen in explanted livers.

Portal Venous Pressure Elevation

Fibrotic and cirrhotic remodeling increases resistance to portal flow, producing portal hypertension and its splenic, variceal and fluid-retention complications.

Downstream

Portal hypertension Portal hypertension is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Splenomegaly Splenomegaly is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Ascites Ascites is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Esophageal varices Esophageal varices is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Higher stages of portal fibrosis have been associated with more severe portal hypertension and increased risk of LT"

Disease-specific clinical-pathologic association.

Impaired Intestinal Lipid Absorption

Reduced intestinal bile delivery impairs fat and fat-soluble-vitamin absorption. Nutritional deficiency and increased metabolic demands contribute to poor growth; vitamin K depletion may impair hemostasis.

Downstream

Failure to thrive Failure to thrive is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Fat malabsorption Fat malabsorption is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Vitamin K deficiency Vitamin K deficiency is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Vitamin D deficiency Vitamin D deficiency is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients with cholestatic conditions are at increased risk of malabsorption of fat-soluble vitamins, like vitamin K."

Cholestatic malabsorption in the BA care guideline.

Post-Kasai Ascending Biliary Infection

The altered biliary-enteric anatomy after Kasai permits ascending infection of the remaining ducts. This secondary treatment-associated complication is distinct from hypotheses about the initiating cause of biliary atresia.

Downstream

Cholangitis Cholangitis is a clinical consequence or manifestation of this process; expression varies with disease stage and subtype.

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients who have undergone a Kasai portoenterostomy procedure are at risk of ascending cholangitis due to the resulting abnormal biliary anatomy."

Clinical review explicitly relates altered anatomy to postoperative cholangitis.

✶

Histopathology

Portal ductular reaction

Proliferating and anastomosing bile ductules at expanded portal-tract margins support large-duct obstruction. They are not unique to biliary atresia, and early biopsies may be nonspecific. An exact human histopathology ontology binding is still needed; the mouse/rat hyperplasia terms are not appropriate substitutes.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Portal tracts show expansion and demonstrate edematous fibroplasia with bile ductular proliferation, consisting of anastomosing ductules located at the periphery of the portal tracts"

Characteristic portal architecture in the pathology review.

Bile plugs in ductules

Inspissated bile within ductular lumina is a useful obstructive histologic finding, interpreted alongside the clinical workup. A compatible histopathology ontology binding is needed; the specific NCIT Bile Plug concept is outside the current permitted hierarchy.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ductular cholestasis (inspissated bile plugs within ductular lumen) is commonly seen and represent a useful diagnostic feature."

Direct microscopic finding described in the review.

Periportal fibrosis

Portal fibroplasia can progress to bridging fibrosis and biliary cirrhotic remodeling. Histologic severity reflects disease stage but is not an infallible predictor of native-liver survival.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Higher stages of portal fibrosis have been associated with more severe portal hypertension and increased risk of LT"

Pathology review also notes conflicting prognostic studies.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 5

Portal hypertension HP:0001409

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly are signs of cirrhosis and portal hypertension, and ascites will be observed in decompensated cases"

Review describes later manifestations and complications; no population frequency is inferred.

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly are signs of cirrhosis and portal hypertension, and ascites will be observed in decompensated cases"

Review describes later manifestations and complications; no population frequency is inferred.

Polysplenia HP:0001748

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The splenic malformation is typically polysplenia, but sometimes can be asplenia or double spleen"

Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.

Asplenia HP:0001746

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The splenic malformation is typically polysplenia, but sometimes can be asplenia or double spleen"

Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.

Congenital heart defects Abnormal heart morphology HP:0001627

Coarse binding: variable spectrum

Show evidence (2 references)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Cardiac anomalies are apparent in about half the cases overall, but there is lack of a consistent cardiac phenotype."

Variable cardiac involvement within the BASM discussion; no single lesion is specified.

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"when we reviewed our experience of biliary atresia-associated cardiac anomalies (n = 37), features indicative of BASM were present in 48%"

Cardiac-associated BA is not confined to BASM.

Digestive 10

Prolonged neonatal jaundice HP:0006579

Show evidence (1 reference)

PMID:34884377 SUPPORT REVIEW SYNTHESIS Human Clinical

"Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life."

Persistent jaundice in the first weeks of life is the defining presenting feature of biliary atresia.

Acholic stools HP:0011985

Show evidence (1 reference)

PMID:34884377 SUPPORT REVIEW SYNTHESIS Human Clinical

"Biliary atresia (BA) is an obliterative condition of the biliary tract that presents with persistent jaundice and pale stools typically in the first few weeks of life."

Pale (acholic) stools are part of the defining presenting signature of biliary atresia, reflecting absent bile pigment in the gut.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools, growth retardation, and hepatomegaly"

Clinical guideline summarizes presenting manifestations.

Biliary cirrhosis HP:0002613

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Biliary pattern cirrhosis with irregular nodules are observed on microscopy."

Pathologic cirrhotic remodeling in explanted livers.

Abnormal abdominal situs Abnormality of abdominal situs HP:0011620

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The other obvious and evident visceral anomalies are: situs inversus, present in about 30–40% of patients with and without malrotation; preduodenal portal vein and a complete absence of the intrahepatic vena cava."

BASM visceral laterality spectrum; does not specify total inversion for all affected individuals.

Cholangitis HP:0030151

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients who have undergone a Kasai portoenterostomy procedure are at risk of ascending cholangitis due to the resulting abnormal biliary anatomy."

Clinical review explicitly relates altered anatomy to postoperative cholangitis.

Intestinal malrotation HP:0002566

Show evidence (1 reference)

PMID:34884377 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

BASM visceral laterality spectrum; does not specify total inversion for all affected individuals.

Ascites HP:0001541

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly are signs of cirrhosis and portal hypertension, and ascites will be observed in decompensated cases"

Review describes later manifestations and complications; no population frequency is inferred.

Esophageal varices Esophageal varix HP:0002040

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"This condition can cause portal hypertension, which in turn may result in esophageal varices and ascites"

Guideline identifies the anatomic variceal complication.

Fat malabsorption HP:0002630

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients with cholestatic conditions are at increased risk of malabsorption of fat-soluble vitamins, like vitamin K."

The guideline links cholestasis with nutrient malabsorption.

Genitourinary 1

Dark urine HP:0040319

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools, growth retardation, and hepatomegaly"

Clinical guideline summarizes presenting manifestations.

Integument 1

Pruritus HP:0000989

Show evidence (1 reference)

PMID:42666930 SUPPORT DIRECT Human Clinical

"We report the use of maralixibat for the treatment of cholestatic pruritus in BA for six patients."

Selected symptomatic case series establishes occurrence, not prevalence.

Metabolism 3

Conjugated hyperbilirubinemia HP:0002908

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Biliary atresia (BA) and choledochal cysts are known to cause obstructive jaundice, and conjugated hyperbilirubinemia will be observed."

The defining cholestatic biochemical phenotype is not unique to biliary atresia.

Vitamin K deficiency Decreased circulating vitamin K concentration HP:0011892

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly are signs of cirrhosis and portal hypertension, and ascites will be observed in decompensated cases"

Review describes later manifestations and complications; no population frequency is inferred.

Vitamin D deficiency Decreased circulating vitamin D concentration HP:0100512

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the presence of cholestasis, vitamins A, D, E and K should be given to prevent the development of fat-soluble vitamin deficiency"

Clinical review explicitly includes vitamin D among the deficiencies requiring prevention.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools, growth retardation, and hepatomegaly"

Clinical guideline summarizes presenting manifestations.

🧬

Genetic Associations

GPC1

Gene: GPC1 hgnc:4449 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:32315284 SUPPORT Human Clinical

"Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1."

Nominal common-variant associations; neither P value survives correction for the tested markers.

PMID:23336978 SUPPORT DIRECT Human Clinical

"We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1"

Rare copy-number association, not proof of sufficiency or penetrance.

PMID:23336978 SUPPORT DIRECT Model Organism

"Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype."

Developmental perturbation and rescue in zebrafish.

ADD3

Gene: ADD3 hgnc:245 relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:32315284 SUPPORT Human Clinical

"Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP"

Association in the studied cohort; the marker does not by itself establish causality or predict individual disease.

PMID:41589307 SUPPORT DIRECT In Vitro

"four elements (E2, E4, E9 and E10) showed allele-specific reporter activity differences"

H69 cell reporter assays resolve functional differences among linked regulatory fragments.

PMID:41589307 SUPPORT DIRECT Model Organism

"Both overexpression and knockdown of add3a in zebrafish disrupted hepatobiliary function and development, resulting in gallbladder hypoplasia/agenesis and reduced intrahepatic bile duct density."

Bidirectional dosage perturbation in a model, distinct from the effect of any individual human allele.

PKD1L1

Gene: PKD1L1 hgnc:18053 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:30664273 SUPPORT Human Clinical

"deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans."

Candidate human variants from an ascertained cohort, requiring further functional and genetic validation.

PMID:37675454 SUPPORT Model Organism

"These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system, supporting a role for this gene as a cause of BASM."

Functional relevance of pkd1l1 to fish biliary development; this does not validate each human variant as pathogenic.

CFC1

Gene: CFC1 hgnc:18292 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:18162845 SUPPORT DIRECT Human Clinical

"The heterozygous transition c.433G>A (Ala145Thr) located in exon 5 was identified in 5 patients, with a twice-higher frequency than in control patients."

Small candidate-gene study; no Mendelian penetrance inference.

ARF6

Gene: ARF6 hgnc:659 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:26379158 SUPPORT DIRECT Human Clinical

"the SNPs rs3126184 and rs10140366 in a 3' flanking enhancer region for ARF6 demonstrated higher minor allele frequencies"

Initial association study, with linked regulatory markers rather than proven causal variants.

PMID:26379158 SUPPORT DIRECT Model Organism

"Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA."

Perturbation and rescue support the candidate pathway in zebrafish.

EFEMP1

Gene: EFEMP1 hgnc:3218 gene page relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:30102696 SUPPORT DIRECT Human Clinical

"Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1"

Association signal within EFEMP1; gene assignment and allelic mechanism remain candidate interpretations.

PMID:39717503 SUPPORT DIRECT Model Organism

"in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased by approximately half."

Reduced elastic-fiber organization in heterozygous mouse ducts supports mechanical relevance.

💊

Medical Actions

Kasai Hepatoportoenterostomy

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Time-sensitive surgery excises the fibrotic extrahepatic remnant and connects a Roux-en-Y jejunal limb to the porta hepatis to establish bile drainage. Earlier intervention generally improves outcomes; age alone is not a universal cutoff for eligibility. Progressive intrahepatic disease can persist despite jaundice clearance, requiring long-term follow-up.

Mechanism Target:

BYPASSES Fibro-obliteration of the Biliary Tree — The portoenterostomy surgically bypasses the obliterated extrahepatic biliary tree, re-establishing bile drainage from the porta hepatis.

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the 1950s, with the development of Kasai portoenterostomy by Dr. Morio Kasai, it became possible to treat BA surgically"

Surgical drainage bypasses the extrahepatic obstruction.

Show evidence (1 reference)

PMID:36051179 SUPPORT REVIEW SYNTHESIS Human Clinical

"BA is always treated surgically, and performing the surgery before the age of 2 mo greatly increases its effectiveness and extends the time until the need for liver transplantation arises."

Establishes the Kasai portoenterostomy as first-line surgery and its strong age-dependence (best before ~2 months).

Liver Transplantation

Action: liver transplantation Ontology label: Liver Transplantation NCIT:C15271

Platform: Surgery

Indicated after failed drainage or progressive liver disease, including decompensated cirrhosis, refractory portal-hypertensive complications, severe growth failure or recurrent severe cholangitis. Selected infants with advanced disease may undergo primary transplantation. Assessment depends on the clinical course, not a single universal age or laboratory threshold.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Indications for LT after KPE include poor bile drainage and unresolved jaundice, poor bile flow in the early stages, advanced development of cirrhosis despite good bile flow."

Consensus guidance describes post-Kasai transplant indications.

Ursodeoxycholic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: ursodeoxycholic acid CHEBI:9907

Platform: Small molecule

Commonly used empirically after Kasai to improve bile flow and biochemical indices. Evidence for improved native-liver survival is insufficient; dosing and duration vary between centers.

Mechanism Target:

MODULATES Impaired Bile Drainage — As a choleretic bile acid, UDCA promotes bile flow and shifts the bile-acid pool to less hepatotoxic species, mitigating the cholestatic node.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Currently, the use of these medications is largely empirical, with different medical facilities adopting varying dosing schedules. There are no definitive guidelines on when to discontinue treatment"

The guideline describes empirical use of bile-acid-modulating medication after Kasai.

Prophylactic Antibiotics for Cholangitis

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Post-Kasai prophylaxis is common and conditionally recommended in some guidance, but studies conflict and a reliable reduction in cholangitis or improved native-liver survival has not been established. Prophylaxis must be distinguished from treatment of a suspected acute episode.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Studies have produced conflicting results on the effectiveness of antibiotics in preventing postoperative cholangitis after KPE"

Evidence for preventive antibiotics is uncertain.

Fat-Soluble Vitamin and Nutritional Support

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Platform: Other

Provide individualized energy-dense feeding, including medium-chain triglycerides while retaining essential long-chain fats, and monitor growth and fat-soluble vitamins A, D, E and K. Replace deficiencies and use tube feeding or, when necessary, parenteral nutrition if growth remains inadequate.

Show evidence (2 references)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Malnutrition is a common complication in children with BA, necessitating regular testing for fat-soluble vitamins and micronutrients, with supplementation of deficits as needed"

Consensus supports nutritional surveillance and supplementation.

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"For children with cholestasis, formulas enriched with MCT (>30% of total fat) are recommended, while ensuring that at least 20% of energy intake comes from long-chain triglycerides (LCT) to prevent essential fatty acid deficiency (EFAD)"

MCT enrichment must preserve an adequate source of essential fatty acids.

Post-Kasai Corticosteroid Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Platform: Small molecule

Randomized trial findings differ. The multicenter double-blind START trial (140 infants) did not significantly improve six-month bile drainage or two-year native-liver survival and produced earlier serious adverse events. A later single-center open-label randomized trial (200 type III cases) reported improved jaundice clearance and native-liver survival with 10–12 weeks of steroids. Differences in regimen, population and study design limit a universal treatment conclusion; use remains center-dependent.

Show evidence (2 references)

PMID:24794368 SUPPORT Human Clinical

"high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded."

START did not demonstrate a significant benefit for its tested regimen; its authors could not exclude a smaller clinical effect.

PMID:35170539 SUPPORT DIRECT Human Clinical

"The proportion of participants that are jaundice free without liver transplantation was significantly higher in the steroid group than in the control group at 6 months (54.1% vs 31.0%, P = 0.0015)."

Later open-label randomized evidence differs from START; this does not establish equal benefit across regimens or populations.

Maralixibat (IBAT Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: maralixibat CHEBI:748720

Platform: Small molecule

Investigational in biliary atresia. The completed 75-participant EMBARK randomized trial did not improve its primary 26-week total-bilirubin endpoint versus placebo. A separate uncontrolled six-patient compassionate-use series reported pruritus improvement, with inconsistent biochemical responses and two subsequent transplants. Symptomatic observations in selected children do not establish disease modification or native-liver survival benefit.

Mechanism Target:

MODULATES Impaired Bile Drainage — IBAT inhibition reduces enterohepatic bile-acid recycling as a pharmacologic rationale. EMBARK did not establish a clinical improvement in post-Kasai cholestasis.

Show evidence (1 reference)

PMID:32653991 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation."

A proposed mechanism, not proof of clinical efficacy in biliary atresia.

Show evidence (2 references)

url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000974-22/results SUPPORT DIRECT Human Clinical

"Primary: Mean change in Total Serum Bilirubin ... Maralixibat v Placebo ... Number of subjects included in analysis ... 75 ... P-value ... = 0.7419 ... Parameter type ... Least-Square mean ... Point estimate ... -0.39 ... Confidence interval ... 95% ... -2.76 ... 1.97"

Sponsor-posted final EU registry results for NCT04524390: no significant primary bilirubin benefit at 26 weeks; adjusted difference −0.39 mg/dL (95% CI −2.76 to 1.97).

PMID:42666930 SUPPORT DIRECT Human Clinical

"All patients reported improved CSS with no increased usage of other antipruritic medications, and the medication was well tolerated."

Six-patient retrospective compassionate-use series; no control group and short follow-up.

N-Acetylcysteine (post-Kasai)

Action: Pharmacotherapy NCIT:C15986

Agent: N-acetyl-L-cysteine CHEBI:28939

Platform: Small molecule

Experimental glutathione-precursor/choleretic strategy. A nonrandomized phase II pilot tested intravenous NAC for seven days after Kasai; none of 12 evaluable infants achieved total serum bile acids ≤10 µmol/L within 24 weeks, so the second stage did not open. Secondary outcomes did not differ from matched historical controls. One enrolled infant stopped treatment for worsening preexisting tachycardia, a serious event considered possibly drug-related in the full text. Longer courses remain unproven. A separate small Chinese pilot (ChiCTR2000040505; six treated and six untreated BA infants in the transcriptomic analysis) reported short-term bilirubin and immune-signature changes. This exploratory study used a different perioperative schedule and does not establish long-term clinical efficacy or contradict the US trial’s failure to meet its prespecified endpoint.

Show evidence (5 references)

PMID:40489761 SUPPORT DIRECT Human Clinical

"There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2."

The stringent primary endpoint was not met; this does not establish efficacy for other schedules.

PMID:40489761 SUPPORT DIRECT Human Clinical

"One serious adverse event was considered possibly related to the drug. It involved worsening tachycardia in a participant who had preexisting tachycardia."

The full text provides a safety qualification absent from the broad abstract summary.

PMID:40489761 SUPPORT DIRECT BACKGROUND Human Clinical

"NAC provides the amino acid cysteine, which drives production of the anti-oxidative and anti-inflammatory molecule glutathione."

The trial rationale concerns glutathione availability; it did not test correction of a CD177-specific neutrophil mechanism.

+ 2 more references

Treatment of Acute Cholangitis

Action: Antibiotic Therapy NCIT:C15620

Platform: Other

Suspected post-Kasai cholangitis requires prompt assessment and antibiotic treatment, with microbiology-guided adjustment and escalation for severe or refractory illness. This is distinct from uncertain preventive antibiotic regimens.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Cholangitis should be treated aggressively and regularly once diagnosed."

Consensus guidance supports active treatment of this postoperative complication.

Long-Term Hepatology Surveillance

Platform: Other

Continue surveillance after jaundice clears: growth and nutrition, liver biochemistry and synthetic function, vitamin status, portal hypertension and recurrent cholangitis remain relevant. Progressive disease should prompt timely transplant assessment.

Show evidence (1 reference)

PMID:42569433 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Regular follow-up is still needed for children whose jaundice clears."

Clearance of jaundice does not end the need for disease monitoring.

Odevixibat

Action: Pharmacotherapy NCIT:C15986

Agent: odevixibat CHEBI:757063

Platform: Small molecule

Experimental IBAT inhibition after Kasai. In July 2026, the sponsor reported that the 254-participant randomized phase III BOLD trial did not improve native-liver survival versus placebo. The publicly available topline announcement is not a peer-reviewed full results paper. The BOLD extension remained active but not recruiting in the registry at review.

Show evidence (1 reference)

url:https://www.ipsen.com/press-release/ipsen-provides-update-on-phase-iii-bold-trial-in-biliary-atresia-3332691/ SUPPORT DIRECT Human Clinical

"announced today that the Phase III BOLD trial evaluating Bylvay versus placebo for patients living with biliary atresia (BA) who have already undergone a Kasai hepatoportoenterostomy (HPE) did not meet the primary endpoint of improvement in native liver survival vs placebo."

Ipsen sponsor topline announcement dated 24 July 2026; the report does not provide a peer-reviewed effect estimate.

Intravenous Immunoglobulin

Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Agent: Therapeutic Immune Globulin NCIT:C2701

Platform: Other

The multicenter open-label PRIME phase I/IIa study tested three infusions after Kasai in 29 infants. Administration was feasible, but bilirubin and one-year native-liver survival did not improve compared with historical START placebo controls. It does not establish efficacy or comparative safety from a randomized concurrent comparison.

Show evidence (1 reference)

PMID:30664564 SUPPORT DIRECT Human Clinical

"Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver."

PRIME was an open-label single-arm phase I/IIa study with historical START placebo controls, not a concurrent randomized comparison.

Rectal Budesonide

Action: Pharmacotherapy NCIT:C15986

Agent: budesonide CHEBI:3207

Platform: Small molecule

Off-label postoperative therapy evaluated in a retrospective cohort against historical and untreated controls. Reported jaundice-free native-liver survival associations favored treated nonsyndromic cases, but treatment selection and changes in care can confound the result. No randomized evidence establishes benefit, and the report contains inconsistent two-year percentages between its abstract and table.

Show evidence (2 references)

PMID:40600375 SUPPORT DIRECT Human Clinical

"We performed a retrospective cohort study and included all patients after HPE who received rectal budesonide (2 mg) for 3 months from 2011 to 2022, compared to a historical control group without any glucocorticoid treatment."

Observational design does not support a causal efficacy conclusion.

PMID:40600375 SUPPORT DIRECT Human Clinical

"However, these benefits were exclusive to patients with nonsyndromic BA."

Reported subgroup limitation; further prospective randomized evaluation is required.

Obeticholic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: obeticholic acid CHEBI:43602

Platform: Small molecule

Investigational FXR agonist assessed after Kasai. The phase II CARE study was terminated because recruitment was insufficient. A separate phase II/III study, NCT06121375, enrolled 28 participants and was terminated following the sponsor decision linked in the registry to the Ocaliva withdrawal request and OCA clinical hold. These stopping reasons must not be misrepresented as demonstrated efficacy or lack of efficacy in biliary atresia.

Show evidence (2 references)

clinicaltrials:NCT05321524 SUPPORT DIRECT Human Clinical

"This is a Phase 2, multicenter, open-label, single dose and multi-dose, dose-finding study with an optional open-label extension (OLE) to assess the safety, tolerability, and pharmacokinetics of obeticholic acid (OCA) in pediatric subjects with biliary atresia with successful..."

Registry summary identifies the CARE study population.

clinicaltrials:NCT06121375 SUPPORT DIRECT Human Clinical

"This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy)."

Registry summary identifies the separate phase II/III program; status and stopping reason were checked in the live record on 1 October 2026.

🌍

Environmental Factors

Perinatal hepatotropic viral infection

Viral exposure is a proposed trigger, not an established cause of human biliary atresia. Neonatal RRV infection induces an age-dependent obstructive cholangiopathy in mice. Human detection of viruses such as CMV is heterogeneous and cannot alone establish whether infection caused, followed, or modified the biliary disease.

Show evidence (1 reference)

PMID:23844248 SUPPORT DIRECT Model Organism

"Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived."

Experimental susceptibility depends on neonatal timing; this does not establish human viral causation.

Biliatresone toxin exposure

Biliatresone is an experimental electrophilic toxin that selectively damages extrahepatic cholangiocytes in zebrafish. Human exposure as a cause of biliary atresia is unproven. Low-dose prenatal exposure in mice altered offspring bile-acid profiles and hepatic immune cells without producing histologic duct injury or fibrosis at the measured time points.

Show evidence (3 references)

PMID:27102575 SUPPORT Model Organism

"Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae."

Biliatresone selectively injures extrahepatic cholangiocytes in zebrafish larvae; human etiologic relevance is unproven.

PMID:38578745 SUPPORT DIRECT Model Organism

"Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal."

Prenatal low-dose model produced biochemical and immune changes rather than overt fibro-obliterative atresia.

PMID:38578745 SUPPORT DIRECT Model Organism

"serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21"

Measured offspring bile-acid phenotype after prenatal exposure.

Prenatal maternal infection

A Taiwanese administrative-data case-control study associated recorded maternal intestinal and genitourinary infections with offspring biliary atresia. Diagnoses were code-based, pathogens were usually unspecified, and unmeasured genetic and environmental confounding remained. The findings do not demonstrate fetal infection, a causal injury pathway, or a prevention effect.

Show evidence (1 reference)

PMID:38170523 SUPPORT Human Clinical

"Results of this case-control study indicate an association between prenatal intestinal infection and genitourinary tract infection in mothers and BA occurrence in their offspring."

A large Taiwanese case-control study links prenatal maternal gut and genitourinary infection to offspring biliary atresia risk.

🔬

Biochemical Markers

Elevated conjugated (direct) bilirubin (Elevated)

Context: Conjugated/direct hyperbilirubinemia requires urgent evaluation for neonatal cholestasis, including biliary atresia. After the neonatal screening window, a direct bilirubin above 1 mg/dL warrants evaluation regardless of its percentage of total bilirubin. In the first days of life, use age- and assay-specific reference intervals; an absolute 1 mg/dL screening cutoff can miss affected newborns. Direct and conjugated assays are not identical.

Show evidence (2 references)

url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"for this guideline, an abnormal direct/conjugated bilirubin is defined as a serum value >1.0 mg/dL (17 mmol/L), because it is physiologically and clinically complex to consider incorporating consideration of whether or not the direct fraction exceeds 20% of the TB level"

The 2017 NASPGHAN/ESPGHAN guideline defines abnormal direct/conjugated bilirubin independently of the former 20% rule.

url:https://pmc.ncbi.nlm.nih.gov/articles/7093763/ SUPPORT DIRECT Human Clinical

"1 infant with a true positive screening result had a stage 1 bilirubin level of 0.4 mg/dL, which was abnormally high in the 98.4th to 99.6th percentile for that site"

The primary screening study demonstrates why newborn thresholds must be age- and laboratory-specific.

Elevated gamma-glutamyltransferase (GGT) (Elevated)

Context: GGT is commonly elevated, often disproportionately to aminotransferases, but varies with age and cannot establish or exclude biliary atresia alone.

Show evidence (1 reference)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Transaminases and gamma-glutamyl transferase (GGT) are almost always elevated in BA, and GGT is disproportionately higher than transaminases, while this is opposite in neonatal hepatitis."

Clinical review describes the typical biochemical pattern; neither enzyme is diagnostic alone.

Elevated circulating hepatic transaminases (Elevated)

Context: ALT and AST can be elevated with accompanying hepatocellular injury. Values are nonspecific, and early biochemical screening may identify affected newborns before aminotransferases rise.

Show evidence (2 references)

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Transaminases and gamma-glutamyl transferase (GGT) are almost always elevated in BA, and GGT is disproportionately higher than transaminases, while this is opposite in neonatal hepatitis."

Clinical review describes the typical biochemical pattern; neither enzyme is diagnostic alone.

url:https://pmc.ncbi.nlm.nih.gov/articles/7093763/ SUPPORT DIRECT Human Clinical

"biliary atresia, which can be difficult to detect during early stages of the disease when aminotransferase levels and liver stiffness may still be normal"

Normal early aminotransferases must not delay assessment of abnormal direct/conjugated bilirubin.

Elevated serum matrix metalloproteinase-7 (MMP7) (Elevated)

Context: Serum MMP-7 is a promising adjunct for distinguishing biliary atresia from other neonatal cholestases. Thresholds depend on assay and age: the North American study used 52.8 ng/mL on a single-plex assay and 18.2 ng/mL on a different platform. A separate prospective ELISA cohort validated 18 ng/mL with 95.9% sensitivity and 87.3% specificity. False-negative and false-positive results occur; these thresholds are not interchangeable or a substitute for definitive assessment.

Show evidence (2 references)

PMID:38446707 SUPPORT DIRECT Human Clinical

"Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs."

The same clinical sample set yielded different thresholds with different assay platforms.

PMID:38978022 SUPPORT DIRECT Human Clinical

"The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%)"

Prospective validation of the 18 ng/mL ELISA threshold; incomplete sensitivity and specificity preclude an absolute rule-out or rule-in interpretation.

🔬

Diagnosis

Abdominal ultrasonography (triangular cord sign)

First-line imaging evaluates gallbladder morphology and contraction, the triangular cord sign and associated malformations. Findings are operator- and age-dependent; a normal ultrasound does not exclude biliary atresia. The original small study reported 85% sensitivity and 100% specificity for its triangular cord assessment, which should not be generalized to every setting.

abdominal ultrasonography NCIT:C17230

Show evidence (2 references)

PMID:9396524 SUPPORT Human Clinical

"Although 17 of 20 ultrasonographic examinations from infants who had BA denoted TC, 43 ultrasonographic examinations from infants with either neonatal hepatitis (NH) or other causes of cholestasis denoted no TC, showing a diagnostic accuracy of 95% with 85% sensitivity and 100% specificity."

The triangular cord sign on ultrasound is highly specific for biliary atresia in the workup of infantile cholestasis.

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Most, but not all of those with BA have a hypoplastic or absent gallbladder, and so normal ultrasonography does not exclude BA."

A normal gallbladder or ultrasound cannot exclude the disease.

Hepatobiliary scintigraphy (HIDA)

Hepatobiliary scintigraphy is sensitive but has limited specificity: absent bowel tracer excretion also occurs in other cholestases. Demonstrated excretion makes biliary atresia unlikely, but rare apparent false-negative studies are reported. It should not delay definitive evaluation; routine phenobarbital pretreatment can add several days.

Show evidence (2 references)

url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Limited reports describe infants with apparently initially excreting HBS and a subsequent diagnosis of BA, although the technical limitations of the study may have been a factor in its utility"

The guideline documents rare apparent excretion despite subsequent biliary-atresia diagnosis.

url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Many clinicians and radiologists administer phenobarbital for 5 days before the study, in an attempt to enhance biliary excretion of the isotope and increase its discriminatory value"

Premedication may delay an already time-sensitive diagnostic pathway.

Intraoperative cholangiography

Operative cholangiography, interpreted with duct-remnant histology and the clinical workup, is the reference standard for defining extrahepatic duct patency. If biliary atresia is confirmed, Kasai portoenterostomy can usually follow during the same operation. A hypoplastic biliary tree in Alagille syndrome or cystic fibrosis can confound interpretation; cholangiography is not infallible.

intraoperative cholangiography NCIT:C61508

Show evidence (2 references)

url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The intraoperative cholangiogram and histologic examin- ation of the duct remnant is considered the criterion standard to diagnose BA"

The guideline combines operative anatomy with remnant histology.

url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Hence, preoperative testing for CF and ALGS is helpful in assisting in the interpretation ... and decreasing false-positive results."

Clinical mimics affect operative interpretation.

Infant stool color card screening

Parents compare infant stool color with a reference card and promptly report pale stools. National programs support earlier recognition, but stools may initially retain pigment. Taiwanese before-and-after cohort findings associate screening-era care with lower hospitalization and mortality; this observational design cannot isolate screening from other changes in care.

Show evidence (2 references)

PMID:27015203 SUPPORT Human Clinical

"Since 2004, Taiwan has implemented a national screening program that uses an infant stool color card (SCC) for the early detection of BA."

Stool color card screening is a validated national program for early detection of biliary atresia.

PMID:36051179 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Acholic stool may initially be absent and some stools may contain bile pigment"

Early pigmented stools do not exclude biliary atresia.

Newborn direct or conjugated bilirubin screening

A two-stage strategy measures direct/conjugated bilirubin in the first 60 hours using laboratory-specific newborn reference intervals, then repeats abnormal results by the two-week visit. Rising values or repeat values above 1 mg/dL prompt further assessment. In 124,385 newborns, all seven known cases were detected, but sensitivity had a wide confidence interval and false-negative ascertainment was incomplete. A separate pre-post analysis associated implementation with younger Kasai age, not proof of a survival benefit.

Show evidence (3 references)

PMID:32207797 SUPPORT DIRECT Human Clinical

"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."

First-stage screening as summarized in the abstract; full methods describe site-specific newborn reference intervals.

PMID:32207797 SUPPORT DIRECT Human Clinical

"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."

Second-stage screen requires a rise or a value above 1 mg/dL.

PMID:32207797 SUPPORT DIRECT Human Clinical

"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."

The abstract explicitly qualifies sensitivity and incomplete ascertainment.

Primary-care assessment at two to four weeks

The 2025 AAP clinical report recommends assessing eye color, stool color and prior laboratory results at the two- to four-week visit to decide whether direct/conjugated bilirubin measurement is needed. Persistent jaundice or pale stools requires prompt evaluation.

Show evidence (1 reference)

DOI:10.1542/peds.2024-070077 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The strategy involves examining every infant’s eye color, stool color, and prior laboratory results to determine whether measurement of a direct or conjugated bilirubin level is warranted."

AAP clinical report, abstract available; full report retrieval was blocked.

Liver biopsy

Portal expansion, ductular reaction and bile plugs support biliary obstruction, but early biopsy can be nonspecific and similar changes occur in other neonatal cholestases. Interpret expert histology alongside imaging and clinical evaluation rather than using a negative early biopsy to exclude biliary atresia.

Show evidence (1 reference)

PMID:32518681 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen."

Disease-associated obstructive histology, interpreted in clinical context.

📊

Prevalence

South Korea (nationwide birth cohort)

Birth Prevalence 10.6 per 100,000 1–9 per 10,000 (births)

Korean nationwide cohort: 1.06 cases per 10,000 live births. This estimate is specific to its population and ascertainment period.

Show evidence (1 reference)

PMID:28244293 SUPPORT Human Clinical

"The overall incidence of BA was 1.06 cases per 10,000 live births."

National cohort birth prevalence/incidence figure for biliary atresia in an East-Asian population.

Texas, USA (1999–2014; cases without known genetic syndromes)

Birth Prevalence 6.5 per 100,000 1–9 per 100,000 (births)

305 cases among 4,689,920 live births after excluding other liver diseases and 15 cases with chromosomal abnormalities or other Mendelian disorders. Female sex had an adjusted prevalence ratio of 1.68; associations with prematurity and maternal diabetes were observational and do not establish causation.

Show evidence (1 reference)

PMID:35364097 SUPPORT DIRECT Human Clinical

"The prevalence of biliary atresia over the study period was 0.65 per 10 000 live births."

Population-specific birth prevalence from the Texas registry.

🔬

Clinical Trials

NCT04524390 PHASE_II COMPLETED

EMBARK: randomized phase II post-Kasai maralixibat trial; no significant primary bilirubin benefit at 26 weeks.

Show evidence (2 references)

clinicaltrials:NCT04524390 SUPPORT DIRECT Human Clinical

"A study to evaluate the efficacy and safety of maralixibat in infants with Biliary Atresia (BA) after Hepatoportoenterostomy (HPE, also known as the Kasai procedure)."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000974-22/results SUPPORT DIRECT Human Clinical

Sponsor-posted final EU registry results for NCT04524390: no significant primary bilirubin benefit at 26 weeks; adjusted difference −0.39 mg/dL (95% CI −2.76 to 1.97).

NCT04336722 PHASE_III COMPLETED

BOLD: randomized phase III post-Kasai odevixibat trial; sponsor topline report found no native-liver survival benefit.

Show evidence (2 references)

clinicaltrials:NCT04336722 SUPPORT DIRECT Human Clinical

"Double-blind, randomized, placebo-controlled, Phase 3 study to investigate the efficacy and safety of odevixibat compared to placebo in children with biliary atresia who have undergone a Kasai hepatoportoenterostomy."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

url:https://www.ipsen.com/press-release/ipsen-provides-update-on-phase-iii-bold-trial-in-biliary-atresia-3332691/ SUPPORT DIRECT Human Clinical

Ipsen sponsor topline announcement dated 24 July 2026; the report does not provide a peer-reviewed effect estimate.

NCT05426733 PHASE_III ACTIVE_NOT_RECRUITING

BOLD-EXT: open-label extension for long-term odevixibat follow-up after the parent trial.

Show evidence (1 reference)

url:https://clinicaltrials.gov/api/v2/studies/NCT05426733 SUPPORT DIRECT Other

"Patients who completed treatment in the A4250-011 BOLD study and meet eligibility criteria for Study A4250-016 (BOLD-EXT) can participate. The duration of the treatment period is 104 weeks, followed by a 4-week Safety Follow-up Period."

The registry detailed description identifies the parent study, eligibility context and extension follow-up; it reports no efficacy result.

NCT05321524 PHASE_II TERMINATED

CARE: phase II obeticholic-acid study, terminated for infeasible recruitment.

Show evidence (1 reference)

clinicaltrials:NCT05321524 SUPPORT DIRECT Human Clinical

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

NCT06121375 PHASE_III TERMINATED

Separate phase II/III obeticholic-acid study, terminated after 28 participants. The registry attributes termination to the sponsor decision following the FDA withdrawal request and clinical hold, not a biliary-atresia efficacy analysis.

Show evidence (1 reference)

clinicaltrials:NCT06121375 SUPPORT DIRECT Human Clinical

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

NCT03499249 PHASE_II COMPLETED

Phase II short-course intravenous NAC pilot; none of 12 evaluable participants met the primary endpoint. One serious adverse event, worsening of preexisting tachycardia, was considered possibly drug-related.

Show evidence (3 references)

clinicaltrials:NCT03499249 SUPPORT DIRECT Human Clinical

"In this study, the investigators test whether intravenous N-acetylcysteine (NAC) can improve bile flow after KP. ... This study follows the "minimax" Phase 2 clinical trial design."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

PMID:40489761 SUPPORT DIRECT Human Clinical

"There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2."

The stringent primary endpoint was not met; this does not establish efficacy for other schedules.

PMID:40489761 SUPPORT DIRECT Human Clinical

"One serious adverse event was considered possibly related to the drug. It involved worsening tachycardia in a participant who had preexisting tachycardia."

The full text provides a safety qualification absent from the broad abstract summary.

NCT00294684 NOT_APPLICABLE COMPLETED

START: randomized placebo-controlled postoperative corticosteroid trial; no significant primary bile-drainage benefit.

Show evidence (2 references)

clinicaltrials:NCT00294684 SUPPORT DIRECT Human Clinical

"The Children Liver Disease Research and Education Network (ChiLDREN) is conducting a clinical trial to evaluate whether long-term treatment with corticosteroids improves the outcome of the Kasai or gall-bladder Kasai in infants with biliary atresia."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

PMID:24794368 SUPPORT Human Clinical

"high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded."

START did not demonstrate a significant benefit for its tested regimen; its authors could not exclude a smaller clinical effect.

NCT01854827 PHASE_II COMPLETED

PRIME: open-label phase I/IIa IVIG trial with historical controls; no bilirubin or native-liver survival benefit.

Show evidence (2 references)

clinicaltrials:NCT01854827 SUPPORT DIRECT Human Clinical

"The Children Liver Disease Research and Education Network (ChiLDREN) is conducting a clinical trial to determine the feasibility, acceptability, tolerability and safety profile of IVIG treatment administered to infants after hepatic portoenterostomy (HPE) for biliary atresia, as well as..."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

PMID:30664564 SUPPORT DIRECT Human Clinical

"Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver."

PRIME was an open-label single-arm phase I/IIa study with historical START placebo controls, not a concurrent randomized comparison.

NCT06553768 PHASE_III ACTIVE_NOT_RECRUITING

EXPAND: phase III maralixibat study for refractory cholestatic pruritus across multiple liver disorders, including eligible biliary-atresia patients; distinct from the infant post-Kasai EMBARK trial.

Show evidence (1 reference)

clinicaltrials:NCT06553768 SUPPORT DIRECT Human Clinical

"The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric and adult participants who have cholestatic liver disease with pruritus that has been refractory to other therapies, and who have no other treatment options."

Generated registry brief summary establishes trial identity and study objective; live status was checked separately.

ChiCTR2000040505 PHASE_IV

Chinese nonrandomized NAC program with published immune and short-term biochemical analyses. ICTRP lists phase 4 and planned preoperative/postoperative groups, but its last refresh was 8 March 2021; current recruitment status is left unspecified. The 2022 and 2023 reports describe related work and should not be treated as independent efficacy replications.

Show evidence (3 references)

PMID:35803543 SUPPORT DIRECT Human Clinical

"The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505)."

Published registration identifier for the pilot.

ICTRP:ChiCTR2000040505 SUPPORT DIRECT Other

"Study design | Non randomized control"

Structured registration identifies the nonrandomized design.

ICTRP:ChiCTR2000040505 SUPPORT DIRECT Other

"Preoperative intervention group:N-Acetylcysteine;Postoperative intervention group:N-Acetylcysteine;Preoperative control group:Conventional therapy;postoperative control group:Conventional therapy;"

Registry specifies both perioperative schedules and their comparison groups.

🧫

Experimental Models

H69 ADD3 regulatory-element reporter assays CELL_LINE

Allelic fragments from the ADD3 susceptibility interval were cloned into reporters. Four showed differing haplotype activity, whereas the fragment containing the lead marker did not.

Cell source

Immortalized human H69 cholangiocytes

Publication

PMID:41589307

Pathograph links

Altered ADD3 Regulatory Activity measures fidelity: moderate Reports allelic transcriptional activity of cloned DNA fragments.

Limitations: Does not measure native enhancer-promoter contacts or endogenous expression in patients.

Show evidence (1 reference)

PMID:41589307 SUPPORT DIRECT In Vitro

"four elements (E2, E4, E9 and E10) showed allele-specific reporter activity differences"

Direct reporter measurement in the H69 human cholangiocyte cell line.

RRV-infected macrophage conditioned-medium assay CELL_LINE

Conditioned medium from infected macrophages stimulates neutrophil chemotaxis; CXCL2 depletion abolishes the measured response.

Cell source

Murine RAW264.7 macrophages and isolated neutrophils

Publication

PMID:20234283

Pathograph links

Macrophage CXCL2-Dependent Neutrophil Chemotaxis perturbs fidelity: moderate Tests the CXCL2 dependence of conditioned-medium chemotaxis.

Limitations: Does not demonstrate necessity for injury in an intact animal or a human infant.

Show evidence (1 reference)

PMID:20234283 SUPPORT DIRECT In Vitro

"addition of anti-Mip2/Cxcl2 antibodies depleted this chemokine in the conditioned media and completely prevented neutrophil chemotaxis."

Conditioned-medium depletion experiment; the causal intervention is in vitro.

🐁

Animal Models

Rhesus rotavirus (RRV) neonatal mouse model

Neonatal BALB/c infection with RRV produces age-dependent epithelial injury, inflammation and extrahepatic obstruction. Early and late infection have substantially different outcomes. This defined viral model tests selected injury mechanisms; it does not establish the cause or all subtypes of human disease.

Species

Mouse

Genotype

Wild-type BALB/c neonate infected with rhesus rotavirus

Publication

PMID:23844248

Pathograph links

Cholangiocyte Injury of the Bile Duct Epithelium partially recapitulates fidelity: moderate Early infection produces biliary epithelial injury and obstruction.

Limitations: Susceptibility depends on mouse age and viral conditions; BASM developmental defects and human etiologic heterogeneity are not reproduced.

Show evidence (1 reference)

PMID:23844248 SUPPORT DIRECT Model Organism

"the amount of cholangiocyte epithelial damage and bile duct edema was significantly greater in the early infection group"

Histologic epithelial injury in the time-dependent RRV mouse model.

Biliatresone zebrafish model

Exposure of zebrafish larvae to the plant toxin biliatresone selectively injures the extrahepatic biliary epithelium, providing a toxin-driven model of the extrahepatic cholangiopathy of biliary atresia.

Species

Zebrafish

Genotype

Wild-type larvae exposed to the isoflavonoid toxin biliatresone

Publication

PMID:27102575

Pathograph links

Cholangiocyte Injury of the Bile Duct Epithelium recapitulates fidelity: moderate Biliatresone reproduces selective extrahepatic-cholangiocyte injury, modeling the toxin route to the cholangiocyte-injury node.

Limitations: Zebrafish biliary anatomy differs from the human extrahepatic tree, and the specific human relevance of biliatresone exposure remains unproven; the model captures the injury mechanism rather than human etiology.

Show evidence (1 reference)

PMID:27102575 SUPPORT Model Organism

"Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae."

Demonstrates selective extrahepatic-cholangiocyte toxicity, grounding the toxin model of the injury node.

Reduced Cholangiocyte Glutathione Reserve perturbs fidelity: moderate Glutathione depletion increases toxin susceptibility, while antioxidant manipulations reduce injury.

Limitations: Experimental toxin exposure is not a demonstrated cause of human biliary atresia.

Show evidence (1 reference)

PMID:27102575 SUPPORT DIRECT Model Organism

"GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic cholangiocytes to the toxin"

Manipulating antioxidant reserve changes susceptibility in fish.

Gpc1 knockdown zebrafish

Knockdown impairs the biliary network; gpc1 mRNA rescue and partial cyclopamine rescue support specificity and Hedgehog involvement.

Species

Zebrafish

Genotype

gpc1 morpholino knockdown

Publication

PMID:23336978

Pathograph links

Disrupted Biliary Morphogenesis perturbs fidelity: moderate Knockdown impairs the biliary network; gpc1 mRNA rescue and partial cyclopamine rescue support specificity and Hedgehog involvement.

Limitations: Morpholino perturbation is not a human deletion genotype; the model does not demonstrate penetrance or progressive human remnant fibrosis.

Show evidence (1 reference)

PMID:23336978 SUPPORT DIRECT Model Organism

"Knockdown of gpc1 in zebrafish led to developmental biliary defects."

Experimental biliary developmental phenotype.

Add3a dosage perturbation zebrafish

Both increased and decreased add3a dosage perturb biliary development.

Species

Zebrafish

Genotype

add3a overexpression or knockdown

Publication

PMID:41589307

Pathograph links

Disrupted Biliary Morphogenesis perturbs fidelity: moderate Both increased and decreased add3a dosage perturb biliary development.

Limitations: Direct dosage manipulation does not reproduce the endogenous effect of a particular human enhancer allele.

Show evidence (1 reference)

PMID:41589307 SUPPORT DIRECT Model Organism

"Both overexpression and knockdown of add3a in zebrafish disrupted hepatobiliary function and development, resulting in gallbladder hypoplasia/agenesis and reduced intrahepatic bile duct density."

Independent dosage perturbations provide a plausible bridge to biliary development, not the effect of the assayed human variants in their native locus.

Arf6 knockdown zebrafish

Perturbation and rescue test EGFR–ARF6 involvement in biliary network development.

Species

Zebrafish

Genotype

arf6 morpholino knockdown, with EGFR-inhibition and mRNA-rescue arms

Publication

PMID:26379158

Pathograph links

Reduced EGFR-ARF6 Developmental Signaling perturbs fidelity: moderate Perturbation and rescue test EGFR–ARF6 involvement in biliary network development.

Limitations: The human associated noncoding alleles were not directly modeled.

Show evidence (1 reference)

PMID:26379158 SUPPORT DIRECT Model Organism

"Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6 at lower doses of each agent and rescued with arf6 mRNA."

Perturbation and rescue support EGFR–ARF6 involvement in fish development.

Pkd1l1 mutant zebrafish

Mutants have laterality abnormalities, sparse intrahepatic biliary networks and impaired biliary transport; most retain a gallbladder.

Species

Zebrafish

Genotype

Maternal-zygotic pkd1l1 hsc117 four-base-pair deletion

Publication

PMID:37675454

Pathograph links

Disrupted Biliary Morphogenesis perturbs fidelity: moderate Mutants have laterality abnormalities, sparse intrahepatic biliary networks and impaired biliary transport; most retain a gallbladder.

Limitations: Fish loss of function does not validate each human PKD1L1 variant or reproduce the full BASM phenotype.

Show evidence (1 reference)

PMID:37675454 SUPPORT DIRECT Model Organism

"These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system"

Fish loss-of-function data support developmental plausibility rather than variant-specific human causality.

Efemp1 heterozygous mouse duct mechanics

Reduced organized elastic fibers accompany altered pressure-dependent duct mechanics.

Species

Mouse

Genotype

Adult Efemp1 heterozygous loss

Publication

PMID:39717503

Pathograph links

Impaired Extrahepatic Duct Elastic-Fiber Organization perturbs fidelity: moderate Reduced organized elastic fibers accompany altered pressure-dependent duct mechanics.

Limitations: Adult heterozygous ducts did not establish neonatal atresia or the effect direction of human susceptibility alleles.

Show evidence (1 reference)

PMID:39717503 SUPPORT DIRECT Model Organism

"in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased by approximately half."

Mouse matrix-organization phenotype.

T-bet-deficient RRV mouse

T-bet loss preserves duct patency despite continued obstructive-cholangiopathy symptoms and unchanged mortality.

Species

Mouse

Genotype

T-bet knockout with neonatal RRV infection

Publication

PMID:34943969

Pathograph links

Th1-Associated Cytotoxic Inflammation perturbs fidelity: moderate T-bet loss preserves duct patency despite continued obstructive-cholangiopathy symptoms and unchanged mortality.

Limitations: Anatomic duct protection is not complete clinical or survival rescue.

Show evidence (1 reference)

PMID:34943969 SUPPORT DIRECT Model Organism

The primary study distinguishes anatomic protection from survival benefit.

Treg augmentation in RRV mouse

Treatment after infection expands Tregs, improves survival and reduces biliary inflammation.

Species

Mouse

Genotype

RRV infection with JES6-1/IL-2-mediated Treg augmentation

Publication

PMID:39131670

Pathograph links

Reduced Regulatory T-Cell Restraint rescues fidelity: moderate Treatment after infection expands Tregs, improves survival and reduces biliary inflammation.

Limitations: Murine cytokine-complex treatment is not an established therapy for human infants.

Show evidence (1 reference)

PMID:39131670 SUPPORT DIRECT Model Organism

"Treg augmentation in the murine model led to increased survival, decreased direct bilirubin levels and liver inflammation, and expansion of resident macrophages."

Intervention result in RRV mice, not established human treatment efficacy.

Cd177-deficient RRV mouse

Cd177 loss delays onset and reduces model morbidity and mortality.

Species

Mouse

Genotype

Cd177 knockout on BALB/c background with RRV infection

Publication

PMID:35803543

Pathograph links

Neutrophil Extracellular Trap Formation perturbs fidelity: moderate Cd177 loss delays onset and reduces model morbidity and mortality.

Limitations: The human clinical effect of selectively interrupting NET formation remains unresolved.

Show evidence (1 reference)

PMID:35803543 SUPPORT DIRECT Model Organism

"Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality."

Mouse genetic intervention.

Low-dose prenatal biliatresone mouse exposure

Offspring showed bile-acid and immune changes without histologic liver or duct injury or fibrosis at the measured neonatal time points.

Species

Mouse

Genotype

Wild-type offspring after maternal low-dose biliatresone exposure

Publication

PMID:38578745

Pathograph links

Cholangiocyte Injury of the Bile Duct Epithelium fails to recapitulate fidelity: moderate The tested prenatal exposure did not induce the histologic injury phenotype.

Limitations: This negative result is specific to the tested exposure schedule and P5/P21 observations; it does not exclude all possible dose-dependent effects.

Show evidence (1 reference)

PMID:38578745 SUPPORT DIRECT Model Organism

"Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal."

Prenatal low-dose model produced biochemical and immune changes rather than overt fibro-obliterative atresia.

{ }

Source YAML

click to show

name: Biliary Atresia
creation_date: '2026-08-12T00:00:00Z'
category: Complex
disease_term:
  preferred_term: biliary atresia
  term:
    id: MONDO:0008867
    label: biliary atresia
description: >-
  Biliary atresia is an infantile fibro-obliterative cholangiopathy that obstructs
  bile drainage and causes
  conjugated hyperbilirubinemia, pale stools and progressive liver disease. Injury
  commonly begins before visible
  jaundice, and abnormal direct/conjugated bilirubin can be present shortly after
  birth. Clinical presentations
  include isolated disease, laterality-associated malformations and cystic biliary
  remnants. Genetic susceptibility,
  developmental abnormalities and dysregulated immune responses contribute to mechanistic
  models, while specific
  viral or toxin causes remain unproven in humans. Kasai portoenterostomy can restore
  drainage and prolong
  native-liver survival, but many patients develop continuing fibrosis, portal hypertension
  or recurrent cholangitis
  and require liver transplantation.

parents:
- Neonatal Cholestasis

classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
has_subtypes:
- name: Isolated BA
  display_name: Isolated (non-syndromic) biliary atresia
  description: >-
    Biliary atresia without a recognized associated malformation syndrome, comprising
    most cases. The historical
    term perinatal form describes presentation, not proof of postnatal acquisition:
    direct/conjugated bilirubin
    may already be abnormal in the first days of life.
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In the majority of cases, currently termed isolated BA, there are still too
      few clues as to aetiology
      or indeed pathogenesis.
    explanation: >-
      Review synthesis of this clinical subgroup; definitions and overlap vary.
    quote_role: REVIEW_SYNTHESIS
- name: BASM
  display_name: Biliary atresia splenic malformation syndrome
  description: >-
    Biliary atresia with splenic and other laterality-associated malformations, including
    polysplenia or asplenia,
    abnormal visceral situs, intestinal malrotation, preduodenal portal vein and interrupted
    inferior vena
    cava. Definitions vary between cohorts. It accounts for roughly 10–15% in some
    Western series but is much
    less frequent in some Asian series; prognosis depends on associated anatomy and
    clinical context.
  subtype_term:
    preferred_term: biliary atresia with splenic malformation syndrome
    term:
      id: MONDO:0016577
      label: biliary atresia with splenic malformation syndrome
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The commonest of these is the Biliary Atresia Splenic Malformation (BASM) syndrome,
      which accounts for
      about 10–15% of European and American series ..., but is distinctly rare in
      Chinese and Japanese series
      (<2%) ....
    explanation: >-
      Review synthesis of this clinical subgroup; definitions and overlap vary.
    quote_role: REVIEW_SYNTHESIS
- name: CBA
  display_name: Cystic biliary atresia
  description: >-
    Biliary atresia with cystic dilatation of part of the extrahepatic remnant, sometimes
    detected prenatally.
    It must be distinguished from a choledochal cyst. Timely Kasai surgery often gives
    better jaundice-clearance
    outcomes than other biliary-atresia variants, although late deterioration can
    still occur.

  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Post-operatively, these infants have >75% chance of clearance of jaundice and
      native liver preservation,
      though their prognosis does appear to have a marked relationship with age at
      surgery ....
    explanation: >-
      Review synthesis of this clinical subgroup; definitions and overlap vary.
    quote_role: REVIEW_SYNTHESIS
- name: CMV-associated BA
  display_name: Cytomegalovirus-associated biliary atresia
  description: >-
    Clinical subgroup with evidence of CMV infection at presentation, often defined
    by CMV IgM. Associations
    with more severe disease and poorer outcomes have been reported, but seropositivity
    at diagnosis does not
    establish congenital infection, timing, or viral causation of biliary atresia.
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Therefore, using CMV IgM antibodies as a marker of infection up to 30% of Chinese
      BA series have been
      positive ... compared to about 10% in a UK series ....
    explanation: >-
      Review synthesis of this clinical subgroup; definitions and overlap vary.
    quote_role: REVIEW_SYNTHESIS
- name: CABA
  display_name: Cardiac-associated biliary atresia
  description: >-
    A clinical risk subgroup with cardiac anomalies, partly overlapping BASM. The
    phenotype is heterogeneous
    and does not establish one common pathogenesis; hemodynamically important heart
    disease affects operative
    planning and prognosis.
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Indeed, when we reviewed our experience of biliary atresia-associated cardiac
      anomalies (n = 37), features
      indicative of BASM were present in 48% ....
    explanation: >-
      Review synthesis of this clinical subgroup; definitions and overlap vary.
    quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Non-Mendelian / multifactorial
  description: >-
    Usually sporadic and non-Mendelian. A systematic review of 35 reported twin pairs
    found 34 discordant pairs,
    but published cases do not provide a population recurrence or penetrance estimate.
    Common susceptibility
    alleles and rare candidate variants may contribute. Biallelic PKD1L1 variants
    in five of 67 broadly defined
    BASM cases support a candidate recessive contribution in some patients, not an
    established Mendelian explanation
    for BASM as a whole.
  inheritance_term:
    preferred_term: Non-Mendelian inheritance
    term:
      id: HP:0001426
      label: Non-Mendelian inheritance
  evidence:
  - reference: PMID:32504124
    reference_title: 'Biliary atresia in twins: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      97.1% twins were discordant, among 55.9% of which were monozygotic twin sets,
      indicating that BA may
      be related to genetic phenotype or penetrance.
    explanation: >-
      Published-case synthesis, with marked twin discordance; it does not estimate
      population penetrance or
      prove a particular environmental or epigenetic cause.

    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30664273
    reference_title: Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Five BASM subjects harbored rare and potentially deleterious biallelic variants
      in polycystic kidney
      disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling
      and embryonic laterality
      determination in fish, mice, and humans.
    explanation: >-
      Candidate biallelic variants in a minority of the ascertained BASM cohort.
prevalence:
- population: South Korea (nationwide birth cohort)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10.6
  notes: >-
    Korean nationwide cohort: 1.06 cases per 10,000 live births. This estimate is
    specific to its population
    and ascertainment period.
  evidence:
  - reference: PMID:28244293
    reference_title: Epidemiology of Biliary Atresia in Korea.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall incidence of BA was 1.06 cases per 10,000 live births.
    explanation: >-
      National cohort birth prevalence/incidence figure for biliary atresia in
      an East-Asian population.
- population: Texas, USA (1999–2014; cases without known genetic syndromes)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 6.5
  notes: >-
    305 cases among 4,689,920 live births after excluding other liver diseases and
    15 cases with chromosomal
    abnormalities or other Mendelian disorders. Female sex had an adjusted prevalence
    ratio of 1.68; associations
    with prematurity and maternal diabetes were observational and do not establish
    causation.
  evidence:
  - reference: PMID:35364097
    reference_title: 'The Epidemiology of Biliary Atresia: Exploring the Role of Developmental Factors on Birth Prevalence.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The prevalence of biliary atresia over the study period was 0.65 per 10 000
      live births.
    explanation: >-
      Population-specific birth prevalence from the Texas registry.
pathophysiology:
- name: Cholangiocyte Injury of the Bile Duct Epithelium
  biological_scale: CELLULAR
  description: >-
    Cholangiocyte epithelial damage is a central lesion. RRV infection and biliatresone
    exposure produce experimentally
    defined injury in mice and zebrafish, respectively; neither demonstrates the initiating
    cause in human
    disease. Immune attack and developmental susceptibility may contribute through
    distinct, incompletely resolved
    routes.
  cell_types:
  - preferred_term: extrahepatic cholangiocyte
    term:
      id: CL:0019020
      label: extrahepatic cholangiocyte
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  biological_processes:
  - preferred_term: cholangiocyte apoptotic process
    modifier: INCREASED
    term:
      id: GO:1902488
      label: cholangiocyte apoptotic process
  evidence:
  - reference: PMID:23844248
    reference_title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      the amount of cholangiocyte epithelial damage and bile duct edema was significantly
      greater in the early
      infection group
    explanation: >-
      Histologic epithelial injury in the time-dependent RRV mouse model.
  - reference: PMID:27102575
    reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in
      zebrafish larvae.
    explanation: >-
      The plant toxin biliatresone selectively injures extrahepatic cholangiocytes,
      demonstrating that a targeted cholangiocyte insult can initiate a BA-like
      extrahepatic cholangiopathy.
  downstream:
  - target: Immune-Mediated Periductal Inflammation
    description: >-
      Epithelial injury participates in the fibroinflammatory response; initial human
      triggers remain uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23844248
      reference_title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        the amount of cholangiocyte epithelial damage and bile duct edema was significantly
        greater in the
        early infection group
      explanation: >-
        Histologic epithelial injury in the time-dependent RRV mouse model.
  - target: Ductular Epithelial Expansion
    description: >-
      A reactive epithelial response accompanies obstructive injury; lineage origin
      remains partly inferred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32518681
      reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Portal tracts show expansion and demonstrate edematous fibroplasia with bile
        ductular proliferation
      explanation: >-
        Histologic epithelial expansion.
      quote_role: REVIEW_SYNTHESIS
- name: Immune-Mediated Periductal Inflammation
  biological_scale: TISSUE
  description: >-
    Periductal innate and adaptive immune activation accompanies biliary epithelial
    injury. Human tissue studies
    show inflammatory infiltrates and regulatory abnormalities; perturbation studies
    in neonatal RRV mice support
    contributions from Th1, Th17, B-cell and macrophage pathways. No single experimental
    immune mechanism establishes
    the cause of all human cases.
  cell_types:
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  - preferred_term: cytotoxic T cell
    term:
      id: CL:0000910
      label: cytotoxic T cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: T cell mediated cytotoxicity
    modifier: INCREASED
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Mild lymphocytic inflammation is usually present within portal tracts in BA.
      Other inflammatory cells,
      including eosinophils, plasma cells and macrophages, are also present.
    explanation: >-
      Human pathology synthesis describes mixed portal inflammation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:36333281
    reference_title: Single-cell and spatial transcriptomics reveal the fibrosis-related immune landscape of biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      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.
    explanation: >-
      Spatial association of immune populations with scar tissue, not a causal intervention.
  downstream:
  - target: Portal Mesenchymal Cell Activation
    description: >-
      Immune populations associate spatially with fibrotic tissue; inferred profibrotic
      signaling requires
      functional validation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36333281
      reference_title: Single-cell and spatial transcriptomics reveal the fibrosis-related immune landscape of biliary atresia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        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.
      explanation: >-
        Spatial association of immune populations with scar tissue, not a causal intervention.
- name: Portal Mesenchymal Cell Activation
  biological_scale: CELLULAR
  conforms_to: fibrotic_response#Mesenchymal Cell Activation
  description: >-
    Sustained inflammation activates portal fibroblasts and transdifferentiates
    hepatic stellate cells into a myofibroblast-like, matrix-secreting phenotype —
    the organ-specific mesenchymal activation step of the conserved fibrotic
    response in the biliary atresia portal tract.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  biological_processes:
  - preferred_term: hepatic stellate cell activation
    modifier: INCREASED
    term:
      id: GO:0035733
      label: hepatic stellate cell activation
  downstream:
  - target: Fibro-obliteration of the Biliary Tree
    description: >-
      Activated mesenchymal cells contribute excess matrix to duct scarring.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32518681
      reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The transformation and proliferation of hepatic stellate cells (HSCs) from
        fat-storing cells to myofibroblasts
        in BA plays an important role in hepatic fibrogenesis. HSCs are responsible
        for increased extracellular
        matrix, which leads to progressive scarring
      explanation: >-
        The pathology review supports mesenchymal activation and matrix production
        in biliary atresia.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The transformation and proliferation of hepatic stellate cells (HSCs) from fat-storing
      cells to myofibroblasts
      in BA plays an important role in hepatic fibrogenesis. HSCs are responsible
      for increased extracellular
      matrix, which leads to progressive scarring
    explanation: >-
      The pathology review supports mesenchymal activation and matrix production in
      biliary atresia.
    quote_role: REVIEW_SYNTHESIS
- name: Fibro-obliteration of the Biliary Tree
  biological_scale: TISSUE
  conforms_to: fibrotic_response#Excessive ECM Deposition
  description: >-
    Activated portal myofibroblasts deposit excess extracellular matrix around and
    within the injured ducts, producing a fibro-obliterative process that
    progressively narrows and obliterates the extrahepatic biliary tree and damages
    the intrahepatic ducts, forming the characteristic fibrous remnant at the porta
    hepatis. This obliteration is the anatomic substrate that the Kasai
    portoenterostomy attempts to bypass.
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: INCREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological findings in liver biopsies include the expansion of the portal
      tracts, with edematous
      fibroplasia and bile ductular proliferation, with bile plugs in duct lumen.
    explanation: >-
      Portal-tract fibroplasia and ductular reaction on biopsy evidence the
      fibro-obliterative remodeling of this node.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The destructive fibroinflammatory process that underlies BA, may involve a short
      segment of a duct, an
      entire duct or the entire biliary system.
    explanation: >-
      Fibroinflammatory remodeling of the resected biliary tree.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Impaired Bile Drainage
    description: >-
      Scarring obstructs the biliary lumen.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32518681
      reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the
        intrahepatic and extrahepatic
        biliary system, resulting in obstruction of bile flow and neonatal jaundice.
      explanation: >-
        Obstructive bile-flow impairment and neonatal jaundice, distinct from subsequent
        cirrhotic remodeling.

      quote_role: REVIEW_SYNTHESIS
- name: Impaired Bile Drainage
  biological_scale: ORGANISM
  description: >-
    Obstruction of the biliary tree reduces delivery of bile to the intestine and
    retains conjugated bilirubin
    and bile acids. Drainage may remain impaired after Kasai, while ongoing intrahepatic
    disease contributes
    to later liver injury.
  biological_processes:
  - preferred_term: bile acid secretion
    modifier: DECREASED
    term:
      id: GO:0032782
      label: bile acid secretion
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the
      intrahepatic and extrahepatic
      biliary system, resulting in obstruction of bile flow and neonatal jaundice.
    explanation: >-
      Obstructive bile-flow impairment and neonatal jaundice, distinct from subsequent
      cirrhotic remodeling.

    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Biliary Cirrhotic Remodeling
    description: >-
      Persistent obstruction contributes to progressive liver injury and cirrhotic
      remodeling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32653991
      reference_title: Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        As a result of blockage or destruction of the biliary tract, bile acids accumulate
        and drive inflammation,
        fibrosis, and disease progression.
      explanation: >-
        Review synthesis linking bile retention to later injury.
      quote_role: REVIEW_SYNTHESIS
  - target: Impaired Intestinal Lipid Absorption
    description: >-
      Reduced bile delivery impairs nutrient absorption.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Patients with cholestatic conditions are at increased risk of malabsorption
        of fat-soluble vitamins,
        like vitamin K.
      explanation: >-
        Cholestatic malabsorption in the BA care guideline.
      quote_role: REVIEW_SYNTHESIS
  - target: Conjugated hyperbilirubinemia
    description: >-
      Conjugated hyperbilirubinemia is a clinical consequence or manifestation of
      this process; expression
      varies with disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Biliary atresia (BA) and choledochal cysts are known to cause obstructive
        jaundice, and conjugated
        hyperbilirubinemia will be observed.
      explanation: >-
        The defining cholestatic biochemical phenotype is not unique to biliary atresia.
      quote_role: REVIEW_SYNTHESIS
  - target: Prolonged neonatal jaundice
    description: >-
      Prolonged neonatal jaundice is a clinical consequence or manifestation of this
      process; expression varies
      with disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biliary atresia (BA) is an obliterative condition of the biliary tract that
        presents with persistent
        jaundice and pale stools typically in the first few weeks of life.
      explanation: >-
        Persistent jaundice in the first weeks of life is the defining presenting
        feature of biliary atresia.

      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Acholic stools
    description: >-
      Acholic stools is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biliary atresia (BA) is an obliterative condition of the biliary tract that
        presents with persistent
        jaundice and pale stools typically in the first few weeks of life.
      explanation: >-
        Pale (acholic) stools are part of the defining presenting signature of
        biliary atresia, reflecting absent bile pigment in the gut.

      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Dark urine
    description: >-
      Dark urine is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
        growth retardation,
        and hepatomegaly
      explanation: >-
        Clinical guideline summarizes presenting manifestations.
      quote_role: REVIEW_SYNTHESIS
  - target: Hepatomegaly
    description: >-
      Hepatomegaly is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
        growth retardation,
        and hepatomegaly
      explanation: >-
        Clinical guideline summarizes presenting manifestations.
      quote_role: REVIEW_SYNTHESIS
  - target: Pruritus
    description: >-
      Pruritus is a clinical consequence or manifestation of this process; expression
      varies with disease stage
      and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42666930
      reference_title: 'Real-world use of maralixibat in biliary atresia: a case series.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        We report the use of maralixibat for the treatment of cholestatic pruritus
        in BA for six patients.
      explanation: >-
        Selected symptomatic case series establishes occurrence, not prevalence.
- name: Embryonic Patterning Disturbance
  description: >-
    The combination of biliary atresia with splenic, visceral-situs, vascular and
    cardiac malformations suggests
    disturbed embryonic patterning in BASM. CFC1, a NODAL coreceptor, and PKD1L1 are
    candidate links to left-right
    signaling in a subset, with supportive animal data; the underlying defect remains
    unresolved in most patients.
    The molecular-function annotation identifies the linked protein’s normal activity;
    it does not establish
    the functional effect of each human susceptibility allele.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      As this biliary timeline is shared by the determination of visceral situs, spleen
      formation, evolution
      of the portal venous and caval venous system anomalies it is not too much to
      speculate that BASM is also
      an embryonic defect.
    explanation: >-
      Developmental interpretation of the BASM phenotype, not a proven single molecular
      cause.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:18162845
    reference_title: CFC1 gene involvement in biliary atresia with polysplenia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The heterozygous transition c.433G>A (Ala145Thr) located in exon 5 was identified
      in 5 patients, with
      a twice-higher frequency than in control patients.
    explanation: >-
      Small candidate-gene study; no Mendelian penetrance inference.
  downstream:
  - target: Disrupted Biliary Morphogenesis
    description: >-
      A candidate developmental contribution in BASM; the molecular intermediate is
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        As this biliary timeline is shared by the determination of visceral situs,
        spleen formation, evolution
        of the portal venous and caval venous system anomalies it is not too much
        to speculate that BASM is
        also an embryonic defect.
      explanation: >-
        Developmental interpretation of the BASM phenotype, not a proven single molecular
        cause.
      quote_role: REVIEW_SYNTHESIS
  - target: Polysplenia
    description: >-
      Polysplenia is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The splenic malformation is typically polysplenia, but sometimes can be asplenia
        or double spleen
      explanation: >-
        Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.
      quote_role: REVIEW_SYNTHESIS
  - target: Abnormal abdominal situs
    description: >-
      Abnormal abdominal situs is a clinical consequence or manifestation of this
      process; expression varies
      with disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The other obvious and evident visceral anomalies are: situs inversus, present
        in about 30–40% of patients
        with and without malrotation; preduodenal portal vein and a complete absence
        of the intrahepatic vena
        cava.
      explanation: >-
        BASM visceral laterality spectrum; does not specify total inversion for all
        affected individuals.
      quote_role: REVIEW_SYNTHESIS
  - target: Asplenia
    description: >-
      Asplenia is a clinical consequence or manifestation of this process; expression
      varies with disease stage
      and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The splenic malformation is typically polysplenia, but sometimes can be asplenia
        or double spleen
      explanation: >-
        Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.
      quote_role: REVIEW_SYNTHESIS
  - target: Intestinal malrotation
    description: >-
      Intestinal malrotation is a clinical consequence or manifestation of this process;
      expression varies
      with disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The other obvious and evident visceral anomalies are: situs inversus, present
        in about 30–40% of patients
        with and without malrotation; preduodenal portal vein and a complete absence
        of the intrahepatic vena
        cava.
      explanation: >-
        BASM visceral laterality spectrum; does not specify total inversion for all
        affected individuals.
      quote_role: REVIEW_SYNTHESIS
  - target: Congenital heart defects
    description: >-
      Congenital heart defects is a clinical consequence or manifestation of this
      process; expression varies
      with disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34884377
      reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Cardiac anomalies are apparent in about half the cases overall, but there
        is lack of a consistent cardiac
        phenotype.
      explanation: >-
        Variable cardiac involvement within the BASM discussion; no single lesion
        is specified.
      quote_role: REVIEW_SYNTHESIS
  genes:
  - preferred_term: CFC1
    term:
      id: hgnc:18292
      label: CFC1
  molecular_functions:
  - preferred_term: CFC1 coreceptor activity
    term:
      id: GO:0015026
      label: coreceptor activity
- name: Disrupted Biliary Morphogenesis
  description: >-
    Susceptibility-gene perturbations can impair developing biliary networks. Gpc1,
    add3a, arf6 and pkd1l1
    studies provide distinct experimental routes, but sparse fish ducts are not equivalent
    to the human fibro-obliterated
    extrahepatic remnant. The molecular-function annotation identifies the linked
    protein’s normal activity;
    it does not establish the functional effect of each human susceptibility allele.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:23336978
    reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Knockdown of gpc1 in zebrafish led to developmental biliary defects.
    explanation: >-
      Experimental biliary developmental phenotype.
  - reference: PMID:37675454
    reference_title: Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      These data highlight the essential role of pkd1l1 in normal development and
      function of the zebrafish
      biliary system
    explanation: >-
      Fish loss-of-function data support developmental plausibility rather than variant-specific
      human causality.
  downstream:
  - target: Impaired Bile Drainage
    description: >-
      Experimental developmental defects impair transport; their contribution in individual
      human cases varies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23336978
      reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Knockdown of gpc1 in zebrafish led to developmental biliary defects.
      explanation: >-
        Experimental biliary developmental phenotype.
  genes:
  - preferred_term: PKD1L1
    term:
      id: hgnc:18053
      label: PKD1L1
  molecular_functions:
  - preferred_term: PKD1L1 calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
- name: Altered ADD3 Regulatory Activity
  description: >-
    At the human ADD3 susceptibility locus, H69 cholangiocyte reporter assays detect
    allele-dependent activity
    in four fragments: risk haplotypes increase activity at E2, E4 and E10 but decrease
    it at E9. The fragment
    containing lead marker rs17095355 has no significant allelic difference. These
    assays concern cloned regulatory
    elements; they do not establish endogenous expression changes, a causal nucleotide,
    or chromatin contacts
    in patient cholangiocytes. The molecular-function annotation identifies the linked
    protein’s normal activity;
    it does not establish the functional effect of each human susceptibility allele.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:41589307
    reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      four elements (E2, E4, E9 and E10) showed allele-specific reporter activity
      differences
    explanation: >-
      Direct reporter measurement in the H69 human cholangiocyte cell line.
  downstream:
  - target: Disrupted Biliary Morphogenesis
    description: >-
      Reporter effects and fish dosage experiments suggest a susceptibility mechanism;
      they do not trace one
      human allele through to disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41589307
      reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Both overexpression and knockdown of add3a in zebrafish disrupted hepatobiliary
        function and development,
        resulting in gallbladder hypoplasia/agenesis and reduced intrahepatic bile
        duct density.
      explanation: >-
        Independent dosage perturbations provide a plausible bridge to biliary development,
        not the effect
        of the assayed human variants in their native locus.
  genes:
  - preferred_term: ADD3
    term:
      id: hgnc:245
      label: ADD3
  molecular_functions:
  - preferred_term: ADD3 actin binding
    term:
      id: GO:0003779
      label: actin binding
- name: Excess Hedgehog Signaling in Developmental Models
  description: >-
    Gpc1 or add3a knockdown increases Hedgehog-pathway readouts in zebrafish. Cyclopamine
    partially rescues
    the associated biliary defects, supporting a model-specific contribution of excessive
    signaling. A uniform
    Hedgehog abnormality caused by each human susceptibility allele has not been demonstrated.
    The molecular-function
    annotation identifies the linked protein’s normal activity; it does not establish
    the functional effect
    of each human susceptibility allele.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:23336978
    reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially
      rescued the gpc1-knockdown
      phenotype.
    explanation: >-
      Pharmacologic rescue in fish.
  - reference: PMID:27526058
    reference_title: Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      MO-mediated knockdown of add3a also showed higher mRNA expression of hedgehog
      (Hh) targets. Inhibition
      of Hh signaling rescued biliary defects caused by add3a knockdown.
    explanation: >-
      An additional fish perturbation/rescue route.
  downstream:
  - target: Disrupted Biliary Morphogenesis
    description: >-
      Inhibitor rescue supports a Hedgehog contribution in the gpc1 fish model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23336978
      reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially
        rescued the gpc1-knockdown
        phenotype.
      explanation: >-
        Pharmacologic rescue in fish.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: INCREASED
  genes:
  - preferred_term: GPC1
    term:
      id: hgnc:4449
      label: GPC1
  molecular_functions:
  - preferred_term: GPC1 growth factor binding
    term:
      id: GO:0019838
      label: growth factor binding
- name: Reduced EGFR-ARF6 Developmental Signaling
  description: >-
    Arf6 knockdown and EGFR inhibition produce sparse intrahepatic biliary networks
    and impaired bile transport
    in zebrafish, with arf6 mRNA rescue. The human noncoding association does not
    directly establish deficient
    ARF6 expression or this complete pathway in affected infants. The molecular-function
    annotation identifies
    the linked protein’s normal activity; it does not establish the functional effect
    of each human susceptibility
    allele.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:26379158
    reference_title: The Role of ARF6 in Biliary Atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6
      at lower doses of
      each agent and rescued with arf6 mRNA.
    explanation: >-
      Perturbation and rescue support EGFR–ARF6 involvement in fish development.
  downstream:
  - target: Disrupted Biliary Morphogenesis
    description: >-
      Developmental perturbation impairs the experimental intrahepatic network.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26379158
      reference_title: The Role of ARF6 in Biliary Atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with
        Mo-arf6 at lower doses of
        each agent and rescued with arf6 mRNA.
      explanation: >-
        Perturbation and rescue support EGFR–ARF6 involvement in fish development.
  genes:
  - preferred_term: ARF6
    term:
      id: hgnc:659
      label: ARF6
  molecular_functions:
  - preferred_term: ARF6 GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
- name: Impaired Extrahepatic Duct Elastic-Fiber Organization
  description: >-
    Adult Efemp1 heterozygous mouse ducts have fewer organized elastic fibers despite
    preserved total elastin,
    with altered responses to pressure. This suggests structural susceptibility involving
    fibulin-3, but neither
    spontaneous atresia nor the direction of effect of human EFEMP1 risk variants
    was established. A mechanical
    contribution to epithelial vulnerability remains a hypothesis without a demonstrated
    causal edge to injury.
    The molecular-function annotation identifies the linked protein’s normal activity;
    it does not establish
    the functional effect of each human susceptibility allele.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:39717503
    reference_title: Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased
      by approximately half.
    explanation: >-
      Mouse matrix-organization phenotype.
  - reference: PMID:39717503
    reference_title: Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Pressure myography showed that Efemp1 +/- ducts have altered mechanics compared
      to control ducts
    explanation: >-
      Measured duct mechanics following heterozygous gene loss.
  downstream: []
  genes:
  - preferred_term: EFEMP1
    term:
      id: hgnc:3218
      label: EFEMP1
  molecular_functions:
  - preferred_term: EFEMP1 extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
- name: Reduced Cholangiocyte Glutathione Reserve
  description: >-
    In zebrafish, extrahepatic cholangiocytes have a relatively oxidized glutathione
    state and are susceptible
    to biliatresone-induced redox stress. Glutathione depletion sensitizes biliary
    cells, whereas NAC supplementation
    or Nrf2 activation reduces injury. This is a toxin-model mechanism; intrinsic
    glutathione deficiency has
    not been established as a general initiating human defect.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:27102575
    reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic
      cholangiocytes to the toxin
    explanation: >-
      Manipulating antioxidant reserve changes susceptibility in fish.
  downstream:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    description: >-
      Lower reserve sensitizes fish cholangiocytes to electrophilic toxin injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27102575
      reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic
        cholangiocytes to the toxin
      explanation: >-
        Manipulating antioxidant reserve changes susceptibility in fish.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
- name: Reduced Regulatory T-Cell Restraint
  description: >-
    Human BA samples show reduced Treg frequency and inadequate CTLA-4 upregulation,
    including blood collected
    at transplantation; these observations do not establish an initiating neonatal
    defect. Treg augmentation
    after infection improves survival and biliary injury in the RRV mouse model, supporting
    a regulatory contribution
    to ongoing inflammation.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:39131670
    reference_title: Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patients with BA had decreased peripheral blood Treg frequency and lack of cytotoxic
      T lymphocyte-associated
      antigen-4 (CTLA-4) upregulation despite a highly activated, effector Treg phenotype.
    explanation: >-
      Human clinical sample phenotype, with stage and comparator limitations.
  - reference: PMID:39131670
    reference_title: Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Treg augmentation in the murine model led to increased survival, decreased direct
      bilirubin levels and
      liver inflammation, and expansion of resident macrophages.
    explanation: >-
      Intervention result in RRV mice, not established human treatment efficacy.
  downstream:
  - target: Immune-Mediated Periductal Inflammation
    description: >-
      Treg augmentation reduces model inflammation; the human initiating role is unproven.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39131670
      reference_title: Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Treg augmentation in the murine model led to increased survival, decreased
        direct bilirubin levels
        and liver inflammation, and expansion of resident macrophages.
      explanation: >-
        Intervention result in RRV mice, not established human treatment efficacy.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
- name: Th1-Associated Cytotoxic Inflammation
  description: >-
    T-bet-dependent inflammatory and cytotoxic programs contribute to duct injury
    in the RRV mouse model. T-bet
    deletion reduces these programs and preserves duct patency in many mice, but cholestatic
    symptoms and mortality
    persist. Duct patency therefore does not establish complete disease rescue.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:34943969
    reference_title: T-Bet Deficiency Attenuates Bile Duct Injury in Experimental Biliary Atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Even though the percentage of T-bet KO mice displaying symptoms of an obstructive
      cholangiopathy and
      overall mortality rate was not different compared to wild-type mice, the extrahepatic
      bile ducts of T-bet
      KO mice remained patent.
    explanation: >-
      The primary study distinguishes anatomic protection from survival benefit.
  downstream:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    description: >-
      T-bet perturbation alters biliary injury without rescuing survival.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34943969
      reference_title: T-Bet Deficiency Attenuates Bile Duct Injury in Experimental Biliary Atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Even though the percentage of T-bet KO mice displaying symptoms of an obstructive
        cholangiopathy and
        overall mortality rate was not different compared to wild-type mice, the extrahepatic
        bile ducts of
        T-bet KO mice remained patent.
      explanation: >-
        The primary study distinguishes anatomic protection from survival benefit.
- name: Dendritic-Cell-Dependent Th17 Polarization
  description: >-
    In the post-obstructive phase of RRV-induced disease, dendritic cells promote
    Th17 responses. Depletion
    decreases hepatic IL-17A and intrahepatic injury without preventing the initial
    extrahepatic obstruction.
    Human IL-17A-positive-cell and macrophage associations support relevance but do
    not constitute equivalent
    intervention evidence.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:27641439
    reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production
      and ameliorated intrahepatic
      bile duct injury.
    explanation: >-
      Dendritic-cell perturbation in the RRV model.
  - reference: PMID:27641439
    reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive
      disease undergoing
      liver transplantation.
    explanation: >-
      Cellular cytokine-production finding in human clinical samples.
  downstream:
  - target: Cholangiocyte CCL2 Induction
    description: >-
      Th17-derived IL-17A can stimulate the cholangiocyte chemokine response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27641439
      reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in
        neonatal cholangiocytes
        in vitro
      explanation: >-
        Direct cell-culture response to IL-17A.
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
- name: Cholangiocyte CCL2 Induction
  description: >-
    IL-17A induces CCL2 expression in cultured neonatal cholangiocytes. In this assay
    it does not directly
    kill the biliary cells; the proposed injury pathway involves recruitment of inflammatory
    cells.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:27641439
    reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in neonatal
      cholangiocytes in
      vitro
    explanation: >-
      Direct cell-culture response to IL-17A.
  downstream:
  - target: CCR2-Dependent Inflammatory Macrophage Recruitment
    description: >-
      CCL2 signaling recruits CCR2-positive inflammatory macrophages in the model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27641439
      reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment
        of inflammatory
        macrophages to the liver in vivo.
      explanation: >-
        In vivo perturbation of the recruitment pathway.
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
- name: CCR2-Dependent Inflammatory Macrophage Recruitment
  description: >-
    CCL2/CCR2 signaling recruits inflammatory Ly6C-high macrophages during later RRV-model
    injury. CCR2 blockade
    reduces recruitment, and disrupted IL-17 signaling preserves intrahepatic ducts
    and improves survival.
    In human tissue, IL-17A-positive cells correlate with CD68-positive infiltration;
    causal human intervention
    evidence is lacking.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:27641439
    reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment
      of inflammatory macrophages
      to the liver in vivo.
    explanation: >-
      In vivo perturbation of the recruitment pathway.
  - reference: PMID:27641439
    reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the prevalence of IL-17A+ cells was positively correlated with the degree of
      CD68+ macrophage infiltration
      at diagnosis.
    explanation: >-
      Human tissue association, not a test of CCR2 blockade.
  downstream:
  - target: Immune-Mediated Periductal Inflammation
    description: >-
      Recruitment expands the model inflammatory infiltrate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27641439
      reference_title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment
        of inflammatory
        macrophages to the liver in vivo.
      explanation: >-
        In vivo perturbation of the recruitment pathway.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
- name: Macrophage CXCL2-Dependent Neutrophil Chemotaxis
  description: >-
    RRV-infected RAW264.7 macrophage conditioned medium recruits neutrophils, and
    CXCL2/Mip2 depletion abolishes
    this response. RRV is detected in hepatic macrophages in vivo, but the necessity
    of this chemotactic pathway
    for duct injury in vivo was not demonstrated. Infected cholangiocyte conditioned
    medium did not reproduce
    the response.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:20234283
    reference_title: Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis by Mip2/Cxcl2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      addition of anti-Mip2/Cxcl2 antibodies depleted this chemokine in the conditioned
      media and completely
      prevented neutrophil chemotaxis.
    explanation: >-
      Conditioned-medium depletion experiment; the causal intervention is in vitro.
  downstream:
  - target: Immune-Mediated Periductal Inflammation
    description: >-
      The cell-culture recruitment mechanism may amplify inflammation; its necessity
      in vivo remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20234283
      reference_title: Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis by Mip2/Cxcl2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        addition of anti-Mip2/Cxcl2 antibodies depleted this chemokine in the conditioned
        media and completely
        prevented neutrophil chemotaxis.
      explanation: >-
        Conditioned-medium depletion experiment; the causal intervention is in vitro.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
- name: B-Cell-Dependent Inflammatory Amplification
  description: >-
    B-cell-deficient mice resist RRV-induced biliary obstruction and have reduced
    Th1 inflammation. Treg depletion
    does not abolish this protection. Antigen presentation is a proposed explanation;
    this experiment does
    not establish that autoantibodies themselves cause human disease.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:23991203
    reference_title: B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct
      obstruction.
    explanation: >-
      Genetic B-cell deficiency protects against model pathology.
  downstream:
  - target: Immune-Mediated Periductal Inflammation
    description: >-
      B-cell deficiency limits model inflammatory injury; the responsible B-cell function
      is incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23991203
      reference_title: B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct
        obstruction.
      explanation: >-
        Genetic B-cell deficiency protects against model pathology.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
- name: Neutrophil Extracellular Trap Formation
  description: >-
    CD177-positive neutrophils in the RRV model exhibit increased oxidative activity
    and NET formation; coculture
    experiments link NET-associated activity to biliary epithelial apoptosis. Cd177
    loss reduces experimental
    disease severity. Human NAC pilot observations are exploratory and do not establish
    durable clinical benefit.
    The 2025 corrigendum corrects duplicated representative flow plots, with the authors
    reporting unchanged
    underlying statistics.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:35803543
    reference_title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and
      mortality.
    explanation: >-
      Mouse genetic intervention.
  - reference: PMID:35803543
    reference_title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      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.
    explanation: >-
      The epithelial injury assay is in coculture, distinct from the in vivo mouse
      outcome.
  downstream:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    description: >-
      NET-associated coculture activity damages biliary epithelium.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35803543
      reference_title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        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.
      explanation: >-
        The epithelial injury assay is in coculture, distinct from the in vivo mouse
        outcome.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
- name: Ductular Epithelial Expansion
  description: >-
    Expanded portal biliary epithelium is a characteristic tissue response. A 2025
    human single-cell study
    found cells coexpressing hepatocyte and cholangiocyte markers; RNA velocity and
    pseudotime inferred a hepatocyte-to-biliary
    trajectory. These computational trajectories are not lineage tracing, and their
    downstream fibrogenic function
    remains partly inferential.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Portal tracts show expansion and demonstrate edematous fibroplasia with bile
      ductular proliferation
    explanation: >-
      Histologic epithelial expansion.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40366121
    reference_title: Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the reprogrammed cells expressed both hepatocyte and cholangiocyte markers.
    explanation: >-
      Human tissue-derived single-cell coexpression.
  - reference: PMID:40366121
    reference_title: Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: >-
      Pseudotime analysis depicted a differentiation trajectory from hepatocytes across
      reprogrammed cells
      to cholangiocytes in BA.
    explanation: >-
      Computational trajectory inference; not direct observation of human cell fate
      conversion.
  downstream: []
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
- name: Biliary Cirrhotic Remodeling
  description: >-
    Persistent biliary injury and matrix deposition distort liver architecture into
    irregular regenerative
    nodules and scarring. Progression can continue despite restored extrahepatic drainage.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Biliary pattern cirrhosis with irregular nodules are observed on microscopy.
    explanation: >-
      Architectural endpoint seen in explanted livers.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Portal Venous Pressure Elevation
    description: >-
      Distorted hepatic architecture contributes to increased portal resistance.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32518681
      reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Higher stages of portal fibrosis have been associated with more severe portal
        hypertension and increased
        risk of LT
      explanation: >-
        Disease-specific clinical-pathologic association.
      quote_role: REVIEW_SYNTHESIS
  - target: Biliary cirrhosis
    description: >-
      Biliary cirrhosis is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32518681
      reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Biliary pattern cirrhosis with irregular nodules are observed on microscopy.
      explanation: >-
        Pathologic cirrhotic remodeling in explanted livers.
      quote_role: REVIEW_SYNTHESIS
  conforms_to: cholestatic_liver_injury#Biliary Fibrosis Progressing to Biliary Cirrhosis
- name: Portal Venous Pressure Elevation
  description: >-
    Fibrotic and cirrhotic remodeling increases resistance to portal flow, producing
    portal hypertension and
    its splenic, variceal and fluid-retention complications.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Higher stages of portal fibrosis have been associated with more severe portal
      hypertension and increased
      risk of LT
    explanation: >-
      Disease-specific clinical-pathologic association.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Portal hypertension
    description: >-
      Portal hypertension is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
        are signs of cirrhosis
        and portal hypertension, and ascites will be observed in decompensated cases
      explanation: >-
        Review describes later manifestations and complications; no population frequency
        is inferred.
      quote_role: REVIEW_SYNTHESIS
  - target: Splenomegaly
    description: >-
      Splenomegaly is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
        are signs of cirrhosis
        and portal hypertension, and ascites will be observed in decompensated cases
      explanation: >-
        Review describes later manifestations and complications; no population frequency
        is inferred.
      quote_role: REVIEW_SYNTHESIS
  - target: Ascites
    description: >-
      Ascites is a clinical consequence or manifestation of this process; expression
      varies with disease stage
      and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
        are signs of cirrhosis
        and portal hypertension, and ascites will be observed in decompensated cases
      explanation: >-
        Review describes later manifestations and complications; no population frequency
        is inferred.
      quote_role: REVIEW_SYNTHESIS
  - target: Esophageal varices
    description: >-
      Esophageal varices is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        This condition can cause portal hypertension, which in turn may result in
        esophageal varices and ascites
      explanation: >-
        Guideline identifies the anatomic variceal complication.
      quote_role: REVIEW_SYNTHESIS
- name: Impaired Intestinal Lipid Absorption
  description: >-
    Reduced intestinal bile delivery impairs fat and fat-soluble-vitamin absorption.
    Nutritional deficiency
    and increased metabolic demands contribute to poor growth; vitamin K depletion
    may impair hemostasis.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patients with cholestatic conditions are at increased risk of malabsorption
      of fat-soluble vitamins,
      like vitamin K.
    explanation: >-
      Cholestatic malabsorption in the BA care guideline.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Failure to thrive
    description: >-
      Failure to thrive is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
        growth retardation,
        and hepatomegaly
      explanation: >-
        Clinical guideline summarizes presenting manifestations.
      quote_role: REVIEW_SYNTHESIS
  - target: Fat malabsorption
    description: >-
      Fat malabsorption is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42569433
      reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Patients with cholestatic conditions are at increased risk of malabsorption
        of fat-soluble vitamins,
        like vitamin K.
      explanation: >-
        The guideline links cholestasis with nutrient malabsorption.
      quote_role: REVIEW_SYNTHESIS
  - target: Vitamin K deficiency
    description: >-
      Vitamin K deficiency is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
        are signs of cirrhosis
        and portal hypertension, and ascites will be observed in decompensated cases
      explanation: >-
        Review describes later manifestations and complications; no population frequency
        is inferred.
      quote_role: REVIEW_SYNTHESIS
  - target: Vitamin D deficiency
    description: >-
      Vitamin D deficiency is a clinical consequence or manifestation of this process;
      expression varies with
      disease stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        In the presence of cholestasis, vitamins A, D, E and K should be given to
        prevent the development of
        fat-soluble vitamin deficiency
      explanation: >-
        Clinical review explicitly includes vitamin D among the deficiencies requiring
        prevention.
      quote_role: REVIEW_SYNTHESIS
- name: Post-Kasai Ascending Biliary Infection
  description: >-
    The altered biliary-enteric anatomy after Kasai permits ascending infection of
    the remaining ducts. This
    secondary treatment-associated complication is distinct from hypotheses about
    the initiating cause of biliary
    atresia.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patients who have undergone a Kasai portoenterostomy procedure are at risk of
      ascending cholangitis due
      to the resulting abnormal biliary anatomy.
    explanation: >-
      Clinical review explicitly relates altered anatomy to postoperative cholangitis.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Cholangitis
    description: >-
      Cholangitis is a clinical consequence or manifestation of this process; expression
      varies with disease
      stage and subtype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Patients who have undergone a Kasai portoenterostomy procedure are at risk
        of ascending cholangitis
        due to the resulting abnormal biliary anatomy.
      explanation: >-
        Clinical review explicitly relates altered anatomy to postoperative cholangitis.
      quote_role: REVIEW_SYNTHESIS
phenotypes:
- name: Conjugated hyperbilirubinemia
  description: >-
    Elevation of the direct (conjugated) bilirubin fraction due to obstructed bile
    flow; the biochemical hallmark of neonatal cholestasis and the finding that
    mandates urgent evaluation for biliary atresia.
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Biliary atresia (BA) and choledochal cysts are known to cause obstructive jaundice,
      and conjugated hyperbilirubinemia
      will be observed.
    explanation: >-
      The defining cholestatic biochemical phenotype is not unique to biliary atresia.
    quote_role: REVIEW_SYNTHESIS
- name: Prolonged neonatal jaundice
  description: >-
    Jaundice persisting beyond the first two weeks of life. In biliary atresia the
    jaundice is cholestatic (conjugated) rather than the benign unconjugated
    physiologic jaundice of the newborn.
  phenotype_term:
    preferred_term: Prolonged neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biliary atresia (BA) is an obliterative condition of the biliary tract that
      presents with persistent
      jaundice and pale stools typically in the first few weeks of life.
    explanation: >-
      Persistent jaundice in the first weeks of life is the defining presenting
      feature of biliary atresia.

    quote_role: REVIEW_SYNTHESIS
- name: Acholic stools
  description: >-
    Pale stools reflect reduced delivery of bile pigment to the intestine. They may
    develop after an initially
    pigmented-stool period, so their early absence does not exclude biliary atresia.
  phenotype_term:
    preferred_term: Acholic stools
    term:
      id: HP:0011985
      label: Acholic stools
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biliary atresia (BA) is an obliterative condition of the biliary tract that
      presents with persistent
      jaundice and pale stools typically in the first few weeks of life.
    explanation: >-
      Pale (acholic) stools are part of the defining presenting signature of
      biliary atresia, reflecting absent bile pigment in the gut.

    quote_role: REVIEW_SYNTHESIS
- name: Dark urine
  description: >-
    Dark urine from renal excretion of conjugated bilirubin that cannot be
    excreted via the obstructed biliary route.
  phenotype_term:
    preferred_term: Dark urine
    term:
      id: HP:0040319
      label: Dark urine

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
      growth retardation, and
      hepatomegaly
    explanation: >-
      Clinical guideline summarizes presenting manifestations.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatomegaly
  description: >-
    Enlargement of the liver, typically firm, reflecting cholestasis and evolving
    fibrosis.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
      growth retardation, and
      hepatomegaly
    explanation: >-
      Clinical guideline summarizes presenting manifestations.
    quote_role: REVIEW_SYNTHESIS
- name: Biliary cirrhosis
  description: >-
    Progressive secondary biliary cirrhosis resulting from persistent obstruction
    and cholestatic injury; may already be present at diagnosis and progresses
    despite surgery in many patients.
  phenotype_term:
    preferred_term: Biliary cirrhosis
    term:
      id: HP:0002613
      label: Biliary cirrhosis

  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Biliary pattern cirrhosis with irregular nodules are observed on microscopy.
    explanation: >-
      Pathologic cirrhotic remodeling in explanted livers.
    quote_role: REVIEW_SYNTHESIS
- name: Portal hypertension
  description: >-
    Elevated portal venous pressure secondary to hepatic fibrosis/cirrhosis,
    leading to splenomegaly, varices, and ascites.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
      are signs of cirrhosis
      and portal hypertension, and ascites will be observed in decompensated cases
    explanation: >-
      Review describes later manifestations and complications; no population frequency
      is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Splenomegaly
  description: >-
    Spleen enlargement may develop with portal hypertension. This acquired enlargement
    is distinct from congenital
    polysplenia or asplenia in BASM.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
      are signs of cirrhosis
      and portal hypertension, and ascites will be observed in decompensated cases
    explanation: >-
      Review describes later manifestations and complications; no population frequency
      is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Failure to thrive
  description: >-
    Poor weight gain and growth from fat malabsorption (fat-soluble vitamin
    deficiency) and the metabolic demands of chronic liver disease.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools,
      growth retardation, and
      hepatomegaly
    explanation: >-
      Clinical guideline summarizes presenting manifestations.
    quote_role: REVIEW_SYNTHESIS
- name: Polysplenia
  subtype: BASM
  description: >-
    Multiple small spleens, a defining feature of the biliary atresia splenic
    malformation (BASM) subtype, part of the laterality/heterotaxy phenotype.
  phenotype_term:
    preferred_term: Polysplenia
    term:
      id: HP:0001748
      label: Polysplenia

  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The splenic malformation is typically polysplenia, but sometimes can be asplenia
      or double spleen
    explanation: >-
      Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.
    quote_role: REVIEW_SYNTHESIS
- name: Abnormal abdominal situs
  subtype: BASM
  description: >-
    Visceral situs abnormalities occur in BASM. The cited review does not specify
    complete thoracoabdominal
    mirror-image reversal in every case, so situs inversus totalis is not assumed.
  phenotype_term:
    preferred_term: Abnormality of abdominal situs
    term:
      id: HP:0011620
      label: Abnormality of abdominal situs
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The other obvious and evident visceral anomalies are: situs inversus, present
      in about 30–40% of patients
      with and without malrotation; preduodenal portal vein and a complete absence
      of the intrahepatic vena
      cava.
    explanation: >-
      BASM visceral laterality spectrum; does not specify total inversion for all
      affected individuals.
    quote_role: REVIEW_SYNTHESIS
- name: Cholangitis
  description: >-
    Ascending bacterial cholangitis is a frequent complication after the Kasai
    portoenterostomy, in which the Roux limb provides a conduit for enteric
    bacteria to reach the residual intrahepatic ducts.
  phenotype_term:
    preferred_term: Cholangitis
    term:
      id: HP:0030151
      label: Cholangitis

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patients who have undergone a Kasai portoenterostomy procedure are at risk of
      ascending cholangitis due
      to the resulting abnormal biliary anatomy.
    explanation: >-
      Clinical review explicitly relates altered anatomy to postoperative cholangitis.
    quote_role: REVIEW_SYNTHESIS
- name: Asplenia
  description: >-
    Congenital absence of the spleen is an alternative BASM splenic phenotype.
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The splenic malformation is typically polysplenia, but sometimes can be asplenia
      or double spleen
    explanation: >-
      Congenital splenic-number abnormalities in BASM, distinct from splenomegaly.
    quote_role: REVIEW_SYNTHESIS
  subtype: BASM
- name: Intestinal malrotation
  description: >-
    Developmental gut-rotation abnormality can accompany the BASM laterality phenotype.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The other obvious and evident visceral anomalies are: situs inversus, present
      in about 30–40% of patients
      with and without malrotation; preduodenal portal vein and a complete absence
      of the intrahepatic vena
      cava.
    explanation: >-
      BASM visceral laterality spectrum; does not specify total inversion for all
      affected individuals.
    quote_role: REVIEW_SYNTHESIS
  subtype: BASM
- name: Congenital heart defects
  description: >-
    Cardiac anomalies occur in BASM and in a partly overlapping cardiac-associated
    BA group. The review reports
    cardiac defects in about half of BASM cases without one consistent pattern; conversely,
    only 48% of its
    37 cardiac-associated BA cases had BASM features.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Cardiac anomalies are apparent in about half the cases overall, but there is
      lack of a consistent cardiac
      phenotype.
    explanation: >-
      Variable cardiac involvement within the BASM discussion; no single lesion is
      specified.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34884377
    reference_title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      when we reviewed our experience of biliary atresia-associated cardiac anomalies
      (n = 37), features indicative
      of BASM were present in 48%
    explanation: >-
      Cardiac-associated BA is not confined to BASM.
    quote_role: REVIEW_SYNTHESIS
- name: Pruritus
  description: >-
    Cholestatic itching can become prominent in selected patients with ongoing disease,
    but is not a universal
    presenting feature.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:42666930
    reference_title: 'Real-world use of maralixibat in biliary atresia: a case series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We report the use of maralixibat for the treatment of cholestatic pruritus in
      BA for six patients.
    explanation: >-
      Selected symptomatic case series establishes occurrence, not prevalence.
- name: Ascites
  description: >-
    Abdominal fluid accumulation may complicate decompensated portal-hypertensive
    liver disease.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
      are signs of cirrhosis
      and portal hypertension, and ascites will be observed in decompensated cases
    explanation: >-
      Review describes later manifestations and complications; no population frequency
      is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Esophageal varices
  description: >-
    Portal hypertension can produce gastroesophageal varices and bleeding.
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This condition can cause portal hypertension, which in turn may result in esophageal
      varices and ascites
    explanation: >-
      Guideline identifies the anatomic variceal complication.
    quote_role: REVIEW_SYNTHESIS
- name: Fat malabsorption
  description: >-
    Reduced delivery of bile to the gut impairs fat and fat-soluble-vitamin absorption,
    contributing to growth
    failure.
  phenotype_term:
    preferred_term: Fat malabsorption
    term:
      id: HP:0002630
      label: Fat malabsorption
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patients with cholestatic conditions are at increased risk of malabsorption
      of fat-soluble vitamins,
      like vitamin K.
    explanation: >-
      The guideline links cholestasis with nutrient malabsorption.
    quote_role: REVIEW_SYNTHESIS
- name: Vitamin K deficiency
  description: >-
    Vitamin K malabsorption can cause bleeding and requires nutritional assessment
    and replacement.
  phenotype_term:
    preferred_term: Decreased circulating vitamin K concentration
    term:
      id: HP:0011892
      label: Decreased circulating vitamin K concentration
  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Bleeding may occur due to vitamin K malabsorption; hepatomegaly and splenomegaly
      are signs of cirrhosis
      and portal hypertension, and ascites will be observed in decompensated cases
    explanation: >-
      Review describes later manifestations and complications; no population frequency
      is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Vitamin D deficiency
  description: >-
    Fat-soluble-vitamin depletion requires monitoring, with skeletal complications
    possible in chronic disease.
  phenotype_term:
    preferred_term: Decreased circulating vitamin D concentration
    term:
      id: HP:0100512
      label: Decreased circulating vitamin D concentration
  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In the presence of cholestasis, vitamins A, D, E and K should be given to prevent
      the development of
      fat-soluble vitamin deficiency
    explanation: >-
      Clinical review explicitly includes vitamin D among the deficiencies requiring
      prevention.
    quote_role: REVIEW_SYNTHESIS
biochemical:
- name: Elevated conjugated (direct) bilirubin
  presence: Elevated
  context: >-
    Conjugated/direct hyperbilirubinemia requires urgent evaluation for neonatal cholestasis,
    including biliary
    atresia. After the neonatal screening window, a direct bilirubin above 1 mg/dL
    warrants evaluation regardless
    of its percentage of total bilirubin. In the first days of life, use age- and
    assay-specific reference
    intervals; an absolute 1 mg/dL screening cutoff can miss affected newborns. Direct
    and conjugated assays
    are not identical.

  evidence:
  - reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    reference_title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      for this guideline, an abnormal direct/conjugated bilirubin is defined as a serum
      value >1.0 mg/dL (17 mmol/L), because it is physiologically and clinically complex
      to consider incorporating consideration of whether or not the direct fraction
      exceeds 20% of the TB level
    explanation: >-
      The 2017 NASPGHAN/ESPGHAN guideline defines abnormal direct/conjugated bilirubin
      independently of the
      former 20% rule.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/7093763/
    reference_title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      1 infant with a true positive screening result had a stage 1 bilirubin level
      of 0.4 mg/dL, which was
      abnormally high in the 98.4th to 99.6th percentile for that site
    explanation: >-
      The primary screening study demonstrates why newborn thresholds must be age-
      and laboratory-specific.
- name: Elevated gamma-glutamyltransferase (GGT)
  presence: Elevated
  context: >-
    GGT is commonly elevated, often disproportionately to aminotransferases, but varies
    with age and cannot
    establish or exclude biliary atresia alone.

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Transaminases and gamma-glutamyl transferase (GGT) are almost always elevated
      in BA, and GGT is disproportionately
      higher than transaminases, while this is opposite in neonatal hepatitis.
    explanation: >-
      Clinical review describes the typical biochemical pattern; neither enzyme is
      diagnostic alone.
    quote_role: REVIEW_SYNTHESIS
- name: Elevated circulating hepatic transaminases
  presence: Elevated
  context: >-
    ALT and AST can be elevated with accompanying hepatocellular injury. Values are
    nonspecific, and early
    biochemical screening may identify affected newborns before aminotransferases
    rise.

  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Transaminases and gamma-glutamyl transferase (GGT) are almost always elevated
      in BA, and GGT is disproportionately
      higher than transaminases, while this is opposite in neonatal hepatitis.
    explanation: >-
      Clinical review describes the typical biochemical pattern; neither enzyme is
      diagnostic alone.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/7093763/
    reference_title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      biliary atresia, which can be difficult to detect during early stages of the
      disease when aminotransferase
      levels and liver stiffness may still be normal
    explanation: >-
      Normal early aminotransferases must not delay assessment of abnormal direct/conjugated
      bilirubin.
- name: Elevated serum matrix metalloproteinase-7 (MMP7)
  presence: Elevated
  context: >-
    Serum MMP-7 is a promising adjunct for distinguishing biliary atresia from other
    neonatal cholestases.
    Thresholds depend on assay and age: the North American study used 52.8 ng/mL on
    a single-plex assay and
    18.2 ng/mL on a different platform. A separate prospective ELISA cohort validated
    18 ng/mL with 95.9% sensitivity
    and 87.3% specificity. False-negative and false-positive results occur; these
    thresholds are not interchangeable
    or a substitute for definitive assessment.

  evidence:
  - reference: PMID:38446707
    reference_title: Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Serum concentrations produced by time resolved fluorescence energy transfer
      differed from single-plex,
      with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay
      technology and generated
      similar AUROCs.
    explanation: >-
      The same clinical sample set yielded different thresholds with different assay
      platforms.
  - reference: PMID:38978022
    reference_title: 'Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The performance of MMP-7 was successfully validated in the larger prospective
      cohort, resulting in a
      diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity
      of 87.3% (255/292; 95% CI:
      83.0-90.9%)
    explanation: >-
      Prospective validation of the 18 ng/mL ELISA threshold; incomplete sensitivity
      and specificity preclude
      an absolute rule-out or rule-in interpretation.
diagnosis:
- name: Abdominal ultrasonography (triangular cord sign)
  description: >-
    First-line imaging evaluates gallbladder morphology and contraction, the triangular
    cord sign and associated
    malformations. Findings are operator- and age-dependent; a normal ultrasound does
    not exclude biliary atresia.
    The original small study reported 85% sensitivity and 100% specificity for its
    triangular cord assessment,
    which should not be generalized to every setting.
  diagnosis_term:
    preferred_term: abdominal ultrasonography
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:9396524
    reference_title: 'A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although 17 of 20 ultrasonographic examinations from infants who had BA denoted
      TC, 43 ultrasonographic
      examinations from infants with either neonatal hepatitis (NH) or other causes
      of cholestasis denoted
      no TC, showing a diagnostic accuracy of 95% with 85% sensitivity and 100% specificity.
    explanation: >-
      The triangular cord sign on ultrasound is highly specific for biliary
      atresia in the workup of infantile cholestasis.

  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Most, but not all of those with BA have a hypoplastic or absent gallbladder,
      and so normal ultrasonography
      does not exclude BA.
    explanation: >-
      A normal gallbladder or ultrasound cannot exclude the disease.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatobiliary scintigraphy (HIDA)
  description: >-
    Hepatobiliary scintigraphy is sensitive but has limited specificity: absent bowel
    tracer excretion also
    occurs in other cholestases. Demonstrated excretion makes biliary atresia unlikely,
    but rare apparent false-negative
    studies are reported. It should not delay definitive evaluation; routine phenobarbital
    pretreatment can
    add several days.

  evidence:
  - reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    reference_title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Limited reports describe infants with apparently initially excreting HBS and
      a subsequent diagnosis of
      BA, although the technical limitations of the study may have been a factor in
      its utility
    explanation: >-
      The guideline documents rare apparent excretion despite subsequent biliary-atresia
      diagnosis.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    reference_title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Many clinicians and radiologists administer phenobarbital for 5 days before
      the study, in an attempt
      to enhance biliary excretion of the isotope and increase its discriminatory
      value
    explanation: >-
      Premedication may delay an already time-sensitive diagnostic pathway.
    quote_role: REVIEW_SYNTHESIS
- name: Intraoperative cholangiography
  description: >-
    Operative cholangiography, interpreted with duct-remnant histology and the clinical
    workup, is the reference
    standard for defining extrahepatic duct patency. If biliary atresia is confirmed,
    Kasai portoenterostomy
    can usually follow during the same operation. A hypoplastic biliary tree in Alagille
    syndrome or cystic
    fibrosis can confound interpretation; cholangiography is not infallible.
  diagnosis_term:
    preferred_term: intraoperative cholangiography
    term:
      id: NCIT:C61508
      label: Cholangiography

  evidence:
  - reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    reference_title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The intraoperative cholangiogram and histologic examin- ation of the duct remnant
      is considered the criterion
      standard to diagnose BA
    explanation: >-
      The guideline combines operative anatomy with remnant histology.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    reference_title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Hence, preoperative testing for CF and ALGS is helpful in assisting in the interpretation
      ... and decreasing false-positive results.
    explanation: >-
      Clinical mimics affect operative interpretation.
    quote_role: REVIEW_SYNTHESIS
- name: Infant stool color card screening
  description: >-
    Parents compare infant stool color with a reference card and promptly report pale
    stools. National programs
    support earlier recognition, but stools may initially retain pigment. Taiwanese
    before-and-after cohort
    findings associate screening-era care with lower hospitalization and mortality;
    this observational design
    cannot isolate screening from other changes in care.
  evidence:
  - reference: PMID:27015203
    reference_title: 'Infant Stool Color Card Screening Helps Reduce the Hospitalization Rate and Mortality of Biliary Atresia: A 14-Year Nationwide Cohort Study in Taiwan.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since 2004, Taiwan has implemented a national screening program that uses an
      infant stool color card
      (SCC) for the early detection of BA.
    explanation: >-
      Stool color card screening is a validated national program for early
      detection of biliary atresia.

  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Acholic stool may initially be absent and some stools may contain bile pigment
    explanation: >-
      Early pigmented stools do not exclude biliary atresia.
    quote_role: REVIEW_SYNTHESIS
- name: Newborn direct or conjugated bilirubin screening
  description: >-
    A two-stage strategy measures direct/conjugated bilirubin in the first 60 hours
    using laboratory-specific
    newborn reference intervals, then repeats abnormal results by the two-week visit.
    Rising values or repeat
    values above 1 mg/dL prompt further assessment. In 124,385 newborns, all seven
    known cases were detected,
    but sensitivity had a wide confidence interval and false-negative ascertainment
    was incomplete. A separate
    pre-post analysis associated implementation with younger Kasai age, not proof
    of a survival benefit.
  evidence:
  - reference: PMID:32207797
    reference_title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      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.
    explanation: >-
      First-stage screening as summarized in the abstract; full methods describe site-specific
      newborn reference
      intervals.
  - reference: PMID:32207797
    reference_title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      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.
    explanation: >-
      Second-stage screen requires a rise or a value above 1 mg/dL.
  - reference: PMID:32207797
    reference_title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      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.
    explanation: >-
      The abstract explicitly qualifies sensitivity and incomplete ascertainment.
- name: Primary-care assessment at two to four weeks
  description: >-
    The 2025 AAP clinical report recommends assessing eye color, stool color and prior
    laboratory results at
    the two- to four-week visit to decide whether direct/conjugated bilirubin measurement
    is needed. Persistent
    jaundice or pale stools requires prompt evaluation.
  evidence:
  - reference: DOI:10.1542/peds.2024-070077
    reference_title: 'Guidance for the Primary Care Provider in Identifying Infants With Biliary Atresia by 2–4 Weeks of Life: Clinical Report'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The strategy involves examining every infant’s eye color, stool color, and prior
      laboratory results to
      determine whether measurement of a direct or conjugated bilirubin level is warranted.
    explanation: >-
      AAP clinical report, abstract available; full report retrieval was blocked.
    quote_role: REVIEW_SYNTHESIS
- name: Liver biopsy
  description: >-
    Portal expansion, ductular reaction and bile plugs support biliary obstruction,
    but early biopsy can be
    nonspecific and similar changes occur in other neonatal cholestases. Interpret
    expert histology alongside
    imaging and clinical evaluation rather than using a negative early biopsy to exclude
    biliary atresia.
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Histopathological findings in liver biopsies include the expansion of the portal
      tracts, with edematous
      fibroplasia and bile ductular proliferation, with bile plugs in duct lumen.
    explanation: >-
      Disease-associated obstructive histology, interpreted in clinical context.
    quote_role: REVIEW_SYNTHESIS
genetic:
- name: GPC1
  notes: >-
    Candidate susceptibility gene supported by heterozygous 2q37.3 deletions overlapping
    GPC1 in 6/61 cases
    versus 4/5,088 controls and by zebrafish knockdown/rescue experiments. Reduced
    apical GPC1 staining also
    occurred in non-BA infantile cholestasis and was measured in different patients
    from the deletion carriers.
    Common GPC1 SNP associations in the 2020 Han Chinese study were nominal and did
    not survive its multiple-testing
    threshold; they are not definitive Mendelian pathogenic alleles.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: GPC1
    term:
      id: hgnc:4449
      label: GPC1
  evidence:
  - reference: PMID:32315284
    reference_title: Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association
      with BA susceptibility (PAllele
      = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1.
    explanation: >-
      Nominal common-variant associations; neither P value survives correction for
      the tested markers.

  - reference: PMID:23336978
    reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We observed a statistically significant increase in deletions at 2q37.3 in patients
      with BA that resulted
      in deletion of one copy of GPC1
    explanation: >-
      Rare copy-number association, not proof of sufficiency or penetrance.
  - reference: PMID:23336978
    reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially
      rescued the gpc1-knockdown
      phenotype.
    explanation: >-
      Developmental perturbation and rescue in zebrafish.
- name: ADD3
  notes: >-
    Common noncoding susceptibility variants at the ADD3 locus associate with biliary
    atresia, particularly
    in studied Asian populations. rs17095355 is a linked marker, not a demonstrated
    causal nucleotide. In 2026
    H69 reporter experiments, risk haplotypes at E2, E4 and E10 increased activity,
    E9 decreased it, and the
    lead-SNP E1 fragment showed no allelic difference. Reporter activity does not
    directly quantify endogenous
    ADD3 expression. Both overexpression and loss of add3a disrupt zebrafish biliary
    development, supporting
    dosage sensitivity rather than one universal directional effect of every human
    risk allele.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: ADD3
    term:
      id: hgnc:245
      label: ADD3
  evidence:
  - reference: PMID:32315284
    reference_title: Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was
      the top SNP
    explanation: >-
      Association in the studied cohort; the marker does not by itself establish causality
      or predict individual
      disease.
  - reference: PMID:41589307
    reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      four elements (E2, E4, E9 and E10) showed allele-specific reporter activity
      differences
    explanation: >-
      H69 cell reporter assays resolve functional differences among linked regulatory
      fragments.
  - reference: PMID:41589307
    reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Both overexpression and knockdown of add3a in zebrafish disrupted hepatobiliary
      function and development,
      resulting in gallbladder hypoplasia/agenesis and reduced intrahepatic bile duct
      density.
    explanation: >-
      Bidirectional dosage perturbation in a model, distinct from the effect of any
      individual human allele.
- name: PKD1L1
  notes: >-
    Rare candidate biallelic variants were identified in five of 67 children selected
    using a broad BASM definition,
    including some without splenic malformation. Reported variants included missense,
    splice-site and truncating
    changes, with limited patient functional evidence. Zebrafish pkd1l1 loss supports
    a role in laterality
    and biliary development, but does not establish penetrance, causality of each
    human variant, or a general
    Mendelian form of BASM.
  relationship_type: SUSCEPTIBILITY
  subtype: BASM
  gene_term:
    preferred_term: PKD1L1
    term:
      id: hgnc:18053
      label: PKD1L1
  evidence:
  - reference: PMID:30664273
    reference_title: Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1),
      a gene associated with
      ciliary calcium signaling and embryonic laterality determination in fish, mice,
      and humans.
    explanation: >-
      Candidate human variants from an ascertained cohort, requiring further functional
      and genetic validation.
  - reference: PMID:37675454
    reference_title: Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data highlight the essential role of pkd1l1 in normal development and
      function of the zebrafish
      biliary system, supporting a role for this gene as a cause of BASM.
    explanation: >-
      Functional relevance of pkd1l1 to fish biliary development; this does not validate
      each human variant
      as pathogenic.

- name: CFC1
  notes: >-
    A small study of ten patients with biliary atresia and polysplenia identified
    heterozygous c.433G>A (p.Ala145Thr)
    in five, at approximately twice the control frequency. This is a candidate predisposition
    finding, not
    proof of a high-penetrance causal variant or a validated recurrence estimate.
  relationship_type: SUSCEPTIBILITY
  subtype: BASM
  gene_term:
    preferred_term: CFC1
    term:
      id: hgnc:18292
      label: CFC1
  evidence:
  - reference: PMID:18162845
    reference_title: CFC1 gene involvement in biliary atresia with polysplenia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The heterozygous transition c.433G>A (Ala145Thr) located in exon 5 was identified
      in 5 patients, with
      a twice-higher frequency than in control patients.
    explanation: >-
      Small candidate-gene study; no Mendelian penetrance inference.
- name: ARF6
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: ARF6
    term:
      id: hgnc:659
      label: ARF6
  notes: >-
    Candidate common-variant locus downstream of ARF6 in an initial European-ancestry
    study. The linked rs3126184
    and rs10140366 markers overlap a putative regulatory region; direct endogenous
    allelic effects were not
    established. Zebrafish arf6 knockdown and EGFR-inhibition experiments support
    a developmental role. The
    tested ARF6 signal did not replicate in the 2020 Han Chinese cohort, limiting
    generalization.
  evidence:
  - reference: PMID:26379158
    reference_title: The Role of ARF6 in Biliary Atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the SNPs rs3126184 and rs10140366 in a 3' flanking enhancer region for ARF6
      demonstrated higher minor
      allele frequencies
    explanation: >-
      Initial association study, with linked regulatory markers rather than proven
      causal variants.
  - reference: PMID:26379158
    reference_title: The Role of ARF6 in Biliary Atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with Mo-arf6
      at lower doses of
      each agent and rescued with arf6 mRNA.
    explanation: >-
      Perturbation and rescue support the candidate pathway in zebrafish.
- name: EFEMP1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: EFEMP1
    term:
      id: hgnc:3218
      label: EFEMP1
  notes: >-
    Intronic common variants reached genome-wide significance in a meta-analysis of
    two European-American cohorts.
    The causal variant, regulatory target and direction of effect remain unresolved.
    Increased expression in
    diseased human liver also occurred in other cholestatic diseases, so it may reflect
    injury or fibrosis.
    Heterozygous Efemp1 loss in mice reduces organized extrahepatic-duct elastic fibers
    and changes duct mechanics;
    this is functional plausibility, not a knock-in model of the human risk alleles
    or spontaneous biliary
    atresia.
  evidence:
  - reference: PMID:30102696
    reference_title: A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1
    explanation: >-
      Association signal within EFEMP1; gene assignment and allelic mechanism remain
      candidate interpretations.
  - reference: PMID:39717503
    reference_title: Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased
      by approximately half.
    explanation: >-
      Reduced elastic-fiber organization in heterozygous mouse ducts supports mechanical
      relevance.
environmental:
- name: Perinatal hepatotropic viral infection
  exposure_term:
    preferred_term: viral infection
    term:
      id: ECTO:3000001
      label: exposure to virus
  description: >-
    Viral exposure is a proposed trigger, not an established cause of human biliary
    atresia. Neonatal RRV infection
    induces an age-dependent obstructive cholangiopathy in mice. Human detection of
    viruses such as CMV is
    heterogeneous and cannot alone establish whether infection caused, followed, or
    modified the biliary disease.
  evidence:
  - reference: PMID:23844248
    reference_title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Early RRV infection induced symptoms in 95% of pups with a mortality rate of
      80%. In contrast, late infection
      caused symptoms in only 50% of mice, and 100% of pups survived.
    explanation: >-
      Experimental susceptibility depends on neonatal timing; this does not establish
      human viral causation.
- name: Biliatresone toxin exposure
  exposure_term:
    preferred_term: biliatresone toxin exposure
    term:
      id: ECTO:0000537
      label: exposure to toxin
  description: >-
    Biliatresone is an experimental electrophilic toxin that selectively damages extrahepatic
    cholangiocytes
    in zebrafish. Human exposure as a cause of biliary atresia is unproven. Low-dose
    prenatal exposure in mice
    altered offspring bile-acid profiles and hepatic immune cells without producing
    histologic duct injury
    or fibrosis at the measured time points.
  evidence:
  - reference: PMID:27102575
    reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in
      zebrafish larvae.
    explanation: >-
      Biliatresone selectively injures extrahepatic cholangiocytes in zebrafish larvae;
      human etiologic relevance
      is unproven.
  - reference: PMID:38578745
    reference_title: 'Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Pups had no evidence of histological liver or bile duct injury or fibrosis at
      either timepoint. In addition,
      growth was normal.
    explanation: >-
      Prenatal low-dose model produced biochemical and immune changes rather than
      overt fibro-obliterative
      atresia.
  - reference: PMID:38578745
    reference_title: 'Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      serum levels of glycocholic acid were elevated at P5, suggesting altered bile
      metabolism, and the serum
      bile acid profile became increasingly abnormal through P21
    explanation: >-
      Measured offspring bile-acid phenotype after prenatal exposure.
- name: Prenatal maternal infection
  description: >-
    A Taiwanese administrative-data case-control study associated recorded maternal
    intestinal and genitourinary
    infections with offspring biliary atresia. Diagnoses were code-based, pathogens
    were usually unspecified,
    and unmeasured genetic and environmental confounding remained. The findings do
    not demonstrate fetal infection,
    a causal injury pathway, or a prevention effect.
  evidence:
  - reference: PMID:38170523
    reference_title: Maternal Prenatal Infections and Biliary Atresia in Offspring.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Results of this case-control study indicate an association between prenatal
      intestinal infection and
      genitourinary tract infection in mothers and BA occurrence in their offspring.
    explanation: >-
      A large Taiwanese case-control study links prenatal maternal gut and
      genitourinary infection to offspring biliary atresia risk.
treatments:
- name: Kasai Hepatoportoenterostomy
  description: >-
    Time-sensitive surgery excises the fibrotic extrahepatic remnant and connects
    a Roux-en-Y jejunal limb
    to the porta hepatis to establish bile drainage. Earlier intervention generally
    improves outcomes; age
    alone is not a universal cutoff for eligibility. Progressive intrahepatic disease
    can persist despite jaundice
    clearance, requiring long-term follow-up.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Fibro-obliteration of the Biliary Tree
    treatment_effect: BYPASSES
    description: >-
      The portoenterostomy surgically bypasses the obliterated extrahepatic
      biliary tree, re-establishing bile drainage from the porta hepatis.
    evidence:
    - reference: PMID:36051179
      reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        In the 1950s, with the development of Kasai portoenterostomy by Dr. Morio
        Kasai, it became possible
        to treat BA surgically
      explanation: >-
        Surgical drainage bypasses the extrahepatic obstruction.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:36051179
    reference_title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BA is always treated surgically, and performing the surgery before the age of
      2 mo greatly increases
      its effectiveness and extends the time until the need for liver transplantation
      arises.
    explanation: >-
      Establishes the Kasai portoenterostomy as first-line surgery and its strong
      age-dependence (best before ~2 months).

    quote_role: REVIEW_SYNTHESIS
- name: Liver Transplantation
  description: >-
    Indicated after failed drainage or progressive liver disease, including decompensated
    cirrhosis, refractory
    portal-hypertensive complications, severe growth failure or recurrent severe cholangitis.
    Selected infants
    with advanced disease may undergo primary transplantation. Assessment depends
    on the clinical course, not
    a single universal age or laboratory threshold.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Indications for LT after KPE include poor bile drainage and unresolved jaundice,
      poor bile flow in the
      early stages, advanced development of cirrhosis despite good bile flow.
    explanation: >-
      Consensus guidance describes post-Kasai transplant indications.
    quote_role: REVIEW_SYNTHESIS
- name: Ursodeoxycholic Acid
  description: >-
    Commonly used empirically after Kasai to improve bile flow and biochemical indices.
    Evidence for improved
    native-liver survival is insufficient; dosing and duration vary between centers.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  target_mechanisms:
  - target: Impaired Bile Drainage
    treatment_effect: MODULATES
    description: >-
      As a choleretic bile acid, UDCA promotes bile flow and shifts the bile-acid
      pool to less hepatotoxic species, mitigating the cholestatic node.

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Currently, the use of these medications is largely empirical, with different
      medical facilities adopting
      varying dosing schedules. There are no definitive guidelines on when to discontinue
      treatment
    explanation: >-
      The guideline describes empirical use of bile-acid-modulating medication after
      Kasai.
    quote_role: REVIEW_SYNTHESIS
- name: Prophylactic Antibiotics for Cholangitis
  description: >-
    Post-Kasai prophylaxis is common and conditionally recommended in some guidance,
    but studies conflict and
    a reliable reduction in cholangitis or improved native-liver survival has not
    been established. Prophylaxis
    must be distinguished from treatment of a suspected acute episode.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Studies have produced conflicting results on the effectiveness of antibiotics
      in preventing postoperative
      cholangitis after KPE
    explanation: >-
      Evidence for preventive antibiotics is uncertain.
    quote_role: REVIEW_SYNTHESIS
- name: Fat-Soluble Vitamin and Nutritional Support
  description: >-
    Provide individualized energy-dense feeding, including medium-chain triglycerides
    while retaining essential
    long-chain fats, and monitor growth and fat-soluble vitamins A, D, E and K. Replace
    deficiencies and use
    tube feeding or, when necessary, parenteral nutrition if growth remains inadequate.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support

  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Malnutrition is a common complication in children with BA, necessitating regular
      testing for fat-soluble
      vitamins and micronutrients, with supplementation of deficits as needed
    explanation: >-
      Consensus supports nutritional surveillance and supplementation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      For children with cholestasis, formulas enriched with MCT (>30% of total fat)
      are recommended, while
      ensuring that at least 20% of energy intake comes from long-chain triglycerides
      (LCT) to prevent essential
      fatty acid deficiency (EFAD)
    explanation: >-
      MCT enrichment must preserve an adequate source of essential fatty acids.
    quote_role: REVIEW_SYNTHESIS
- name: Post-Kasai Corticosteroid Therapy
  description: >-
    Randomized trial findings differ. The multicenter double-blind START trial (140
    infants) did not significantly
    improve six-month bile drainage or two-year native-liver survival and produced
    earlier serious adverse
    events. A later single-center open-label randomized trial (200 type III cases)
    reported improved jaundice
    clearance and native-liver survival with 10–12 weeks of steroids. Differences
    in regimen, population and
    study design limit a universal treatment conclusion; use remains center-dependent.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  evidence:
  - reference: PMID:24794368
    reference_title: 'Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high-dose steroid therapy following surgery did not result in statistically
      significant treatment differences
      in bile drainage at 6 months, although a small clinical benefit could not be
      excluded.
    explanation: >-
      START did not demonstrate a significant benefit for its tested regimen; its
      authors could not exclude
      a smaller clinical effect.

  - reference: PMID:35170539
    reference_title: 'Effect of Adjuvant Steroid Therapy in Type 3 Biliary Atresia: A Single-Center, Open-Label, Randomized Controlled Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The proportion of participants that are jaundice free without liver transplantation
      was significantly
      higher in the steroid group than in the control group at 6 months (54.1% vs
      31.0%, P = 0.0015).
    explanation: >-
      Later open-label randomized evidence differs from START; this does not establish
      equal benefit across
      regimens or populations.
- name: Maralixibat (IBAT Inhibitor)
  description: >-
    Investigational in biliary atresia. The completed 75-participant EMBARK randomized
    trial did not improve
    its primary 26-week total-bilirubin endpoint versus placebo. A separate uncontrolled
    six-patient compassionate-use
    series reported pruritus improvement, with inconsistent biochemical responses
    and two subsequent transplants.
    Symptomatic observations in selected children do not establish disease modification
    or native-liver survival
    benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: maralixibat
      term:
        id: CHEBI:748720
        label: maralixibat
  evidence:
  - reference: url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000974-22/results
    reference_title: EudraCT Number 2020-000974-22 - Clinical trial results - EU Clinical Trials Register
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Primary: Mean change in Total Serum Bilirubin ... Maralixibat v Placebo ...
      Number of subjects included
      in analysis ... 75 ... P-value ... = 0.7419 ... Parameter type ... Least-Square
      mean ... Point estimate
      ... -0.39 ... Confidence interval ... 95% ... -2.76 ... 1.97
    explanation: >-
      Sponsor-posted final EU registry results for NCT04524390: no significant primary
      bilirubin benefit at
      26 weeks; adjusted difference −0.39 mg/dL (95% CI −2.76 to 1.97).
  - reference: PMID:42666930
    reference_title: 'Real-world use of maralixibat in biliary atresia: a case series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All patients reported improved CSS with no increased usage of other antipruritic
      medications, and the
      medication was well tolerated.
    explanation: >-
      Six-patient retrospective compassionate-use series; no control group and short
      follow-up.
  target_mechanisms:
  - target: Impaired Bile Drainage
    treatment_effect: MODULATES
    description: >-
      IBAT inhibition reduces enterohepatic bile-acid recycling as a pharmacologic
      rationale. EMBARK did not
      establish a clinical improvement in post-Kasai cholestasis.

    evidence:
    - reference: PMID:32653991
      reference_title: Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        By reducing return of bile acids to the cholestatic liver, IBAT inhibitors
        may potentially lessen or
        delay liver damage associated with the hepatotoxicity and cholangiopathy of
        bile acid accumulation.
      explanation: >-
        A proposed mechanism, not proof of clinical efficacy in biliary atresia.
      quote_role: REVIEW_SYNTHESIS
- name: N-Acetylcysteine (post-Kasai)
  description: >-
    Experimental glutathione-precursor/choleretic strategy. A nonrandomized phase
    II pilot tested intravenous
    NAC for seven days after Kasai; none of 12 evaluable infants achieved total serum
    bile acids ≤10 µmol/L
    within 24 weeks, so the second stage did not open. Secondary outcomes did not
    differ from matched historical
    controls. One enrolled infant stopped treatment for worsening preexisting tachycardia,
    a serious event
    considered possibly drug-related in the full text. Longer courses remain unproven.
    A separate small Chinese
    pilot (ChiCTR2000040505; six treated and six untreated BA infants in the transcriptomic
    analysis) reported
    short-term bilirubin and immune-signature changes. This exploratory study used
    a different perioperative
    schedule and does not establish long-term clinical efficacy or contradict the
    US trial’s failure to meet
    its prespecified endpoint.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetyl-L-cysteine
      term:
        id: CHEBI:28939
        label: N-acetyl-L-cysteine
  evidence:
  - reference: PMID:40489761
    reference_title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There were 12 participants in stage 1 who received treatment, with none achieving
      TSBAs ≤10 μmol/L within
      24 weeks of KP. As a result, no participants were enrolled in stage 2.
    explanation: >-
      The stringent primary endpoint was not met; this does not establish efficacy
      for other schedules.
  - reference: PMID:40489761
    reference_title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      One serious adverse event was considered possibly related to the drug. It involved
      worsening tachycardia
      in a participant who had preexisting tachycardia.
    explanation: >-
      The full text provides a safety qualification absent from the broad abstract
      summary.
  - reference: PMID:40489761
    reference_title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      NAC provides the amino acid cysteine, which drives production of the anti-oxidative
      and anti-inflammatory
      molecule glutathione.
    explanation: >-
      The trial rationale concerns glutathione availability; it did not test correction
      of a CD177-specific
      neutrophil mechanism.
    quote_role: BACKGROUND
  - reference: PMID:37869073
    reference_title: Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      scRNA-seq analysis of liver CD45+ immune cells in the control (n = 4), BA (n
      = 6), and BA + NAC (n =
      6) groups was performed
    explanation: >-
      The mechanistic pilot is small and distinct from NCT03499249.
  - reference: PMID:37869073
    reference_title: Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      other parameters representing liver function and the onset of post-surgical
      complications in the BA+NAC
      group were not significantly different from those in the BA group post-surgery
    explanation: >-
      Full-text qualification of the pilot’s favorable bilirubin observations.
- name: Treatment of Acute Cholangitis
  description: >-
    Suspected post-Kasai cholangitis requires prompt assessment and antibiotic treatment,
    with microbiology-guided
    adjustment and escalation for severe or refractory illness. This is distinct from
    uncertain preventive
    antibiotic regimens.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Cholangitis should be treated aggressively and regularly once diagnosed.
    explanation: >-
      Consensus guidance supports active treatment of this postoperative complication.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Long-Term Hepatology Surveillance
  description: >-
    Continue surveillance after jaundice clears: growth and nutrition, liver biochemistry
    and synthetic function,
    vitamin status, portal hypertension and recurrent cholangitis remain relevant.
    Progressive disease should
    prompt timely transplant assessment.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:42569433
    reference_title: Diagnostic and management guidelines for biliary atresia in 2025.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Regular follow-up is still needed for children whose jaundice clears.
    explanation: >-
      Clearance of jaundice does not end the need for disease monitoring.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Long-term hepatology surveillance
  notes: >-
    A fitting treatment-action ontology binding is needed. NCIT:C15719 (Surveillance)
    is outside the permitted intervention hierarchy.
- name: Odevixibat
  description: >-
    Experimental IBAT inhibition after Kasai. In July 2026, the sponsor reported that
    the 254-participant randomized
    phase III BOLD trial did not improve native-liver survival versus placebo. The
    publicly available topline
    announcement is not a peer-reviewed full results paper. The BOLD extension remained
    active but not recruiting
    in the registry at review.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: url:https://www.ipsen.com/press-release/ipsen-provides-update-on-phase-iii-bold-trial-in-biliary-atresia-3332691/
    reference_title: Ipsen provides update on Phase III BOLD trial in biliary atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      announced today that the Phase III BOLD trial evaluating Bylvay versus placebo
      for patients living with
      biliary atresia (BA) who have already undergone a Kasai hepatoportoenterostomy
      (HPE) did not meet the
      primary endpoint of improvement in native liver survival vs placebo.
    explanation: >-
      Ipsen sponsor topline announcement dated 24 July 2026; the report does not provide
      a peer-reviewed effect
      estimate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: odevixibat
      term:
        id: CHEBI:757063
        label: odevixibat
- name: Intravenous Immunoglobulin
  description: >-
    The multicenter open-label PRIME phase I/IIa study tested three infusions after
    Kasai in 29 infants. Administration
    was feasible, but bilirubin and one-year native-liver survival did not improve
    compared with historical
    START placebo controls. It does not establish efficacy or comparative safety from
    a randomized concurrent
    comparison.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:30664564
    reference_title: A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Although IVIg infusions in infants with BA post-HPE were feasible, acceptable
      and safe, there was no
      trend to lower bilirubin levels or improved 360-day survival with the native
      liver.
    explanation: >-
      PRIME was an open-label single-arm phase I/IIa study with historical START placebo
      controls, not a concurrent
      randomized comparison.
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: Therapeutic Immune Globulin
      term:
        id: NCIT:C2701
        label: Therapeutic Immune Globulin
- name: Rectal Budesonide
  description: >-
    Off-label postoperative therapy evaluated in a retrospective cohort against historical
    and untreated controls.
    Reported jaundice-free native-liver survival associations favored treated nonsyndromic
    cases, but treatment
    selection and changes in care can confound the result. No randomized evidence
    establishes benefit, and
    the report contains inconsistent two-year percentages between its abstract and
    table.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:40600375
    reference_title: 'Rectal budesonide: A potential game changer after Kasai hepatoportoenterostomy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We performed a retrospective cohort study and included all patients after HPE
      who received rectal budesonide
      (2 mg) for 3 months from 2011 to 2022, compared to a historical control group
      without any glucocorticoid
      treatment.
    explanation: >-
      Observational design does not support a causal efficacy conclusion.
  - reference: PMID:40600375
    reference_title: 'Rectal budesonide: A potential game changer after Kasai hepatoportoenterostomy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, these benefits were exclusive to patients with nonsyndromic BA.
    explanation: >-
      Reported subgroup limitation; further prospective randomized evaluation is required.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: budesonide
      term:
        id: CHEBI:3207
        label: budesonide
- name: Obeticholic Acid
  description: >-
    Investigational FXR agonist assessed after Kasai. The phase II CARE study was
    terminated because recruitment
    was insufficient. A separate phase II/III study, NCT06121375, enrolled 28 participants
    and was terminated
    following the sponsor decision linked in the registry to the Ocaliva withdrawal
    request and OCA clinical
    hold. These stopping reasons must not be misrepresented as demonstrated efficacy
    or lack of efficacy in
    biliary atresia.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: clinicaltrials:NCT05321524
    reference_title: A Multicenter, Open-Label, Single- and Multiple-Dose, Dose-Finding Study, With an Optional Open-Label Extension to Assess the Safety, Tolerability, and Pharmacokinetics of Obeticholic Acid in Pediatric Subjects With Biliary Atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This is a Phase 2, multicenter, open-label, single dose and multi-dose, dose-finding
      study with an optional
      open-label extension (OLE) to assess the safety, tolerability, and pharmacokinetics
      of obeticholic acid
      (OCA) in pediatric subjects with biliary atresia with successful hepatoportoenterostomy
      (HPE, also known
      as a Kasai portoenterosomy).
    explanation: >-
      Registry summary identifies the CARE study population.
  - reference: clinicaltrials:NCT06121375
    reference_title: A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Obeticholic Acid Compared to Placebo in Pediatric Subjects With Biliary Atresia, Post-hepatoportoenterostomy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This study will evaluate the efficacy, safety and tolerability, as well as PK/PD
      of OCA in eligible pediatric
      participants with biliary atresia with successful hepatoportoenterostomy (HPE,
      also known as a Kasai
      portoenterostomy).
    explanation: >-
      Registry summary identifies the separate phase II/III program; status and stopping
      reason were checked
      in the live record on 1 October 2026.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: obeticholic acid
      term:
        id: CHEBI:43602
        label: obeticholic acid
clinical_trials:
- name: NCT04524390
  phase: PHASE_II
  status: COMPLETED
  description: >-
    EMBARK: randomized phase II post-Kasai maralixibat trial; no significant primary
    bilirubin benefit at 26
    weeks.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: clinicaltrials:NCT04524390
    reference_title: Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects With Biliary Atresia After Hepatoportoenterostomy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      A study to evaluate the efficacy and safety of maralixibat in infants with Biliary
      Atresia (BA) after
      Hepatoportoenterostomy (HPE, also known as the Kasai procedure).
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
  - reference: url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000974-22/results
    reference_title: EudraCT Number 2020-000974-22 - Clinical trial results - EU Clinical Trials Register
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Primary: Mean change in Total Serum Bilirubin ... Maralixibat v Placebo ...
      Number of subjects included
      in analysis ... 75 ... P-value ... = 0.7419 ... Parameter type ... Least-Square
      mean ... Point estimate
      ... -0.39 ... Confidence interval ... 95% ... -2.76 ... 1.97
    explanation: >-
      Sponsor-posted final EU registry results for NCT04524390: no significant primary
      bilirubin benefit at
      26 weeks; adjusted difference −0.39 mg/dL (95% CI −2.76 to 1.97).
- name: NCT04336722
  phase: PHASE_III
  status: COMPLETED
  description: >-
    BOLD: randomized phase III post-Kasai odevixibat trial; sponsor topline report
    found no native-liver survival
    benefit.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: clinicaltrials:NCT04336722
    reference_title: A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children With Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Double-blind, randomized, placebo-controlled, Phase 3 study to investigate the
      efficacy and safety of
      odevixibat compared to placebo in children with biliary atresia who have undergone
      a Kasai hepatoportoenterostomy.
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
  - reference: url:https://www.ipsen.com/press-release/ipsen-provides-update-on-phase-iii-bold-trial-in-biliary-atresia-3332691/
    reference_title: Ipsen provides update on Phase III BOLD trial in biliary atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      announced today that the Phase III BOLD trial evaluating Bylvay versus placebo
      for patients living with
      biliary atresia (BA) who have already undergone a Kasai hepatoportoenterostomy
      (HPE) did not meet the
      primary endpoint of improvement in native liver survival vs placebo.
    explanation: >-
      Ipsen sponsor topline announcement dated 24 July 2026; the report does not provide
      a peer-reviewed effect
      estimate.
- name: NCT05426733
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    BOLD-EXT: open-label extension for long-term odevixibat follow-up after the parent
    trial.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05426733
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05426733
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Patients who completed treatment in the A4250-011 BOLD study and meet eligibility
      criteria for Study
      A4250-016 (BOLD-EXT) can participate. The duration of the treatment period is
      104 weeks, followed by
      a 4-week Safety Follow-up Period.
    explanation: >-
      The registry detailed description identifies the parent study, eligibility context
      and extension follow-up;
      it reports no efficacy result.
- name: NCT05321524
  phase: PHASE_II
  status: TERMINATED
  description: >-
    CARE: phase II obeticholic-acid study, terminated for infeasible recruitment.
  notes: >-
    Registry status and phase checked 1 October 2026. After extensive efforts to improve
    recruitment, it is
    deemed not feasible to enroll the requisite number of subjects to generate data
    needed to meet the study
    objectives. EMA Paediatric Committee agreed with the Sponsor to terminate this
    study.
  evidence:
  - reference: clinicaltrials:NCT05321524
    reference_title: A Multicenter, Open-Label, Single- and Multiple-Dose, Dose-Finding Study, With an Optional Open-Label Extension to Assess the Safety, Tolerability, and Pharmacokinetics of Obeticholic Acid in Pediatric Subjects With Biliary Atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This is a Phase 2, multicenter, open-label, single dose and multi-dose, dose-finding
      study with an optional
      open-label extension (OLE) to assess the safety, tolerability, and pharmacokinetics
      of obeticholic acid
      (OCA) in pediatric subjects with biliary atresia with successful hepatoportoenterostomy
      (HPE, also known
      as a Kasai portoenterosomy).
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
- name: NCT06121375
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Separate phase II/III obeticholic-acid study, terminated after 28 participants.
    The registry attributes
    termination to the sponsor decision following the FDA withdrawal request and clinical
    hold, not a biliary-atresia
    efficacy analysis.
  notes: >-
    Registry status and phase checked 1 October 2026. Combined phases are represented
    by the higher phase in
    the structured field. Intercept made a business decision to terminate the study
    based on FDA's request
    for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies
    under US IND involving
    OCA.
  evidence:
  - reference: clinicaltrials:NCT06121375
    reference_title: A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Obeticholic Acid Compared to Placebo in Pediatric Subjects With Biliary Atresia, Post-hepatoportoenterostomy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This study will evaluate the efficacy, safety and tolerability, as well as PK/PD
      of OCA in eligible pediatric
      participants with biliary atresia with successful hepatoportoenterostomy (HPE,
      also known as a Kasai
      portoenterostomy).
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
- name: NCT03499249
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase II short-course intravenous NAC pilot; none of 12 evaluable participants
    met the primary endpoint. One serious adverse event, worsening of preexisting
    tachycardia, was considered possibly drug-related.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: clinicaltrials:NCT03499249
    reference_title: A Phase 2 Trial of N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In this study, the investigators test whether intravenous N-acetylcysteine (NAC)
      can improve bile flow after KP. ... This study follows the "minimax" Phase 2 clinical
      trial design.
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
  - reference: PMID:40489761
    reference_title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There were 12 participants in stage 1 who received treatment, with none achieving
      TSBAs ≤10 μmol/L within
      24 weeks of KP. As a result, no participants were enrolled in stage 2.
    explanation: >-
      The stringent primary endpoint was not met; this does not establish efficacy
      for other schedules.
  - reference: PMID:40489761
    reference_title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      One serious adverse event was considered possibly related to the drug. It involved
      worsening tachycardia
      in a participant who had preexisting tachycardia.
    explanation: >-
      The full text provides a safety qualification absent from the broad abstract
      summary.
- name: NCT00294684
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    START: randomized placebo-controlled postoperative corticosteroid trial; no significant
    primary bile-drainage
    benefit.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: clinicaltrials:NCT00294684
    reference_title: A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy in Infants With Biliary Atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The Children Liver Disease Research and Education Network (ChiLDREN) is conducting
      a clinical trial to
      evaluate whether long-term treatment with corticosteroids improves the outcome
      of the Kasai or gall-bladder
      Kasai in infants with biliary atresia.
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
  - reference: PMID:24794368
    reference_title: 'Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high-dose steroid therapy following surgery did not result in statistically
      significant treatment differences
      in bile drainage at 6 months, although a small clinical benefit could not be
      excluded.
    explanation: >-
      START did not demonstrate a significant benefit for its tested regimen; its
      authors could not exclude
      a smaller clinical effect.

- name: NCT01854827
  phase: PHASE_II
  status: COMPLETED
  description: >-
    PRIME: open-label phase I/IIa IVIG trial with historical controls; no bilirubin
    or native-liver survival
    benefit.
  notes: >-
    Registry status and phase checked 1 October 2026. Combined phases are represented
    by the higher phase in
    the structured field.
  evidence:
  - reference: clinicaltrials:NCT01854827
    reference_title: A Phase 1/2A Trial of Intravenous Immunoglobulin (IVIG) Therapy Following Portoenterostomy in Infants With Biliary Atresia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The Children Liver Disease Research and Education Network (ChiLDREN) is conducting
      a clinical trial to
      determine the feasibility, acceptability, tolerability and safety profile of
      IVIG treatment administered
      to infants after hepatic portoenterostomy (HPE) for biliary atresia, as well
      as investigate preliminary
      evidence of activity and explore mechanisms of action.
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
  - reference: PMID:30664564
    reference_title: A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Although IVIg infusions in infants with BA post-HPE were feasible, acceptable
      and safe, there was no
      trend to lower bilirubin levels or improved 360-day survival with the native
      liver.
    explanation: >-
      PRIME was an open-label single-arm phase I/IIa study with historical START placebo
      controls, not a concurrent
      randomized comparison.
- name: NCT06553768
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    EXPAND: phase III maralixibat study for refractory cholestatic pruritus across
    multiple liver disorders,
    including eligible biliary-atresia patients; distinct from the infant post-Kasai
    EMBARK trial.
  notes: >-
    Registry status and phase checked 1 October 2026.
  evidence:
  - reference: clinicaltrials:NCT06553768
    reference_title: Randomized Double-Blind Placebo-Controlled Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Participants With Cholestatic Pruritus
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The purpose of this study is to determine whether the investigational treatment
      (maralixibat) is safe
      and effective in pediatric and adult participants who have cholestatic liver
      disease with pruritus that
      has been refractory to other therapies, and who have no other treatment options.
    explanation: >-
      Generated registry brief summary establishes trial identity and study objective;
      live status was checked
      separately.
- name: ChiCTR2000040505
  description: >-
    Chinese nonrandomized NAC program with published immune and short-term biochemical
    analyses. ICTRP lists
    phase 4 and planned preoperative/postoperative groups, but its last refresh was
    8 March 2021; current recruitment
    status is left unspecified. The 2022 and 2023 reports describe related work and
    should not be treated as
    independent efficacy replications.
  evidence:
  - reference: PMID:35803543
    reference_title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The pilot study of N-acetylcysteine treatment in patients with BA was registered
      on the Chinese Clinical
      Trial Registry (ChiCTR2000040505).
    explanation: >-
      Published registration identifier for the pilot.
  - reference: ICTRP:ChiCTR2000040505
    reference_title: 'N-acetylcysteine in children with biliary atresia: a clinical trial'
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Study design | Non randomized control
    explanation: >-
      Structured registration identifies the nonrandomized design.
  - reference: ICTRP:ChiCTR2000040505
    reference_title: 'N-acetylcysteine in children with biliary atresia: a clinical trial'
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Preoperative intervention group:N-Acetylcysteine;Postoperative intervention
      group:N-Acetylcysteine;Preoperative
      control group:Conventional therapy;postoperative control group:Conventional
      therapy;
    explanation: >-
      Registry specifies both perioperative schedules and their comparison groups.
  phase: PHASE_IV
animal_models:
- name: Rhesus rotavirus (RRV) neonatal mouse model
  species: Mouse
  genotype: Wild-type BALB/c neonate infected with rhesus rotavirus
  description: >-
    Neonatal BALB/c infection with RRV produces age-dependent epithelial injury, inflammation
    and extrahepatic
    obstruction. Early and late infection have substantially different outcomes. This
    defined viral model tests
    selected injury mechanisms; it does not establish the cause or all subtypes of
    human disease.
  publication: PMID:23844248
  modeled_mechanisms:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Early infection produces biliary epithelial injury and obstruction.
    limitations: >-
      Susceptibility depends on mouse age and viral conditions; BASM developmental
      defects and human etiologic
      heterogeneity are not reproduced.
    evidence:
    - reference: PMID:23844248
      reference_title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        the amount of cholangiocyte epithelial damage and bile duct edema was significantly
        greater in the
        early infection group
      explanation: >-
        Histologic epithelial injury in the time-dependent RRV mouse model.
- name: Biliatresone zebrafish model
  species: Zebrafish
  genotype: Wild-type larvae exposed to the isoflavonoid toxin biliatresone
  description: >-
    Exposure of zebrafish larvae to the plant toxin biliatresone selectively
    injures the extrahepatic biliary epithelium, providing a toxin-driven model of
    the extrahepatic cholangiopathy of biliary atresia.
  publication: PMID:27102575
  modeled_mechanisms:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Biliatresone reproduces selective extrahepatic-cholangiocyte injury,
      modeling the toxin route to the cholangiocyte-injury node.
    limitations: >-
      Zebrafish biliary anatomy differs from the human extrahepatic tree, and the
      specific human relevance of biliatresone exposure remains unproven; the
      model captures the injury mechanism rather than human etiology.
    evidence:
    - reference: PMID:27102575
      reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs)
        in zebrafish larvae.
      explanation: >-
        Demonstrates selective extrahepatic-cholangiocyte toxicity, grounding
        the toxin model of the injury node.

  - target: Reduced Cholangiocyte Glutathione Reserve
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Glutathione depletion increases toxin susceptibility, while antioxidant manipulations
      reduce injury.
    limitations: >-
      Experimental toxin exposure is not a demonstrated cause of human biliary atresia.
    evidence:
    - reference: PMID:27102575
      reference_title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic
        cholangiocytes to the toxin
      explanation: >-
        Manipulating antioxidant reserve changes susceptibility in fish.
- name: Gpc1 knockdown zebrafish
  species: Zebrafish
  genotype: gpc1 morpholino knockdown
  description: >-
    Knockdown impairs the biliary network; gpc1 mRNA rescue and partial cyclopamine
    rescue support specificity
    and Hedgehog involvement.
  publication: PMID:23336978
  modeled_mechanisms:
  - target: Disrupted Biliary Morphogenesis
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Knockdown impairs the biliary network; gpc1 mRNA rescue and partial cyclopamine
      rescue support specificity
      and Hedgehog involvement.
    limitations: >-
      Morpholino perturbation is not a human deletion genotype; the model does not
      demonstrate penetrance or
      progressive human remnant fibrosis.
    evidence:
    - reference: PMID:23336978
      reference_title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Knockdown of gpc1 in zebrafish led to developmental biliary defects.
      explanation: >-
        Experimental biliary developmental phenotype.
- name: Add3a dosage perturbation zebrafish
  species: Zebrafish
  genotype: add3a overexpression or knockdown
  description: >-
    Both increased and decreased add3a dosage perturb biliary development.
  publication: PMID:41589307
  modeled_mechanisms:
  - target: Disrupted Biliary Morphogenesis
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Both increased and decreased add3a dosage perturb biliary development.
    limitations: >-
      Direct dosage manipulation does not reproduce the endogenous effect of a particular
      human enhancer allele.
    evidence:
    - reference: PMID:41589307
      reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Both overexpression and knockdown of add3a in zebrafish disrupted hepatobiliary
        function and development,
        resulting in gallbladder hypoplasia/agenesis and reduced intrahepatic bile
        duct density.
      explanation: >-
        Independent dosage perturbations provide a plausible bridge to biliary development,
        not the effect
        of
        the assayed human variants in their native locus.
- name: Arf6 knockdown zebrafish
  species: Zebrafish
  genotype: arf6 morpholino knockdown, with EGFR-inhibition and mRNA-rescue arms
  description: >-
    Perturbation and rescue test EGFR–ARF6 involvement in biliary network development.
  publication: PMID:26379158
  modeled_mechanisms:
  - target: Reduced EGFR-ARF6 Developmental Signaling
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Perturbation and rescue test EGFR–ARF6 involvement in biliary network development.
    limitations: >-
      The human associated noncoding alleles were not directly modeled.
    evidence:
    - reference: PMID:26379158
      reference_title: The Role of ARF6 in Biliary Atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Biliary defects were reproduced with the EGFR-blocker AG1478 alone or with
        Mo-arf6 at lower doses of
        each agent and rescued with arf6 mRNA.
      explanation: >-
        Perturbation and rescue support EGFR–ARF6 involvement in fish development.
- name: Pkd1l1 mutant zebrafish
  species: Zebrafish
  genotype: Maternal-zygotic pkd1l1 hsc117 four-base-pair deletion
  description: >-
    Mutants have laterality abnormalities, sparse intrahepatic biliary networks and
    impaired biliary transport;
    most retain a gallbladder.
  publication: PMID:37675454
  modeled_mechanisms:
  - target: Disrupted Biliary Morphogenesis
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Mutants have laterality abnormalities, sparse intrahepatic biliary networks
      and impaired biliary transport;
      most retain a gallbladder.
    limitations: >-
      Fish loss of function does not validate each human PKD1L1 variant or reproduce
      the full BASM phenotype.
    evidence:
    - reference: PMID:37675454
      reference_title: Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        These data highlight the essential role of pkd1l1 in normal development and
        function of the zebrafish
        biliary system
      explanation: >-
        Fish loss-of-function data support developmental plausibility rather than
        variant-specific human causality.
- name: Efemp1 heterozygous mouse duct mechanics
  species: Mouse
  genotype: Adult Efemp1 heterozygous loss
  description: >-
    Reduced organized elastic fibers accompany altered pressure-dependent duct mechanics.
  publication: PMID:39717503
  modeled_mechanisms:
  - target: Impaired Extrahepatic Duct Elastic-Fiber Organization
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Reduced organized elastic fibers accompany altered pressure-dependent duct mechanics.
    limitations: >-
      Adult heterozygous ducts did not establish neonatal atresia or the effect direction
      of human susceptibility
      alleles.
    evidence:
    - reference: PMID:39717503
      reference_title: Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        in adult Efemp1 +/- mouse ducts, elastin organization into fibers is decreased
        by approximately half.
      explanation: >-
        Mouse matrix-organization phenotype.
- name: T-bet-deficient RRV mouse
  species: Mouse
  genotype: T-bet knockout with neonatal RRV infection
  description: >-
    T-bet loss preserves duct patency despite continued obstructive-cholangiopathy
    symptoms and unchanged mortality.
  publication: PMID:34943969
  modeled_mechanisms:
  - target: Th1-Associated Cytotoxic Inflammation
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      T-bet loss preserves duct patency despite continued obstructive-cholangiopathy
      symptoms and unchanged
      mortality.
    limitations: >-
      Anatomic duct protection is not complete clinical or survival rescue.
    evidence:
    - reference: PMID:34943969
      reference_title: T-Bet Deficiency Attenuates Bile Duct Injury in Experimental Biliary Atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Even though the percentage of T-bet KO mice displaying symptoms of an obstructive
        cholangiopathy and
        overall mortality rate was not different compared to wild-type mice, the extrahepatic
        bile ducts of
        T-bet KO mice remained patent.
      explanation: >-
        The primary study distinguishes anatomic protection from survival benefit.
- name: Treg augmentation in RRV mouse
  species: Mouse
  genotype: RRV infection with JES6-1/IL-2-mediated Treg augmentation
  description: >-
    Treatment after infection expands Tregs, improves survival and reduces biliary
    inflammation.
  publication: PMID:39131670
  modeled_mechanisms:
  - target: Reduced Regulatory T-Cell Restraint
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Treatment after infection expands Tregs, improves survival and reduces biliary
      inflammation.
    limitations: >-
      Murine cytokine-complex treatment is not an established therapy for human infants.
    evidence:
    - reference: PMID:39131670
      reference_title: Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Treg augmentation in the murine model led to increased survival, decreased
        direct bilirubin levels
        and liver inflammation, and expansion of resident macrophages.
      explanation: >-
        Intervention result in RRV mice, not established human treatment efficacy.
- name: Cd177-deficient RRV mouse
  species: Mouse
  genotype: Cd177 knockout on BALB/c background with RRV infection
  description: >-
    Cd177 loss delays onset and reduces model morbidity and mortality.
  publication: PMID:35803543
  modeled_mechanisms:
  - target: Neutrophil Extracellular Trap Formation
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Cd177 loss delays onset and reduces model morbidity and mortality.
    limitations: >-
      The human clinical effect of selectively interrupting NET formation remains
      unresolved.
    evidence:
    - reference: PMID:35803543
      reference_title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity
        and mortality.
      explanation: >-
        Mouse genetic intervention.
- name: Low-dose prenatal biliatresone mouse exposure
  species: Mouse
  genotype: Wild-type offspring after maternal low-dose biliatresone exposure
  description: >-
    Offspring showed bile-acid and immune changes without histologic liver or duct
    injury or fibrosis at the
    measured neonatal time points.
  publication: PMID:38578745
  modeled_mechanisms:
  - target: Cholangiocyte Injury of the Bile Duct Epithelium
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    description: >-
      The tested prenatal exposure did not induce the histologic injury phenotype.
    limitations: >-
      This negative result is specific to the tested exposure schedule and P5/P21
      observations; it does not
      exclude all possible dose-dependent effects.
    evidence:
    - reference: PMID:38578745
      reference_title: 'Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Pups had no evidence of histological liver or bile duct injury or fibrosis
        at either timepoint. In
        addition, growth was normal.
      explanation: >-
        Prenatal low-dose model produced biochemical and immune changes rather than
        overt fibro-obliterative
        atresia.
datasets:
synonyms:
- BA
- Extrahepatic biliary atresia
histopathology:
- name: Portal ductular reaction
  description: >-
    Proliferating and anastomosing bile ductules at expanded portal-tract margins
    support large-duct obstruction.
    They are not unique to biliary atresia, and early biopsies may be nonspecific.
    An exact human histopathology
    ontology binding is still needed; the mouse/rat hyperplasia terms are not appropriate
    substitutes.
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Portal tracts show expansion and demonstrate edematous fibroplasia with bile
      ductular proliferation,
      consisting of anastomosing ductules located at the periphery of the portal tracts
    explanation: >-
      Characteristic portal architecture in the pathology review.
    quote_role: REVIEW_SYNTHESIS
  finding_term:
    preferred_term: Portal ductular reaction
- name: Bile plugs in ductules
  finding_term:
    preferred_term: Bile Plug
  description: >-
    Inspissated bile within ductular lumina is a useful obstructive histologic finding,
    interpreted alongside the clinical workup. A compatible histopathology ontology
    binding is needed; the specific NCIT Bile Plug concept is outside the current
    permitted hierarchy.
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Ductular cholestasis (inspissated bile plugs within ductular lumen) is commonly
      seen and represent a
      useful diagnostic feature.
    explanation: >-
      Direct microscopic finding described in the review.
    quote_role: REVIEW_SYNTHESIS
- name: Periportal fibrosis
  finding_term:
    preferred_term: Periportal Fibrosis
    term:
      id: NCIT:C172824
      label: Periportal Fibrosis
  description: >-
    Portal fibroplasia can progress to bridging fibrosis and biliary cirrhotic remodeling.
    Histologic severity
    reflects disease stage but is not an infallible predictor of native-liver survival.
  evidence:
  - reference: PMID:32518681
    reference_title: 'Biliary atresia: pathology, etiology and pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Higher stages of portal fibrosis have been associated with more severe portal
      hypertension and increased
      risk of LT
    explanation: >-
      Pathology review also notes conflicting prognostic studies.
    quote_role: REVIEW_SYNTHESIS
notes: >-
  Clinical phenotypic subgroups overlap and are not a mutually exclusive etiologic
  partition. BASM, CMV-associated
  disease and cardiac-associated disease have variable definitions; the separate surgical
  type I–III classification
  describes the level of duct obstruction. Candidate susceptibility genes and animal
  perturbations do not establish
  Mendelian recurrence risks or human toxin/viral causation.

  Source identification: the NASPGHAN-hosted PDF is the 2017 joint NASPGHAN/ESPGHAN
  infant cholestasis guideline
  (PMID:27429428). The PMC newborn-screening full text is Harpavat et al., JAMA 2020
  (PMID:32207797). The EU
  trial-results page is the sponsor-posted final EMBARK record (EudraCT 2020-000974-22;
  NCT04524390). The Ipsen
  announcement dated 24 July 2026 is the sponsor topline BOLD report, not a peer-reviewed
  full trial publication.
  Trial statuses were checked on 1 October 2026.

  The CD177/NET paper (PMID:35803543) has a corrigendum (PMID:40764185; DOI:10.1016/j.jhep.2025.06.013):
  duplicated
  representative flow-cytometry images in Figure 2D/E were corrected, with unchanged
  underlying statistical
  results according to the journal correction. The ClinicalTrials.gov API record for
  NCT05426733 supplies the
  BOLD-EXT detailed protocol description.
experimental_models:
- name: H69 ADD3 regulatory-element reporter assays
  experimental_model_type: CELL_LINE
  cell_source: Immortalized human H69 cholangiocytes
  description: >-
    Allelic fragments from the ADD3 susceptibility interval were cloned into reporters.
    Four showed differing
    haplotype activity, whereas the fragment containing the lead marker did not.
  publication: PMID:41589307
  modeled_mechanisms:
  - target: Altered ADD3 Regulatory Activity
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Reports allelic transcriptional activity of cloned DNA fragments.
    limitations: >-
      Does not measure native enhancer-promoter contacts or endogenous expression
      in patients.
    evidence:
    - reference: PMID:41589307
      reference_title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        four elements (E2, E4, E9 and E10) showed allele-specific reporter activity
        differences
      explanation: >-
        Direct reporter measurement in the H69 human cholangiocyte cell line.
- name: RRV-infected macrophage conditioned-medium assay
  experimental_model_type: CELL_LINE
  cell_source: Murine RAW264.7 macrophages and isolated neutrophils
  description: >-
    Conditioned medium from infected macrophages stimulates neutrophil chemotaxis;
    CXCL2 depletion abolishes
    the measured response.
  publication: PMID:20234283
  modeled_mechanisms:
  - target: Macrophage CXCL2-Dependent Neutrophil Chemotaxis
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Tests the CXCL2 dependence of conditioned-medium chemotaxis.
    limitations: >-
      Does not demonstrate necessity for injury in an intact animal or a human infant.
    evidence:
    - reference: PMID:20234283
      reference_title: Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis by Mip2/Cxcl2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        addition of anti-Mip2/Cxcl2 antibodies depleted this chemokine in the conditioned
        media and completely
        prevented neutrophil chemotaxis.
      explanation: >-
        Conditioned-medium depletion experiment; the causal intervention is in vitro.
references:
- reference: DOI:10.1542/peds.2024-070077
  title: 'Guidance for the Primary Care Provider in Identifying Infants With Biliary Atresia by 2–4 Weeks of Life: Clinical Report'
- reference: PMID:18162845
  title: CFC1 gene involvement in biliary atresia with polysplenia syndrome.
- reference: PMID:20234283
  title: Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis by Mip2/Cxcl2.
- reference: PMID:23336978
  title: Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
- reference: PMID:23844248
  title: Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.
- reference: PMID:23991203
  title: B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.
- reference: PMID:24794368
  title: 'Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial.'
- reference: PMID:26379158
  title: The Role of ARF6 in Biliary Atresia.
- reference: PMID:27015203
  title: 'Infant Stool Color Card Screening Helps Reduce the Hospitalization Rate and Mortality of Biliary Atresia: A 14-Year Nationwide Cohort Study in Taiwan.'
- reference: PMID:27102575
  title: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.
- reference: PMID:27526058
  title: Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish.
- reference: PMID:27641439
  title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
- reference: PMID:28244293
  title: Epidemiology of Biliary Atresia in Korea.
- reference: PMID:30102696
  title: A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1.
- reference: PMID:30664273
  title: Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.
- reference: PMID:30664564
  title: A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia.
- reference: PMID:32315284
  title: Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility.
- reference: PMID:32504124
  title: 'Biliary atresia in twins: a systematic review and meta-analysis.'
- reference: PMID:32518681
  title: 'Biliary atresia: pathology, etiology and pathogenesis.'
- reference: PMID:32653991
  title: Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.
- reference: PMID:34884377
  title: 'Biliary Atresia: Clinical Phenotypes and Aetiological Heterogeneity.'
- reference: PMID:34943969
  title: T-Bet Deficiency Attenuates Bile Duct Injury in Experimental Biliary Atresia.
- reference: PMID:35170539
  title: 'Effect of Adjuvant Steroid Therapy in Type 3 Biliary Atresia: A Single-Center, Open-Label, Randomized Controlled Trial.'
- reference: PMID:35364097
  title: 'The Epidemiology of Biliary Atresia: Exploring the Role of Developmental Factors on Birth Prevalence.'
- reference: PMID:35803543
  title: CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia.
- reference: PMID:36051179
  title: Biliary atresia and congenital disorders of the extrahepatic bile ducts.
- reference: PMID:36333281
  title: Single-cell and spatial transcriptomics reveal the fibrosis-related immune landscape of biliary atresia.
- reference: PMID:37675454
  title: Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.
- reference: PMID:37869073
  title: Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.
- reference: PMID:38170523
  title: Maternal Prenatal Infections and Biliary Atresia in Offspring.
- reference: PMID:38446707
  title: Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.
- reference: PMID:38578745
  title: 'Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.'
- reference: PMID:38978022
  title: 'Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study.'
- reference: PMID:39131670
  title: Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.
- reference: PMID:39717503
  title: Biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics.
- reference: PMID:40366121
  title: Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.
- reference: PMID:40489761
  title: A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.
- reference: PMID:40600375
  title: 'Rectal budesonide: A potential game changer after Kasai hepatoportoenterostomy.'
- reference: PMID:40764185
  title: "Corrigendum to: 'CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia' (J Hepatol [2022] 77:1299-1310)."
- reference: PMID:41589307
  title: Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.
- reference: PMID:42569433
  title: Diagnostic and management guidelines for biliary atresia in 2025.
- reference: PMID:42666930
  title: 'Real-world use of maralixibat in biliary atresia: a case series.'
- reference: PMID:9396524
  title: 'A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis.'
- reference: clinicaltrials:NCT00294684
  title: A Randomized, Double-Blinded, Placebo-Controlled Trial of Corticosteroid Therapy Following Portoenterostomy in Infants With Biliary Atresia
- reference: clinicaltrials:NCT01854827
  title: A Phase 1/2A Trial of Intravenous Immunoglobulin (IVIG) Therapy Following Portoenterostomy in Infants With Biliary Atresia
- reference: clinicaltrials:NCT03499249
  title: A Phase 2 Trial of N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy
- reference: clinicaltrials:NCT04336722
  title: A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children With Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy
- reference: clinicaltrials:NCT04524390
  title: Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects With Biliary Atresia After Hepatoportoenterostomy
- reference: clinicaltrials:NCT05321524
  title: A Multicenter, Open-Label, Single- and Multiple-Dose, Dose-Finding Study, With an Optional Open-Label Extension to Assess the Safety, Tolerability, and Pharmacokinetics of Obeticholic Acid in Pediatric Subjects With Biliary Atresia
- reference: clinicaltrials:NCT05426733
  title: An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of Odevixibat (A4250) in Children With Biliary Atresia (BOLD-EXT)
- reference: clinicaltrials:NCT06121375
  title: A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Obeticholic Acid Compared to Placebo in Pediatric Subjects With Biliary Atresia, Post-hepatoportoenterostomy
- reference: clinicaltrials:NCT06553768
  title: Randomized Double-Blind Placebo-Controlled Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Participants With Cholestatic Pruritus
- reference: url:https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
  title: https://naspghan.org/files/documents/pdfs/position-papers/Guideline_for_the_Evaluation_of_Cholestatic.23.pdf
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/7093763/
  title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements - PMC
- reference: url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000974-22/results
  title: EudraCT Number 2020-000974-22 - Clinical trial results - EU Clinical Trials Register
- reference: url:https://www.ipsen.com/press-release/ipsen-provides-update-on-phase-iii-bold-trial-in-biliary-atresia-3332691/
  title: Ipsen provides update on Phase III BOLD trial in biliary atresia
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05426733
  title: https://clinicaltrials.gov/api/v2/studies/NCT05426733
- reference: PMID:32207797
  title: Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements.
- reference: PMID:27429428
  title: 'Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.'
- reference: ICTRP:ChiCTR2000040505
  title: 'N-acetylcysteine in children with biliary atresia: a clinical trial'

📚

References & Deep Research

References

DOI:10.1542/peds.2024-070077

Guidance for the Primary Care Provider in Identifying Infants With Biliary Atresia by 2–4 Weeks of Life: Clinical Report