Abstract
Background
Biliary atresia is a rare, progressive cholangiopathy of infancy and a leading cause of pediatric liver failure. Syndromic forms associated with laterality defects and congenital heart disease are uncommon and pose diagnostic challenges.
Case Presentation
A 3-month-old female infant, born at term via home delivery to a consanguineous couple, presented with persistent jaundice since birth. Examination revealed icterus, anemia, hepatomegaly, and a pansystolic murmur. Laboratory tests showed conjugated hyperbilirubinemia, elevated liver enzymes, and coagulopathy, while infectious, metabolic, and endocrine causes were excluded. Imaging revealed a small gallbladder with a triangular cord sign, biliary obstruction on HIDA scan, and situs inversus. Echocardiography identified a small perimembranous ventricular septal defect. Percutaneous liver biopsy confirmed bile duct proliferation, fibrosis, and cholestasis, consistent with extrahepatic biliary atresia.
Diagnostic Assessment
Syndromic biliary atresia was diagnosed based on clinical, radiological, and histopathological findings, with associated situs inversus and a congenital heart defect.
Therapeutic Intervention and Outcome
The patient received supportive care including vitamin K and nutritional supplementation. Pediatric surgical consultation was obtained; however, in view of advanced fibrosis, the syndromic constellation, and the family’s decision to decline operative intervention after counseling, Kasai portoenterostomy was not performed. Liver transplantation was discussed but declined by the family. The infant’s condition deteriorated and she died approximately one month after diagnosis from complications of advanced liver disease.
Conclusion
Early recognition of biliary atresia and its syndromic associations is crucial. Delayed presentation and limited access to specialized care can adversely affect outcomes, underscoring the need for timely diagnosis, multidisciplinary evaluation, and family counseling.
1. Introduction
Biliary atresia is a destructive cholangiopathy in neonates, characterized by progressive inflammatory and fibrotic processes that lead to the obliteration or stenosis of both intrahepatic and extrahepatic biliary structures. 1 It is the most frequent cause of progressive liver failure in infants and represents the primary indication for liver transplantation in the pediatric population, with untreated cases often resulting in death before the age of two.2,3 The worldwide incidence of biliary atresia is estimated to range from 1 in 8,000 to 1 in 16,700 live births, with a slightly greater frequency observed in females.4,5 In East Asia, the condition is notably more prevalent, with reported rates between 1 in 5,000 and 1 in 9,000 live births.6,7
While the majority of biliary atresia cases (approximately 80–90%) are isolated and referred to as “classical,” a smaller subset (10–20%) presents with associated congenital anomalies. 8 These include polysplenia, situs anomalies, intestinal malrotation, vascular malformations such as a preduodenal portal vein, and congenital heart defects. These syndromic forms of biliary atresia present a more complex clinical picture and may influence both surgical approach and long-term outcomes.
The co-occurrence of biliary atresia and situs inversus, though infrequent, is clinically significant due to the complexity it introduces in both diagnosis and surgical management. Situs inversus, present in approximately 0.01% of the population, results in a complete mirror-image reversal of internal organ positioning. 9 When combined with dextrocardia, this anatomical variation necessitates a high index of suspicion and careful surgical adaptation to avoid misidentification of key structures.
We present the case of a 3-month-old female infant with advanced biliary atresia and associated visceral and cardiovascular malformations, highlighting the diagnostic complexity of syndromic biliary atresia in a resource-limited setting.
2. Case Presentation
2.1. Patient Information
A 3-month-old female infant, born at term via an unassisted home vaginal delivery to a consanguineous couple, presented to the pediatric outpatient department with a history of progressive jaundice since birth. There was no associated history of inadequate feeding, lethargy, rectal bleeding, pruritus, or abdominal distension. On initial parental history, stool and urine colors were reported as normal; however, on detailed reassessment using a stool-color reference, it became apparent that the parents had likely not recognized progressively acholic stools at home, and during the patient’s subsequent admission progressively pale stools and darker urine were documented by clinical staff. The patient had previously been admitted during the first weeks of life for neonatal jaundice and received phototherapy and supportive care.
No prenatal ultrasounds were conducted, and the mother received no antenatal care. In the third trimester, she reported self-limiting eczema and a urinary tract infection. The neonate passed meconium within the first hour of life and was breastfed immediately thereafter. There was no history of neonatal seizures, cyanosis, or fever.
Family history was significant for five elder siblings, two of whom died in early infancy—one from a diagnosed congenital heart disease at 18 months of age, the other from an undetermined cause. The remaining siblings were healthy.
2.2. Clinical Findings
On examination, the infant appeared ill but had no dysmorphic features. She was icteric and anemic, with no cyanosis, dehydration, or peripheral edema. Neurological assessment revealed a Glasgow Coma Scale score of 15/15.
Cardiovascular examination demonstrated normal heart sounds with a grade IV pansystolic murmur, best heard at the left lower sternal border. Abdominal examination revealed a soft, non-distended abdomen with hepatomegaly; the liver was palpable 4 cm below the xiphisternum, measured approximately 11 cm in span, and had a firm consistency with smooth margins. The spleen was not palpable, and there was no clinically detectable ascites or visible abdominal venous distension at the time of initial presentation. An umbilical hernia measuring 1 × 1 cm was noted. Bowel sounds were present.
2.3. Timeline of Clinical Events
Timeline of Clinical Events
OPD, outpatient department; PT, prothrombin time; INR, international normalized ratio; HIDA, hepatobiliary iminodiacetic acid; VSD, ventricular septal defect.
2.4. Diagnostic Assessment
Initial laboratory investigations demonstrated significant conjugated hyperbilirubinemia, elevated liver enzymes, and coagulopathy: total bilirubin 20 mg/dL, direct bilirubin 15.1 mg/dL, indirect bilirubin 4.9 mg/dL, ALT 186 IU/L, ALP 624 IU/L, PT 21.4 seconds, APTT 48.7 seconds, and INR 2.07. Gamma-glutamyl transferase (GGT) was not measured during the initial admission, which we acknowledge as a limitation of the diagnostic workup at our institution.
Given the presence of neonatal cholestasis, further evaluation was undertaken. Serologic testing for hepatitis B and C (HBsAg and HCV PCR) was negative. Although CMV IgM was elevated on TORCH screening, CMV PCR was negative, and the infectious-disease team advised against antiviral therapy. Urine succinylacetone testing was negative, effectively excluding tyrosinemia. Thyroid function tests and serum alpha-1 antitrypsin levels were within normal limits.
Abdominal ultrasonography revealed an enlarged liver located in the midline (11.7 × 6.0 cm) with homogeneous parenchyma and well-defined margins. The intrahepatic biliary ducts were not dilated. The gallbladder appeared small, and the common bile duct measured 0.2 cm. The triangular cord sign was positive, with anterior periportal echogenic thickening measuring approximately 4.5 mm (above the diagnostic threshold of ≥4 mm), a finding highly suggestive of biliary atresia (Figure 1). Imaging also demonstrated situs inversus, with the stomach and spleen positioned on the right side. Abdominal ultrasound demonstrating the triangular cord sign (anterior periportal echogenic thickening, measuring approximately 4.5 mm), a finding highly suggestive of biliary atresia. The scan also reveals an enlarged liver (11.7 × 6.0 cm) positioned in the midline, with no dilation of the intrahepatic biliary ducts
A hepatobiliary iminodiacetic acid (HIDA) scan demonstrated poor hepatic uptake of tracer and absence of gallbladder visualization at 24 hours, confirming biliary obstruction and hepatocellular dysfunction (Figure 2). Transient elastography (Fibroscan) revealed advanced hepatic fibrosis (METAVIR stage F4), with a liver stiffness measurement of approximately 17.6 kPa, consistent with cirrhosis. Hepatobiliary iminodiacetic acid (HIDA) scan showing poor hepatic uptake of tracer and absence of gallbladder visualization at 24 hours. These findings confirm biliary obstruction and hepatocellular dysfunction
Echocardiography showed a small perimembranous ventricular septal defect with a left-to-right shunt and associated aneurysmal changes. Cross-sectional computed tomography (CT) imaging further confirmed situs anomalies (Figure 3). Cross-sectional computed tomography (CT) image confirming situs anomalies, with the stomach and spleen positioned on the right side of the abdomen
Percutaneous needle liver biopsy was performed under ultrasound guidance using a 16-gauge core biopsy needle. Histopathological examination demonstrated bile ductular proliferation, hepatocellular and ductular cholestasis, moderate portal fibrosis, and chronic inflammatory infiltrates predominantly composed of lymphocytes—findings consistent with extrahepatic biliary atresia.
Summary of Laboratory and Diagnostic Investigations
ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HCV PCR, hepatitis C virus polymerase chain reaction; CMV, cytomegalovirus; IgM, immunoglobulin M; A1AT, alpha-1 antitrypsin; HIDA, hepatobiliary iminodiacetic acid; VSD, ventricular septal defect.
2.5. Diagnostic Reasoning
The clinical presentation of persistent jaundice beyond the neonatal period, in conjunction with marked conjugated hyperbilirubinemia and elevated cholestatic enzymes, strongly suggested an obstructive etiology. The absence of infectious (hepatitis viruses, CMV PCR), metabolic (tyrosinemia), and endocrine (hypothyroidism, alpha-1 antitrypsin deficiency) causes further narrowed the differential diagnosis.
Radiological findings, particularly the positive triangular cord sign on ultrasound and absent tracer excretion on HIDA scan, were highly indicative of biliary atresia. Histopathological confirmation of bile ductular proliferation and portal fibrosis established the diagnosis definitively.
The coexistence of situs inversus and a congenital heart defect supported a syndromic form of biliary atresia, possibly arising from a disturbance in embryological left–right axis development.
In view of this syndromic presentation and the history of parental consanguinity, genetic counseling and chromosomal microarray analysis were offered to the family to evaluate for an underlying syndromic or ciliopathy-related etiology. However, dedicated genetic testing was not pursued, as such specialized investigations are not routinely available at our institution and the family declined referral to a tertiary genetics center for both financial and personal reasons. The absence of formal genetic evaluation is acknowledged as a limitation of this report.
2.6. Therapeutic Intervention
The patient was approximately 3 months (≈90 days) of age at the time of definitive diagnosis. She was managed conservatively with vitamin K (5 mg twice daily) to correct coagulopathy, together with nutritional and supportive care. Nutritional management consisted of continued breastfeeding supplemented with a medium-chain triglyceride (MCT)–enriched formula and fat-soluble vitamin supplementation (vitamins A, D, E, and K), in addition to cod liver oil. Ursodeoxycholic acid was initiated as a choleretic agent. Pediatric cardiology recommended observation alone for the small perimembranous ventricular septal defect.
Pediatric surgical consultation was obtained at the time of admission. Although Kasai portoenterostomy is most beneficial when performed before 60 days of age, with diminishing—but not absent—benefit thereafter, the procedure may still be considered in carefully selected infants up to 90–120 days of age. After multidisciplinary discussion involving the pediatric surgery, hepatology, and cardiology teams, several factors led to the decision not to proceed with surgery: (i) histological and elastographic evidence of established cirrhosis (F4) at presentation; (ii) the technical complexity introduced by situs inversus; and, most importantly, (iii) the family’s informed refusal of operative intervention after counseling regarding risks, benefits, and prognosis.
Liver transplantation was discussed with the family as the only definitive therapy, and referral for formal transplant evaluation was proposed. However, the family declined this option as well, citing personal, social, religious, and financial concerns, including the absence of a pediatric liver-transplantation program accessible within their region. As a result, formal transplant workup was not initiated.
2.7. Follow-up and Outcomes
The patient was followed for approximately four weeks after definitive diagnosis. During this interval, her clinical condition deteriorated progressively. She developed worsening jaundice, refractory coagulopathy despite ongoing vitamin K supplementation, feeding intolerance with poor weight gain, and increasing abdominal distension suggestive of evolving ascites. Toward the terminal phase, she demonstrated features of hepatic decompensation, including persistent hypoglycemia, hypoalbuminemia, and intermittent hepatic encephalopathy.
The infant succumbed to her illness approximately one month after diagnosis. The probable immediate cause of death was multi-organ failure secondary to end-stage liver disease, with terminal hepatic and renal dysfunction in the setting of underlying syndromic biliary atresia. The family declined post-mortem examination.
3. Discussion
Biliary atresia (BA) is a rare but severe infantile cholangiopathy characterized by progressive obliteration of the extrahepatic bile ducts. Isolated BA constitutes the majority of cases, while the syndromic or non-isolated form, 10 comprising approximately 10–20% of cases, is associated with a range of congenital anomalies that often complicate diagnosis, treatment, and prognosis.3,11-13 In addition to cardiac anomalies—most commonly atrial or ventricular septal defects, tetralogy of Fallot, and aberrant inferior vena cava— these conditions may involve intra-abdominal organs, including situs inversus, intestinal malrotation, annular pancreas, and preduodenal portal vein. 14 Less commonly reported associations include duodenal or esophageal atresia, renal anomalies (such as polycystic kidneys or pelviureteric junction obstruction), and craniofacial anomalies such as cleft palate. 15
The reported association between BA and laterality defects, particularly situs anomalies, is increasingly recognized; the presence of situs inversus should therefore prompt clinicians to consider syndromic BA as a differential diagnosis in neonates with prolonged jaundice. 16 In contrast to the general-population prevalence of approximately 1 in 10,000–15,000, studies such as that by Gupta et al have reported that up to 28% of children with laterality anomalies may exhibit features of BA. 8 Our patient exhibited a syndromic manifestation characterized by classic features of BA, situs inversus, and a small perimembranous ventricular septal defect. These observations are consistent with the hypothesis that a developmental disruption during early embryogenesis may simultaneously affect hepatobiliary and cardiovascular morphogenesis.
Regional epidemiology provides additional insights into the potential etiopathogenesis of BA. The incidence in Southeast Asia approaches 1 in 5,000 live births, significantly higher than the rates of 1 in 10,000–1 in 10,000–15,000 reported in North America and Western Europe.17,18 This disparity may reflect interactions between environmental exposures and genetic predisposition. Hopkins et al observed a disproportionately elevated prevalence of BA among Asian-born American infants, raising the possibility of underlying genetic susceptibility. 19 Although no specific gene mutation has been definitively established as causative for isolated or syndromic biliary atresia, genome-wide association studies have identified candidate regions such as 2q37 and deletions affecting genes including FOXA2, which are implicated in bile-duct development and laterality.20,21 In the present case, the consanguineous parental background raises—rather than confirms—the possibility of a contributory recessive genetic basis. In the absence of formal genetic testing, however, this remains speculative.
In neonates, biliary atresia should be suspected whenever jaundice persists beyond the first two weeks of life, especially in the presence of cholestatic features such as acholic stools, dark urine, and scleral icterus. 22 Stool-color card screening programs have been shown to improve early detection and have been adopted at the national level in several countries.
Davenport et al reported that 25 of 55 infants (45%) with BA had congenital heart disease, 23 of whom 9 (16%) required cardiac surgery; 7 underwent the cardiac procedure prior to biliary intervention. 24 The presence of such anomalies, particularly in organ systems that develop independently of the hepatobiliary tract, supports the hypothesis that BA may result from a broader embryologic disruption rather than an isolated defect of the bile ducts or liver. 8 Although historically regarded as uniformly fatal, BA has become a treatable disease over the past three decades, largely due to advances in palliative surgical management—most notably the Kasai portoenterostomy— and the increasing availability of liver transplantation as a definitive treatment.
This case also highlights several practical challenges encountered in low- and middle-income settings: delayed presentation, limited access to specialized pediatric surgery and transplantation, and barriers to genetic evaluation. These factors collectively contribute to the poor outcomes observed in syndromic BA in such contexts and underscore the importance of early screening, parental education, and strengthening of referral pathways.
The strengths of this report lie in the comprehensive, multimodal diagnostic evaluation—spanning biochemical, serological, metabolic, imaging, elastographic, and histopathological assessment—that permitted a confident diagnosis in a resource-limited setting, and in the documentation of an uncommon syndromic constellation. Several limitations should nonetheless be acknowledged. As a single case report, it cannot establish causality and its findings are not generalizable. The diagnosis was not confirmed by the reference standard of intraoperative cholangiography, as operative intervention was declined; gamma-glutamyl transferase was not measured; and formal genetic testing was unavailable and declined, leaving the suspected syndromic or ciliopathy-related etiology unconfirmed despite the parental consanguinity. Finally, the early history relied on parental recall that proved initially inaccurate, and the absence of a post-mortem examination together with the short follow-up (approximately four weeks before the infant’s death) limited assessment of the underlying anatomy and of longer-term outcomes.
4. Parents’ Perspective
We initially thought our child’s jaundice was a common condition and did not seek early medical care. When we finally came to the hospital, we were overwhelmed by the diagnosis and the complexity of the treatment options. Despite the doctors’ recommendations, we decided against surgery due to personal and financial concerns. Looking back, we regret the delay in seeking care, and we hope that greater awareness can help other families seek timely treatment.
5. Conclusion
This case underscores the complexity of managing neonatal cholestasis in the presence of multiple congenital anomalies. Early identification of biliary atresia is critical for timely surgical intervention —such as Kasai portoenterostomy—to improve survival and delay progression to end-stage liver disease. The co-occurrence of situs inversus and congenital heart disease in this patient raises the possibility of an underlying laterality disorder or syndromic etiology; where resources allow, formal genetic evaluation should be considered to inform counseling and identify families at risk of recurrence. Strengthening pathways for early diagnosis, multidisciplinary management, and family counseling is essential, particularly in resource-limited settings.
Footnotes
Acknowledgements
The authors thank the Department of Paediatrics at Dow University of Health Sciences for their support.
Ethical Considerations
This single-patient case report was reviewed by the institutional ethics committee of Dow University of Health Sciences/Abbasi Shaheed Hospital, which determined that formal ethical approval was not required for a retrospective, anonymized single-patient case report, in accordance with institutional and national policy.
Consent to Participate
Written informed consent for participation in this report, including the use of anonymized clinical data, was obtained from the patient’s legal guardian (the mother).
Consent for Publication
Written informed consent for publication of this case report, including all clinical details, anonymized diagnostic images, and outcomes, was obtained from the patient’s legal guardian. A copy of the signed consent form is available for review by the editorial office upon request.
Authors Contributions
Mariam Khan, Kanza Farhan, and Maliha Rahim contributed to the initial patient evaluation, data collection, and manuscript drafting. Aisha Farooq assisted with clinical input and interpretation. Ahmed Asad Raza conducted the literature review and assisted in manuscript preparation. Abedin Samadi supervised the project, critically revised the manuscript, and served as corresponding author. Fehmina Arif provided pediatric expertise and guidance on clinical management. All authors reviewed and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The data supporting the findings of this case report are available from the corresponding author upon reasonable request. To protect patient confidentiality, some sensitive clinical data may not be publicly shared.