Challenges in the diagnosis of biliary atresia in cholestatic neonates

Biliary atresia (BA) is an inflammatory and progressive fibrosing cholangiopathy, eventually causing bile duct obliteration. Its incidences are higher in Asia–Pacific regions, with 0.7–3.2 per 10,000 live births, and lower in the UK or the USA, with 0.5–0.7 per 10,000 live births. Without timely diagnosis and Kasai portoenterostomy (KPE), BA can rapidly progress to end-stage liver cirrhosis. Taiwan has implemented the world's first national infant stool card screening for BA since 2004, which has led to earlier diagnosis and KPE with improved outcomes. However, the differential diagnosis of neonatal cholestasis remains a challenge for many pediatricians. No single test or image modality can reliably diagnose BA, beating the gold standard of intraoperative cholangiography (IOC). Among conventional diagnostic protocols, such as clinical tests, blood tests, ultrasonography, duodenal juice sampling, hepatobiliary scintigraphy, and liver biopsy, liver histology has the highest accuracy (88.2%–96.9%). A scoring system employing clay stool, ultrasound features, laboratory tests (gamma-glutamyl transferase [γ-GT] and platelet), and histological features achieved high sensitivity (100%), specificity (97.7%), and accuracy (98%). The serum levels of matrix metallopeptidase-7, a biomarker well correlated with BA-associated liver fibrosis, and interleukin-33, a potent mediator of cholangiocyte proliferation, may facilitate the diagnosis of BA. Direct visualizations of the biliary system by endoscopic retrograde cholangiopancreatography (ERCP) are challenging in infants and thus limited to centers with the expertise and specific infant endoscopy. If feasible, ERCP is successful in 87% of cholestatic infants, with a sensitivity of 92% and specificity of 73%, for diagnosing BA and could avoid unnecessary exploratory laparotomy in 25% of the cases. Magnetic resonance cholangiopancreatography (MRCP) gradually replaced ERCP after more experience and expertise from radiologists.

Prematurity has been recognized as a risk factor for BA, with a higher incidence than in term infants. The diagnosis of BA in premature infants with cholestasis is challenging because of multiple culprits, including immature enterohepatic circulation, parenteral nutrition-related cholestasis, necrotizing enterocolitis, and sepsis, besides shared causes (biliary anomaly, infectious, metabolic, and genetic cholestasis) with term infants. Unfortunately, the outcome of premature infants with BA was reported worse than that of term infants in some studies, partly due to delayed diagnosis. However, studies comparing the accuracy among diagnostic modalities barely focused on cholestatic preemies. In addition, the high risk of liver biopsy in small premature infants has made it unwelcome.

In this issue of Pediatrics and Neonatology, Chen et al. reported a single center's experience in the application of MRCP in cholestatic preterm infants and compared it with that in term infants. However, an unnecessary exploratory laparotomy was performed in 19% of the preterm infants (versus 9% of term infants). If including the second tier test of γ-GT (cutoff 250 IU/L), five MRCP false-positive preterm infants would have avoided unnecessary laparotomy (reduced to 5.5%). Still, two patients with true BA would have been missed. On the contrary, four MRCP false-positive term infants with γ-GT levels <250 IU/L would have avoided unnecessary laparotomy. In their report, the sensitivity of MRCP for diagnosing BA was 100% in preterm infants, but 81% (13/16) in term infants. Two patients with cystic BA were interpreted to have choledochal cysts by MRCP as early as 3 and 7 days. However, one patient underwent IOC and KPE 1 month later with a poor outcome (mortality). A cyst detected at the hepatic hilum in a cholestatic neonate should be regarded as probable BA and requires immediate IOC and KPE if BA is confirmed. Thus, only one term infant in their series with a visible biliary system on MRCP turned out to have a missed BA. From their study, non-visualization of the biliary system on MRCP may help detect probable BA earlier at the expense of an unnecessary laparotomy for some preemies. As for term babies, the inclusion of γ-GT may increase diagnostic accuracy and avoid unnecessary laparotomy. Still, we should remember that liver histology provides the highest accuracy before laparotomy, especially for inconclusive cases without contraindications. Finally, all workups intend to bring patients with probable BA to early IOC and timely KPE, which mandates good communication and shared decision-making with their parents.