Cross-sectional screening study for Biliary Atresia (BA)

In March 2020, Harpavat et. al published their study “Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements” in the Journal of the American Medical Association (DOI: 10.1001/jama.2020.0837).

In this cross-sectional screening study for Biliary Atresia (BA) 124,385 infants born at 14 Texas hospitals had undergone a two-stage screening routine looking at direct/conjugated hyperbilirubinemia to detect BA. Furthermore, the authors did a pre-post evaluation before and after the implementation of the screening program concerning the outcome parameters of the Kasai Portoenterostomy.
124,385 infants were tested for direct or conjugated hyperbilirubinemia in the first 60 hours of life. If the threshold of the populations 95th percentile was exceeded the patients were retested 2 weeks later. Patients with higher bilirubin levels than in the first screening and/or > 1 mg/dl were transferred for further workup (i.e. bilirubin surveillance, imaging, liver biopsy, cholangiography). 119 patients were positive in second screening (0.1% of the total population; 8.9% of those re-tested). 7/119 Patients were diagnosed with BA. Additionally, due to the screening other cholestatic diseases were detected in the remaining 112 patients (Alagille n = 4; A1-antitrypsin deficiency n = 3; ABCB11 deficiency n = 1; Choledochal cyst n = 1). Sensitivity and specificity were 100% and 99.9%, respectively. A positive and negative predictive value of 5.9% and 100% were reported.
Furthermore, the study evaluated clinical outcomes of Kasai Portoenterostomy before and after the screening implementation. Patients were significantly younger at surgery after screening was implemented (56 days [SD 10 days] vs. 36 day [SD 22 days]; p = 0.004). Time to normalization of bilirubin levels and transplant-free survival after Kasai were not significantly different between both groups although a trend in favor of the post-screening group was seen.

Kasai Portoenterostomy before 30 days of life is an important factor for transplant-free survival in BA [1, 2]. This trial evaluated direct/conjugated bilirubin as a newborn screening parameter for Biliary Atresia (BA). The results are favorable. Sensitivity and specificity are excellent. The negative predictive value of 100% suggests that no patient was unidentified in this cohort. Moreover, other neonatal cholestatic diseases where identified when using conjugated / direct bilirubin as a screening parameter. Also for these diseases early diagnosis is of importance.
However, there are a number of limitations to the study and to the implementation of such a screening routine in general. The study was not sufficiently powered in the pre-post study groups; therefore an improvement in outcome after Kasai was not shown. Moreover, patients were included in the post-implementation group who did not primarily participate in the screening program.
Prior to implementing such a screening routine for BA in existing national or international newborn screening programs the following questions will need to be addressed: Do healthcare benefits outweigh the costs? Is conjugated/direct bilirubin reliably quantifiable in dried whole blood samples (as used for present newborn screening)? Is this method more effective than other screening tools (e.g. stool color cards)?
Currently patients with biliary atresia are frequently diagnosed late and therefore palliative Kasai surgery cannot prevent liver failure in early, vulnerable stages of life in a large group of patients. Thus, a screening method enabling early identification of BA is needed. National and/ or European programs within ERN RARE LIVER may be suitable to further explore and implement effective screening tools for early BA identification .

Toni Illhardt
Department of Gastroenterology and Hepatology, University Children’s Hospital, Tuebingen, Germany.

1. Fanna, M., et al., Management of Biliary Atresia in France 1986 to 2015: Long-term Results. J Pediatr Gastroenterol Nutr, 2019. 69(4): p. 416-424.
2. Schreiber, R.A., et al., Biliary atresia: the Canadian experience. J Pediatr, 2007. 151(6): p. 659-65, 665 e1.