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Biliary atresia is a serious pediatric liver disease. It is among the leading causes of newborn cholestasis, the foremost reason for cirrhosis and liver-related death in children, and the most frequent indication for liver transplant in the pediatric population. The condition results from an idiopathic, rapidly progressive, fibrosclerosing obliterative injury to large bile ducts during the first months of life. Although not an inherited disease, biliary atresia is a rare orphan liver disease that occurs in 1:15 000 to 1:20 000 live births in North America and Western Europe, with the highest incidence rates in Asia (1:6000 to 1:9000) and French Polynesia (1:3000).1
Biliary atresia manifests during the first weeks of life with jaundice and pale (acholic) stools in an otherwise healthy infant. In contrast to the approximately two-thirds of newborns with benign, self-resolving physiological or breast milk jaundice due to unconjugated hyperbilirubinemia, biliary atresia results in pathological obstructive jaundice with conjugated (direct) hyperbilirubinemia. The current treatment for biliary atresia involves sequential surgical intervention with the Kasai portoenterostomy in which the obstructed bile duct is resected and a loop of bowel is brought to the porta of the liver to restore bile flow, followed by liver transplant for those infants who progress to cirrhosis and liver failure later in childhood or adulthood. For young infants who do not undergo the Kasai portoenterostomy or if the procedure fails to reestablish bile flow and jaundice persists, semiurgent liver transplant is required within the first 2 years of life. These infants often weigh less than 10 kg and have advanced liver disease, which portends increased risk with liver transplant and considerable mortality while awaiting transplant. Left untreated, infants with biliary atresia will die by age 3 years.2
Disease recognition during the first weeks of life is an important first step in improving outcomes for infants with biliary atresia. Early age at the Kasai portoenterostomy is a key prognostic factor. Considerably more successful outcomes are achieved when surgery is performed at age 60 days or younger, with the best outcomes achieved at age 30 days or younger. Worse outcomes occur when infants undergo the Kasai portoenterostomy at an age older than 90 days.3 In the United States, there has been no decrease in the median age (66 days; interquartile range, 50-79 days) when infants undergo the Kasai portoenterostomy for the past several decades.4
There are major obstacles to early disease recognition. Neonatal jaundice is usually considered inconsequential and no further investigations are pursued despite the recommendation from the American Academy of Pediatrics to test serum total, direct, or conjugated bilirubin in all infants with persistent jaundice for more than 2 weeks. Monitoring for pale stools is not usually performed by clinicians or parents. In addition, given the US schedule for routine care within 2 weeks after birth and first vaccination at 2 months, the window of opportunity for early case identification is often missed.
Biliary atresia satisfies standard criteria for newborn screening, including a clear case definition, the need for early recognition, acceptable treatment regimens that improve outcome, and health care cost savings.5 What is lacking is a suitable screening test. Efforts to incorporate screening into current newborn dried blood spot cards have been hampered by the lack of a suitable biomarker. It is not possible to measure direct or conjugated bilirubin from dried blood spot cards.
The use of infant stool color cards for biliary atresia screening was developed in 1994.6 The most comprehensive and universal biliary atresia screening program using infant stool color cards was introduced in Taiwan in 2004, and several countries have since adopted the program including Canada, Switzerland, and Brazil.7-10 The screening strategy is simple and effective. Parents use the cards depicting photos of normal and abnormal stool color to monitor their infant’s stool at home during the first month of life and contact the screening center with concerns. In Asia, the infant’s stool color card is reviewed by a clinician at the routine 1-month visit. Since the introduction of the screening program, Taiwan has virtually eliminated the need for the Kasai portoenterostomy when older than age 90 days and significantly improved 3-year jaundice-free native liver survival from 32% during the prescreening era to 57% during the postscreening era.7 Studies in the United States and Canada have suggested that screening with stool color cards would be highly cost-effective.11,12
The measurement of conjugated bilirubin in newborn blood samples to detect biliary atresia early was reported by Powell et al13 in 2003. A retrospective study from Texas identified 34 of 73 patients with biliary atresia who had direct or conjugated bilirubin measured early after birth.14 All 34 patients had elevated direct or conjugated bilirubin levels within 17 hours of life and high levels persisting through 96 hours. Based on these findings, the Texas group initiated a prospective study using a 2-step screening approach centered on blood procurement to measure direct or conjugated bilirubin.15 Among 11 636 newborns screened at 4 Houston hospitals over 15 months, 121 infants (1%) had positive test results for direct or conjugated bilirubin levels (>95th percentile reference interval) within less than 60 hours of life. Of these infants with positive test results during screening in step 1, 11 (9%) continued to have positive test results and increasing direct or conjugated bilirubin levels during screening in step 2 at 2 to 3 weeks of age. The 2 infants with biliary atresia had positive test results at both steps 1 and 2. The screening strategy yielded a sensitivity of 100% and a specificity of 99%.
In this issue of JAMA, Harpavat and colleagues16 expanded their evaluation of the 2-step biliary atresia screening strategy. Of 124 385 infants born at 14 south Texas hospitals, 123 279 (99%) had conjugated or direct bilirubin tested within the first 60 hours of life during step 1. There were 1354 infants (1%) with positive screening results during step 1 and 1334 of them underwent step 2 testing by the 2-week well child visit. After step 2, there were 119 infants (9%) with positive screening results and 7 actually had biliary atresia. This yielded a screening sensitivity of 100% (95% CI, 56%-100%), a specificity of 99.9% (95% CI, 99.9%-99.9%), and a positive predictive value of 5.9% (95% CI, 2.6%-12.2%).
Outcome measures were compared between patients who underwent the Kasai portoenterostomy at a single hepatology center before (n = 24) or after (n = 19) implementation of the screening program. The postimplementation group had a significantly earlier age at Kasai portoenterostomy (36 days vs 56 days; P = .004) and nonsignificantly higher 1-year postprocedural transplant-free survival (95% vs 71%; P = .06). However, this outcome analysis was problematic because only 6 of 19 patients in the postimplementation group were actual study patients; another 7 patients were screened at nonstudy hospitals and 6 patients had never been screened. Whisker box plots of the age at Kasai portoenterostomy for each of these subgroups (eFigure in the Supplement for the article) showed that the 6 study patients who were screened, albeit a small number, had an earlier age at the Kasai portoenterostomy compared with the preimplementation screening group.
The authors concluded that their findings help inform the screening strategy. Yet there are several limitations to the study design and some formidable challenges to applying the screening program to a broader community. The authors acknowledged many of these issues, but some merit highlighting. Given the small number of patients with true-positive biliary atresia screened and the lower limits of the sensitivity 95% CIs, this study does not fully inform whether the screening test performance is acceptable. The lack of systematic follow-up of the infants who tested negative during screening raises the possibility that infants with biliary atresia may have been missed. Even if only 1 or 2 patients were missed, the sensitivity would be substantially lower. In this study, more than 50% of 112 patients with false-positive results had no diagnosis despite extensive third-tier evaluation, including 18% having invasive liver biopsy with or without percutaneous cholangiograms. Patients with false-positive findings incur health care costs that affect program cost-effectiveness. Also to be considered is the emotional effect on families with false-positive screening results. These important consequences of screening require further study.
Blood procurement for bilirubin testing was already incorporated in the study hospitals as a care standard for the assessment of newborn jaundice. That birth centers may use transcutaneous bilirubin measurement rather than serum bilirubin measurement to assess neonatal jaundice introduces additional logistical and cost factors that require study when researching the screening program in other jurisdictions. In the current report,16 direct bilirubin testing did not perform as well as conjugated bilirubin testing and reference values varied between laboratories. An added complexity is that the direct and conjugated bilirubin cutoff values for positive screening results differed between steps 1 and 2.
The report by Harpavat and colleagues16 is an encouraging step toward the realization of a newborn biliary atresia screening strategy using direct or conjugated bilirubin measurements. Screening for other newborn conditions has often begun with reports similar to this one. A national universal biliary atresia screening program with this testing approach would require a well-organized and meticulous infrastructure for implementation and execution. Many lines of research are still required before the program could be advocated to public health stakeholders (clinicians, epidemiologists, economists, government and nonprofit agencies) and policymakers. In the meantime, biliary atresia remains a disease in need of early recognition.
Corresponding Author: Richard A. Schreiber, MDCM, BC Children’s Hospital, GI/Hepatology, University of British Columbia, Room K4-200, Vancouver, BC V6H 3V4, Canada (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
Schreiber RA. Newborn Screening for Biliary Atresia. JAMA. 2020;323(12):1137–1138. doi:10.1001/jama.2020.2727
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