Can Free Carnitine or Bilirubin in Blood Be Used in Neonatal Screening for Biliary Atresia?

Abstract

Objective To investigate the efficiency of free carnitine, unconjugated bilirubin (UBIL), bilirubin monoglucuronide (BMG), and bilirubin diglucuronide (BDG) in dry blood spots (DBSs) measured using tandem mass spectrometry (MS/MS) for screening biliary atresia (BA). Materials and Methods All the patients with BA, residing in Shanghai, were collected from four different children's hospitals in Shanghai from January 1, 2015, to June 30, 2017. UBILMS, BMG, BDG, and free carnitine were measured in the DBS samples of 48 patients with BA, 10,008 pediatric patients, and 52,862 newborns using MS/MS. Conjugated bilirubin was measured by MS/MS (CBMS) = BMG + BDG, and total bilirubin was measured by MS/MS (TBMS) = UBILMS + CBMS. Four hundred pediatric patients' direct bilirubin (DB) and total bilirubin (TB), measured by the clinical laboratory and MS/MS, were used as a control. Results The total number of births at the registered permanent residences in Shanghai was 233,000; among them, the occurrence of BA was in 33 patients in 2 years. Therefore, the incidence of BA in Shanghai was 1:7,060. The ratio of DB/TB and CBMS/TBMS of most patients with BA was elevated gradually in the neonatal period and higher than the normal range after 1 month after birth. The area under the receiver operating characteristic curve of DB, DB/TB, CBMS/TBMS, CBMS, and free carnitine for predicting BA was 0.98, 0.95, 0.73, 0.57, and 0.92, respectively. Using the 95% percentile as a cutoff, the sensitivity of DB and free carnitine to predict BA was 100 and 85%, respectively, and the specificity was 52 and 85%, respectively. Conclusion In free carnitine, DB, and CBMS/TBMS tests, blood concentrations are elevated in all infants with BA. However, they may not be elevated while they are newborns. These tests will result in high false negatives or positives. Thus, they should not be used as newborn screening tests for BA due to their lower sensitivity and specificity.

Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements

“…However, normal direct or conjugated bilirubin levels in the newborn period would be very unlikely among those with biliary atresia. [9][10][11][12] In addition, the study's birth prevalence for biliary atresia of 0.6 per 10 000 newborns matches the birth prevalence reported in multiple North American and European studies;…”

“…Screening was based on the observation that infants with biliary atresia have elevated direct or conjugated bilirubin levels starting at birth, and involved implementing a standardized clinical response to levels exceeding the reference intervals. [9][10][11][12] The upper limit of normal for direct bilirubin was derived at each site using the 97.5th percentile value from 120 newborns consecutively measured. 16 Bilirubin reference intervals were recalculated yearly with new machines to control for differences that occur with changes in the direct bilirubin assay's reaction time, pH, or temperature.…”

“…20 The prescreening group included patients treated between January 2008 and June 2011, which was before screening was implemented and before the value of newborn direct or conjugated bilirubin measurements for detecting biliary atresia was known. 9 The postscreening group included patients treated between January 2015 and June 2018, which was after screening had been introduced to the region and implemented at various birth hospitals. Infants in the postscreening implementation group were detected by (1) the screening study, (2) clinicians who learned about the study and implemented a similar direct or conjugated bilirubin screening approach at nonstudy birth hospitals, or (3) clinical symptoms without screening.…”

“…A second potential strategy uses newborn direct or conjugated bilirubin measurements, which are elevated in biliary atresia starting shortly after birth. [9][10][11][12][13][14] This 2-part study included a screening study to determine the diagnostic yield of newborn direct or conjugated bilirubin measurements for biliary atresia and a pre-post study to evaluate the association of screening implementation with clinical outcomes.…”

Reduced peroxisome proliferator-activated receptor-α and bile acid nuclear receptor NR1H4/FXR may affect the hepatic immune microenvironment of biliary atresia

“…We previously reported that pediatric BA patients have abnormal lipid metabolism such as free serum carnitine ( 7 , 8 ). Carnitine is an important carrier of fatty acids; its metabolism, absorption, and utilization are regulated by the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway, and it enter cells under the action of the transporter OCTN2 ( 9 ).…”