A-355 Laboratory Findings of Cholestasis in Infants for Establishing Screening and Diagnostic Criteria

Background Cholestasis in infants indicates a defect of the intrahepatic production or the transmembrane transport of bile, or a mechanical obstruction of bile flow leading to the accumulation of bile components in the liver, blood, and extrahepatic tissues. Major causes include biliary atresia (BA) accounting for 30-40% of neonatal cholestasis, progressive familial intrahepatic cholestasis, preterm birth, metabolic and endocrinological disorders, Alagille syndrome, infectious diseases, and others. The rapid diagnosis of BA is particularly important because hepatoportoenterostomy prior to 2?months of age correlates with better long-term outcomes. However, with the current practice, the average age at diagnosis of BA is about 60?days in the USA. Several laboratory tests are used to support BA diagnosis, including total bilirubin (Tbil), direct bilirubin (Dbil), gamma-glutamyl transferase (GGT), coagulation function, and matrix metalloproteinase-7 (MMP-7), which was shown to have great Receiver Operating Characteristic/Area Under the Curve (ROCAUC) than conventional tests including biopsy histopathology in Pandurangi S et al. 2024. The objective of this study was to examine the distribution of laboratory test results of Tbil, Dbil, GGT, and MMP-7 in BA and other cholestatic conditions in infants, with the intention of establishing clinical cutoffs for screening and diagnostic purposes. Methods Infants presented with suspected cholestasis at a pediatric hospital and a safety net country hospital with MMP-7 testing ordered as part of their diagnostic workup were included. The study period was between July 2023 and February 2025. Plasma levels of Tbil, Dbil, and GGT measured using Atelica (Siemens) or Alinity (Abbott) platforms within 15 days of MMP-7 testing were analyzed. MMP-7 levels were determined using an in-house time-resolved fluorescence energy transfer immunoassay. BA diagnosis was confirmed via the hepatoportoenterostomy Kasai procedure. Institutional Review Board approval was obtained for this study. Results The study included 97 patient encounters, with a median age of 39.2 days (interquartile range (IQR): 19.8-61 days), comprising 70 males and 27 females. BA was confirmed in 10 patients. In BA patients, the median: IQR of Tbil (mg/dl), Dbil (mg/dl), MMP-7 (ng/ml), and GGT (U/L) were 9.7: 7.6-10.2, 6.8:5.6-7.7, 69.6: 44.4-94.6, and 750.5:371.8-890.3 respectively. In non-BA patients, the median: IQR of Tbil (mg/dl), Dbil (mg/dl), MMP-7 (ng/ml), and GGT (U/L) were 5.9: 3.1-8.7, 2.5:1.1-4.9, 15.9: 11-20.4, and 143.5: 71-271.5 respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MMP-7 with the cutoff point 18.2 ng/ml as suggested in Pandurangi S et al. were 100%, 64.8%, 24.4%, and 100% respectively. Whereas the sensitivity, specificity, PPV, and NPV of GGT with age-specific reference upper limit were 90%, 39.3%, 15%, and 97% respectively. Conclusion The ranges of Tbil, Dbil, GGT, and MMP-7 are wide in both BA and non-BA patients. MMP-7 has higher sensitivity, specificity, PPV, and NPV compared to GGT, which indicates that MMP-7 is superior to GGT in association with BA diagnosis. GGT and MMP-7 when interpreted in the context of age-specific reference intervals, may yield cutoffs that serve the purpose of screening and diagnosis.