Factors Determining δ-Bilirubin Levels in Infants With Biliary Atresia

Abstract

Objectives: δ-Bilirubin (Bδ) forms when bilirubin conjugates covalently bind to albumin by way of nonenzymatic transesterification in patients with cholestasis. Infants with cholestasis with biliary atresia form Bδ. The aim of the present study was to investigate the factors determining serum Bδ concentrations in infants with biliary atresia.

Methods: Study patients were infants enrolled in a prospective study (PROBE: Clinicaltrials.gov NCT00061828) of biliary atresia. We acquired data of concurrently measured serum bilirubin analytes (total bilirubin [TB], conjugated bilirubin [Bc], and unconjugated bilirubin) and applied graphical methods and linear mixed effects model to study factors contributing to Bδ variability.

Results: Bδ level increased with increasing levels of Bc and TB. In addition, the length of time cholestasis persisted partially determined the level of Bδ. An increase of 1 mg/dL in Bc is related to approximately 0.36 mg/dL increase in Bδ (P < 0.0001); every 100 days of cholestasis is associated with an approximately 1.0 mg/dL increase in Bδ (P < 0.0001) given the same level of Bc. Serum albumin levels are not significantly related to Bδ (P = 0.89).

Conclusions: Bδ levels in infants with biliary atresia increase with increasing levels of Bc and longer duration of cholestasis. Understanding the relation among Bδ, Bc, TB, and direct-reacting bilirubin levels can help in interpretation of the clinical extent of cholestasis in infants and children with biliary atresia, assisting in the diagnosis and management of these infants.

Figure 1. Bδ and other bilirubin species

A) Dot-dash line is the 45 degree line which indicates the complete identity of values on horizontal and vertical axes. Solid line is the estimated mean of Bc+Bu using LOESS regression. B) Solid line is the estimated mean of Bδ using LOESS regression. Dotted lines are the 95% confidence interval of the predicted mean. Dashed lines are the 95% prediction interval.

Figure 2. Bδ and Bδ/TB and time in subjects with poor drainage after Kasai surgery

Circles and solid line – around time of Kasai (2 weeks before to 1 days after Kasai); triangles and dashed line – 2 days to 3 months after Kasai; cross and dotted line – 3 months to 6 months after Kasai;×and dashed and dotted line – 6 months to 1 year after Kasai. All lines are estimated mean of Bδ using linear regression by time windows. B) Grey dotted shows individual trajectories. Solid line is the estimated mean of Bδ/TB using LOESS regression. Dashed line is the estimated mean of Bδ/TB using joint model of longitudinal and survival data for adjusting informative dropout.

Figure 3. Bδ and Albumin

Black solid line is the predicted mean value of Bδ using LOESS regression. Dotted lines are the 95% confidence intervals of the predicted mean of Bδ. Dashed lines are the 95% prediction interval of Bδ.