Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia

Abstract

Objectives: To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life.

Study design: Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB <2.0, all others TB ≥ 2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression.

Results: Fifty percent (68/137) of infants had TB < 2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB < 2.0 group vs TB ≥ 2 (86% vs 20%, P < .0001). Infants with TB ≥ 2 had diminished weight gain (P < .0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9-14.1, P < .0001), hypoalbuminemia (OR 7.6, 95% CI 3.2-17.7, P < .0001), coagulopathy (OR 10.8, 95% CI 3.1-38.2, P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P < .0001), or LT or death (OR 16.8, 95% CI 7.2-39.2, P < .0001).

Conclusions: Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes.

Trial registration: ClinicalTrials.gov: NCT00061828 and NCT00294684.

Figure 1

Kaplan-Meier estimate and its 95% confidence interval for onset of specific clinical outcomes beginning 3 months after HPE in children who did (blue dashed lines) or who did not achieve a TB < 2.0 mg/dL (red solid lines) in the first 3 months. Curves represent probability of remaining free of the clinical outcome. Rapid and clear differences were observed for thrombocytopenia (A), hypoalbuminemia (B), ascites (C), and death or liver transplant (D). Time zero is the time of the HPE. Secondary lines surrounding primary data lines indicate 95% confidence limits.

Figure 2

Growth curves plotting weight z-score (panel A) and length z-score (panel B) vs. time since HPE. Blue solid lines (subjects who achieved a TB < 2.0 mg/dL in the first 3 months after HPE) and red dashed lines (subjects who did not achieve a TB < 2.0 mg/dL) represent the average value over time and its 95% confidence intervals. The apparent improved length z-score after 1 year (dashed line) was due to censoring of those who died or underwent LT.

Figure 3

online. Trends in TB over time for children who achieved a TB < 2.0 mg/dL in the first 3 months after HPE (panel A) compared to those who did not (panel B). Solid bold lines represent the average value over time (dotted lines 95% confidence intervals). Gray open circles and lines in both panels represent bilirubin trajectories for individual subjects. Horizontal dashed line indicates a TB of 2.0 mg/dL. BA infants generally maintain their group assignment defined at 3 months post-HPE. The trajectories of those that changed status after 3 months post-HPE are seen in panel C.

Figure 4

If the TB is found to be less than 2 mg/dL (34.2 μM) in the first three months, routine follow-up for BA is recommended. If not, heightened nutritional monitoring and supplementation, anticipatory guidance for potential complications of advanced liver disease and liver transplant evaluation is recommended. If in the subsequent three months the TB is found to be less than 1.5 mg/dL, candidacy for liver transplantation should be reassessed in the context of the clinical status of the infant.