What are the causes and treatments of elevated unconjugated bilirubin?

Causes of Elevated Unconjugated Bilirubin

Elevated unconjugated bilirubin results from three primary mechanisms: increased bilirubin production (hemolysis), impaired hepatic uptake/conjugation, or increased enterohepatic circulation, with hemolytic causes and physiological jaundice being most common in neonates.

Pathophysiologic Categories

Increased Bilirubin Production (Hemolysis)

• Blood group incompatibilities including ABO and Rh isoimmunization cause fetal blood hemolysis when maternal antibodies cross the placenta and attack fetal red blood cells 1
• G6PD deficiency occurs in 11-13% of African Americans and was identified as the cause of hyperbilirubinemia in 31.5% of infants who developed kernicterus in one series 2
• Hemolytic disorders from red blood cell membrane defects (hereditary spherocytosis, elliptocytosis) or enzyme deficiencies increase bilirubin production 3
• Cephalohematoma and bruising from birth trauma release additional hemoglobin for breakdown into bilirubin 2

Impaired Hepatic Conjugation

• Physiological jaundice represents the most prevalent type, resulting from normal adaptation of bilirubin metabolism in the neonatal period with immature hepatic conjugation systems 4, 3
• Gilbert syndrome causes mild chronic unconjugated hyperbilirubinemia due to reduced UDP-glucuronosyltransferase activity 3
• Crigler-Najjar syndrome (Type I and II) results from severe deficiency or absence of bilirubin conjugating enzymes 3
• Hypothyroidism impairs hepatic bilirubin conjugation and should be evaluated in infants with jaundice present at or beyond 3 weeks of age 2

Increased Enterohepatic Circulation

• Breastfeeding jaundice occurs when inadequate intake leads to decreased stool output and increased bilirubin reabsorption from the intestine 1
• Breast milk jaundice develops from substances in breast milk that inhibit bilirubin conjugation or increase intestinal reabsorption 1
• Intestinal obstruction or delayed passage of meconium increases enterohepatic circulation of bilirubin 3

Critical Risk Factors for Severe Hyperbilirubinemia

High-Risk Clinical Features

• Jaundice in the first 24 hours always requires immediate TSB or TcB measurement, as this is never physiological 2
• Family history of neonatal jaundice, exclusive breastfeeding, gestational age less than 38 weeks, and male sex increase risk 2
• Asian or Black ethnicity, maternal age older than 25 years, and G6PD deficiency are additional risk factors 2

Assessment of Breastfeeding Adequacy

• Weight loss exceeding 10% by day 3 suggests inadequate intake and requires evaluation 2
• Fewer than 4-6 wet diapers in 24 hours or failure to pass 3-4 stools per day by the fourth day indicates inadequate breastfeeding 2
• Failure of stool transition from meconium to mustard yellow, mushy stool by days 3-4 suggests insufficient intake 2

Treatment Approach Based on Severity

Phototherapy Indications

• Treatment thresholds depend on the infant's age in hours and presence of risk factors, with intervention recommended at lower TSB levels in younger infants to prevent further increases 2
• Phototherapy effectively reduces TSB levels but carries potential harms including weight loss, gastrointestinal problems, interruption of breastfeeding, and possible growth of melanocytic nevi 2
• Infants with G6PD deficiency require intervention at lower TSB levels due to risk of sudden increases in bilirubin 2

Exchange Transfusion

• Reserved for severe hyperbilirubinemia when TSB approaches exchange levels or fails to respond to phototherapy 2
• Significant morbidity (apnea, bradycardia, cyanosis, vasospasm, thrombosis, necrotizing enterocolitis) occurs in up to 5% of exchange transfusions 2
• Mortality risk is approximately 3 per 1000 procedures, though likely lower in otherwise healthy term infants 2

Albumin and Bilirubin/Albumin Ratio Considerations

• Unbound bilirubin more readily crosses the blood-brain barrier and correlates with kernicterus risk in sick preterm newborns 2
• B/A ratio can be used as an approximate surrogate for unbound bilirubin measurement when considering exchange transfusion, though albumin binding varies significantly between newborns 2
• Clinical option to use B/A ratio together with, but not in lieu of, TSB level as an additional factor in determining need for exchange transfusion 2

Critical Diagnostic Pitfalls

Laboratory Evaluation Requirements

• Direct/conjugated bilirubin must be measured if TSB is rising rapidly, infant is receiving phototherapy, or jaundice persists beyond 3 weeks 2
• If TSB ≤5 mg/dL, a direct or conjugated bilirubin >1.0 mg/dL is abnormal and requires evaluation for cholestasis 2
• G6PD levels can be falsely elevated during hemolysis, potentially obscuring the diagnosis; repeat testing at 3 months of age is necessary if deficiency is strongly suspected 2
• Capillary versus venous sampling: obtaining venous samples to "confirm" elevated capillary TSB is not recommended as it delays treatment initiation 2

Timing and Follow-up

• All bilirubin levels must be interpreted according to the infant's age in hours, not days 2
• Visual estimation of bilirubin levels from degree of jaundice leads to errors, particularly in darkly pigmented infants 2
• Predischarge risk assessment using TSB/TcB measurement plotted on hour-specific nomograms identifies infants at risk for subsequent severe hyperbilirubinemia 2