Differential Diagnosis of Neonatal Hyperbilirubinemia
The differential diagnosis for neonatal hyperbilirubinemia must first distinguish between unconjugated (indirect) and conjugated (direct) hyperbilirubinemia, as this fundamentally changes the diagnostic approach and urgency of evaluation. 1
Initial Classification
Measure both total and direct/conjugated bilirubin levels immediately to categorize the hyperbilirubinemia, as conjugated hyperbilirubinemia (direct bilirubin >1.0 mg/dL when TSB ≤5 mg/dL) indicates serious hepatobiliary disease requiring urgent evaluation. 1, 2
Unconjugated (Indirect) Hyperbilirubinemia Differentials
Hemolytic Causes (Most Critical)
ABO incompatibility: Most common immune-mediated hemolysis, occurs when mother is type O and infant is type A or B with positive direct antiglobulin test (DAT). 1, 3, 4
Rh (D) incompatibility: Less common now due to RhoGAM prophylaxis, but causes severe hemolysis when present. 1, 3
G6PD deficiency: Occurs in 11-13% of African Americans and 31.5% of kernicterus cases in one series; causes sudden, dramatic TSB increases and requires lower treatment thresholds. 1 Critical caveat: G6PD levels may be falsely elevated during active hemolysis, so a normal level does not rule out deficiency—repeat testing at 3 months if strongly suspected. 1
Other blood group incompatibilities: Minor blood group antigens (Kell, Duffy, etc.) can cause hemolysis. 3
Increased Bilirubin Production (Non-Immune)
Cephalohematoma or significant bruising: Extravascular blood breakdown increases bilirubin load. 1, 3
Polycythemia: Increased red cell mass from delayed cord clamping, twin-twin transfusion, or maternal-fetal transfusion. 3
Birth trauma: Bruising, intracranial hemorrhage. 4
Decreased Bilirubin Conjugation/Excretion
Breastfeeding jaundice: Poor intake in first 3-5 days leads to dehydration and decreased bilirubin excretion; associated with excessive weight loss (>10%), fewer than 4-6 wet diapers daily, and fewer than 3-4 stools by day 4. 1, 3
Breast milk jaundice: Peaks at 10-14 days, caused by substances in breast milk that inhibit bilirubin conjugation; diagnosis of exclusion after ruling out pathologic causes. 3, 5
Prematurity/late preterm (35-36 weeks): Immature hepatic conjugation and increased enterohepatic circulation. 1, 3, 4
Gilbert syndrome: Genetic polymorphism in UGT1A1 gene causing reduced conjugation capacity. 3, 5
Crigler-Najjar syndrome: Rare, severe deficiency of UGT1A1 enzyme; Type I is life-threatening, Type II responds to phenobarbital. 5
Increased Enterohepatic Circulation
Intestinal obstruction: Pyloric stenosis, intestinal atresia, Hirschsprung disease delay meconium passage. 5
Delayed passage of meconium: Increases bilirubin reabsorption from gut. 5
Metabolic/Endocrine Causes
Hypothyroidism: Decreased metabolic clearance of bilirubin. 2, 4
Galactosemia: Causes both unconjugated and conjugated hyperbilirubinemia; life-threatening if not identified. 2
Infant of diabetic mother: Polycythemia and delayed hepatic maturation. 1, 4
Infection (Sepsis)
Bacterial sepsis: Causes hemolysis and hepatic dysfunction. 4
TORCH infections: Toxoplasmosis, rubella, CMV, herpes, syphilis can cause both unconjugated and conjugated hyperbilirubinemia. 4
Conjugated (Direct) Hyperbilirubinemia Differentials
Any conjugated hyperbilirubinemia is pathologic and requires urgent evaluation for cholestasis and hepatobiliary disease. 1, 2
Biliary Obstruction
Biliary atresia: Progressive obliteration of extrahepatic bile ducts; requires surgical intervention (Kasai procedure) ideally before 60 days of life. 2
Choledochal cyst: Congenital cystic dilatation of bile ducts. 2
Inspissated bile syndrome: Bile duct obstruction from thickened bile, often in hemolytic disease. 2
Hepatocellular Disease
Neonatal hepatitis: Idiopathic or infectious (CMV, herpes, hepatitis B). 2
Metabolic disorders: Alpha-1 antitrypsin deficiency, tyrosinemia, galactosemia. 2
Total parenteral nutrition (TPN)-associated cholestasis: Prolonged TPN use. 2
Genetic/Syndromic
Alagille syndrome: Paucity of intrahepatic bile ducts with characteristic facies and cardiac defects. 2
Progressive familial intrahepatic cholestasis (PFIC): Genetic defects in bile transport. 2
Risk Stratification by Clinical Context
Major Risk Factors for Severe Hyperbilirubinemia (in order of importance):
- Predischarge TSB in high-risk zone (>95th percentile on Bhutani nomogram). 1
- Jaundice observed in first 24 hours of life. 1
- Blood group incompatibility with positive DAT or known hemolytic disease. 1
- Gestational age 35-36 weeks. 1
- Previous sibling who received phototherapy. 1
- Cephalohematoma or significant bruising. 1
- Exclusive breastfeeding with poor intake and excessive weight loss. 1
- East Asian ethnicity. 1, 3
Rapid Rate of Rise Suggests Hemolysis
A TSB rise ≥0.3 mg/dL per hour in first 24 hours or ≥0.2 mg/dL per hour thereafter is exceptional and strongly suggests ongoing hemolysis requiring immediate investigation. 1
Clinical Approach Algorithm
Measure total and direct/conjugated bilirubin on all jaundiced neonates. 1, 2
If conjugated bilirubin elevated (>1.0 mg/dL when TSB ≤5 mg/dL): Urgent hepatobiliary workup including liver function tests, viral studies, metabolic screening, and hepatobiliary imaging. 1, 2
If unconjugated hyperbilirubinemia predominates:
If jaundice persists beyond 3 weeks: Remeasure total and direct bilirubin to rule out cholestasis, as physiologic jaundice resolves by 1-2 weeks in term infants. 2