• Information
  1. Epidemiology
  2. Normal Bilirubin Metabolism
  3. Etiology of Indirect Hyperbilirubinemia
  4. Etiology of Direct Hyperbilirubinemia
  5. Other Risks for Neonatal Hyperbilirubinemia (Table 1)
  6. Symptoms and Complications
  7. Laboratory Evaluation
  8. Therapy

A. Epidemiology

1. 25-50% of term infants develop clinical jaundice
2. Clinical jaundice appears when serum bilirubin > 7 mg/dL
3. 3% of term newborns develop serum levels above 15 mg/dL
4. Peak bilirubin in breast fed infants are higher than in bottle fed infants
5. Gestational age < 37 weeks greatly increases risk of hyperbilirubinemia
6. Divided into indirect (unconjugated) and direct (conjugated) hyperbilirubinemia
7. Most severe sequellae is kernicterus (deposition in brain), usually with levels >30mg/dL

B. Normal Bilirubin Metabolism

1. Most bilirubin from hemoglobin breakdown from red blood cells (RBC)
2. RBC destroyed by senscence (physiologic) or hemolysis (pathologic)
3. Heme moiety is degraded by heme oxygenase yielding:
   1. Biliverdin (green pigment)
   2. Carbon monoxide (which can be measure in neonatal expiratory breaths)
4. Biliverdin is reduced to bilirubin by biliverdin reductase
5. Bilirubin enters the liver and normally undergoes conjugation so it can be excreted
6. Conjugated bilirubin enters intestinal lumin
7. Bacteria can deconjugate bilirubin in the intestine leading to reabsorption
8. This liver-intestine cycle is called enterohepatic recirculation

C. Etiology of Indirect Hyperbilirubinemia

1. Physiologic
   1. Newborns have increased bilirubin production and reduced excretory capacity
   2. Overproduction is due primarily to hemolysis of senscent RBC
   3. Conjugation systems are reduced
   4. Immature uridine diphosphate glucoronyl transferase enzyme
   5. Breast milk feeding
   6. Increased reabsorption (enterohepatic) from sterile GI tract
2. Pathologic
   1. Hemoglobinopathies with increased hemolysis
   2. Sepsis
   3. Rh or ABO incompatability
   4. Various drugs
   5. Hypothyroidism
   6. Defective bilirubin metabolic systems: Gilbert's and Crigler-Najjar Syndromes
   7. Galactosemia
3. Drugs
   1. Aspirin
   2. Sulfonamides
   3. Furosemide
   4. Chloral hydrate
4. Defective Bilirubin Metabolism
   1. Gilbert's Syndrome: deficient hepatic uptake of bilirubin
   2. Deficiency of urinidine diphosphate glucuronyl transferase (Crigler-Najjar Syndromes)
   3. Crigler-Najjar Syndrome I is complete deficiency UDP-GT (may be fatal)
   4. Crigler-Najjar Syndrome II is partial deficiency of UDP-GT (less severe than Type I)

D. Etiology of Direct Hyperbilirubinemia

1. Defined as > 2 mg/dL or > 20% of total bilirubin
2. Viral hepatitis: EBV, CMV, Hepatitis Viruses, Rubella, HSV, Coxsackie
3. Other infection: toxoplasmosis, syphilis
4. Biliary Obstruction
   1. Biliary atresia
   2. Choledochal cysts
   3. Common duct stone
   4. Obstructing tumor or mass
5. Metabolic
   1. Galactosemia
   2. alpha-1-Antitrypsin Deficiency
   3. Cystic fibrosis
   4. Niemann Pick Disease,
   5. Gaucher disease
   6. Glycogen storage diseases
6. Miscellaneous
   1. Alagille syndrome
   2. Byler Syndrome
   3. Hypopituitarism
   4. Parenteral nutrition

E. Other Risks for Neonatal Hyperbilirubinemia (Table 1, Ref [1])

1. Maternal Risk Factors
   1. Asian, Native American, Greek Islander
   2. Diabetes mellitus, Rh or ABO incompatibility
   3. Use of oxytocin in hypotonic solutions during labor
   4. Breast Feeding
2. Perinatal Risk Factors
   1. Birth trauma: cephalhematoma, ecchymoses
   2. Infection: bacterial, viral, protozoal
3. Additional Neonatal Risk Factors
   1. Prematurity
   2. Genetic Factors: bilirubin metabolism, RBC abnormalities
   3. Polycythemia
   4. Low intake of breast milk ("early onset breast milk jaundice)
   5. Hypoalbuminemia

F. Symptoms and Complications

1. Mean indirect bilirubin which causes dermal icterus by zone:
   1. Head >5.9 mg/dL
   2. Chest and arms >8.9 mg/dL
   3. Pelvis >11.8 mg/dL
   4. Legs >15 mg/dL
   5. Hands and feets >15 mg/dL
2. Kernicterus [2]
   1. Deposition in basal ganglia, cerebrum and cerebellum, cerebellum
   2. Lethargy, irritability, hypotonia, opisthonus
   3. Seizures, mental retardation, hearing loss
   4. Usually associated with bilirubin >30mg/dL
   5. Neurologic or behavioral sequellae not found with bilirubin 25-30mg/dL [2]
3. Ictometer or transcutaneous jaundice meter can approximate bilirubin levels
4. Complications of Indirect Hyperbilirubinemia
   1. Lipid soluble indirect bilirubin can cross the immature blood brain barrier
   2. Then deposit in brain tissue increasing risk for kernicterus
   3. Bilirubin <30mg/dL is not associated with neurodevelopmental symptoms [2]
5. Complications of Direct Hyperbilirubinemia: severe permanent liver damage can result

G. Laboratory Evaluation

1. Normal Bilirubin and Pathologic Jaundice
   1. Normal full term infant 5-6mg/dL
   2. Exaggerated physiologic jaundice occurs at 7-17mg/dL
   3. Pathologic Jaundice >17mg/dL
2. Evaluate based on whether serum direct or indirect bilirubinemia exists
3. Evaluation of Indirect Hyperbilirubinemia
   1. Complete blood count (CBC) with differential
   2. Peripheral blood smear
   3. Reticulocyte count
   4. Determination of maternal and fetal blood types
   5. Coomb's test (direct and indirect)
   6. Blood culture
   7. Galactose-1-uridyltransferase
   8. Thyroid function tests
4. Evaluation of Direct Hyperbilirubinemia
   1. Liver function tests (LFT)
   2. PT and PTT
   3. Titers for TORCH, HBSAg, syphilis (VDRL)
   4. alpha-1-antitrypsin level
   5. Sweat test for cystic fibrosis
   6. Right upper quadrant ultrasound
   7. Radionucleotide biliary imaging
   8. Liver biopsy
5. Measurement of bilirubin by transcutaneous noninvasive methods now available
6. Exhaled carbon monoxide levels correlate well with bilirubin levels in newborns and adults

H. Therapy

1. Phototherapy
   1. Converts indirect bilirubin to water soluble photo-isomers
   2. These water soluble isomers can be excreted
   3. Initiate phototherapy at bilirubin levels shown in table below
2. Exchange Transfusion
   1. Directly removes bilirubin from intravscular space
   2. Initiate exchange
3. Bilirubin Levels Triggering Phototherapy or Exchange Transfusion

   Birth Weight	Phototherapy	Exchange transfusion
   <1000gm	5-6 mg/dL	10-12 mg/dL
   1000-1500	7-9	12-15
   1500-2000	10-12	15-20
   2000-1500	10-12	>20-25
   >2500	12-15	>20-25

4. Discontinue Phototherapy
   1. When bilirubin has fallen below initiation level
   2. Expect average rebound of 1 mg/dL
5. Continue breast feeding
6. Protophorphysin
   1. Inhibits heme oxygenase
   2. Can be used to treat Coombs positive hemolysis
7. Phenobarbital is occasionally used in mothers prior to induce bilirubin conjugation / excretion
8. Direct Hyperbilirubinemia: appropriate medical or surgical management

References

1. Dennery PA, Seidman DS, Stevenson DK. 2001. NEJM. 344(8):581
2. Newman TB, Liljestrand P, Jeremy RJ, et al. 2006. NEJM. 354(18):1889