What type of bilirubin causes kernicterus?

Unconjugated Bilirubin Causes Kernicterus

Kernicterus is caused by unconjugated (indirect) bilirubin, which can cross the blood-brain barrier and damage neuronal tissues in the central nervous system. 1, 2

Pathophysiology of Kernicterus

Unconjugated bilirubin is the toxic form of bilirubin that can lead to kernicterus through the following mechanisms:

• Blood-brain barrier penetration: Unconjugated bilirubin, being lipid-soluble, can cross the blood-brain barrier and enter neuronal tissues 2
• Neuronal damage: Once in the brain, unconjugated bilirubin selectively damages vulnerable target brain cells including:
  • Basal ganglia
  • Cerebellum
  • Auditory system 2
• Mitochondrial damage: Unconjugated bilirubin causes damage to the mitochondria in neuronal cells 1
• Oxidative stress: High levels of unconjugated bilirubin induce oxidative stress leading to DNA damage in the cerebellum 3

Clinical Relevance

Understanding that unconjugated bilirubin causes kernicterus is critical because:

1. Prevention strategies: Phototherapy works by converting unconjugated bilirubin to water-soluble photoisomers that can be excreted without conjugation 4

   • Blue-green light (460-490 nm) with an optimal peak of 478 nm is most effective
   • Phototherapy transforms unconjugated bilirubin into excretable water-soluble forms:
     • 4E,15Z photoisomer (majority)
     • 4Z,15E photoisomer (about 20%)
     • Lumirubin (about 5%)

2. Risk assessment: Identifying conditions that increase unconjugated hyperbilirubinemia is essential:

   • Hemolytic disorders (blood group incompatibility, G6PD deficiency)
   • Genetic disorders like Crigler-Najjar syndrome type I 4
   • Prematurity (35-36 weeks gestational age) 4
   • East Asian race 4
   • Exclusive breastfeeding with poor feeding and excessive weight loss 4

3. Monitoring: Total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) measurements are used to assess risk 4

   • Plotting results on a nomogram helps identify infants at high risk for developing severe hyperbilirubinemia

Clinical Manifestations

Kernicterus spectrum disorder presents with:

• Motor-predominant kernicterus: Choreoathetoid cerebral palsy
• Auditory neural sensory dysfunction: Sensorineural hearing loss
• Subtle kernicterus: Cognitive impairment
• Kernicterus plus: Combined manifestations 2, 5

Prevention and Management

To prevent kernicterus:

1. Risk assessment: Before discharge, assess every newborn for risk of developing severe hyperbilirubinemia 4

   • Measure TSB or TcB levels
   • Assess clinical risk factors

2. Phototherapy: Initiate when TSB reaches threshold levels based on age and risk factors 6

   • ≥15 mg/dL at 25-48 hours of age
   • ≥18 mg/dL at 49-72 hours of age
   • ≥20 mg/dL after 72 hours of age

3. Exchange transfusion: Consider when TSB approaches exchange transfusion threshold despite intensive phototherapy or signs of acute bilirubin encephalopathy are present 6

4. Liver transplantation: For conditions with permanent defects in bilirubin metabolism:

   • Crigler-Najjar syndrome type I requires liver transplantation before the development of brain damage 4

Important Considerations

• Drug interactions: Some medications can displace bilirubin from albumin, increasing free unconjugated bilirubin that can cross the blood-brain barrier 1
• Early recognition: Prompt intervention is crucial to prevent progression to kernicterus 6
• Long-term follow-up: Patients with history of severe hyperbilirubinemia require monitoring for neurological sequelae

Understanding that unconjugated bilirubin is the culprit in kernicterus guides appropriate prevention, monitoring, and treatment strategies to protect vulnerable newborns from this devastating but preventable neurological condition.