Indirect Bilirubin Crosses the Blood-Brain Barrier
Unconjugated (indirect) bilirubin is the form that crosses the blood-brain barrier, while conjugated (direct) bilirubin does not cross the intact blood-brain barrier. 1
Mechanism of Bilirubin Transport Across the BBB
Bilirubin transport across the blood-brain barrier follows specific mechanisms:
Albumin binding relationship: Bilirubin is transported in plasma tightly bound to albumin, but only the portion that is unbound or loosely bound can leave the intravascular space and cross the intact blood-brain barrier 1
Lipid solubility: Unconjugated bilirubin is lipophilic, allowing it to diffuse across the blood-brain barrier, while conjugated bilirubin is water-soluble and cannot readily cross 2
Unbound bilirubin (UB): Elevations of unbound bilirubin have been associated with kernicterus in preterm newborns and are more closely associated with abnormalities in audiometric brainstem response than total serum bilirubin levels 1
Clinical Implications
The ability of unconjugated bilirubin to cross the BBB has significant clinical implications:
Risk Factors for Neurotoxicity
Bilirubin/Albumin (B/A) ratio: The ratio of bilirubin (mg/dL) to albumin (g/dL) correlates with measured unbound bilirubin in newborns and can be used as an approximate surrogate for UB measurement 1
Albumin binding capacity: Both albumin levels and the ability of albumin to bind bilirubin vary significantly between newborns, with binding impaired in sick infants 1
BBB disruption: Conditions that disrupt the blood-brain barrier integrity (like inflammation) can increase bilirubin entry into the brain 1
Neurological Effects
Acute effects: High levels of unconjugated bilirubin in the brain can cause measurable transient changes in brainstem-evoked potentials, behavioral patterns, and infant cries at total serum bilirubin (TSB) levels of 15-25 mg/dL 1
Chronic effects: Long-term adverse neurodevelopmental effects may occur with hyperbilirubinemia, though studies on this are limited and conflicting 1
Kernicterus: The most severe form of bilirubin-induced neurological dysfunction occurs when unconjugated bilirubin accumulates in brain tissue, causing permanent neurological damage 3
Protective Mechanisms
The brain has several mechanisms to protect against bilirubin toxicity:
Retro-transfer: Clearance of bilirubin from brain partly involves retro-transfer through the blood-brain barrier back into circulation 4
Metabolic detoxification: Bilirubin can be metabolized in the brain by enzymes located on the inner mitochondrial membrane that oxidize bilirubin at a rate of 100-300 pmol/mg protein/minute 4
Transporter activity: ABC transporters (particularly P-glycoprotein) at the BBB may help limit bilirubin entry into the brain by functioning as efflux pumps 5
Management Implications
Understanding which form of bilirubin crosses the BBB informs clinical management:
Monitor unbound bilirubin: When possible, measuring unbound bilirubin provides better assessment of neurotoxicity risk than total bilirubin alone 1
B/A ratio consideration: Using the bilirubin-to-albumin ratio together with TSB levels can help determine the need for intervention 1
Treatment thresholds: The American Academy of Pediatrics recommends phototherapy for term and near-term infants with TSB levels reaching specific thresholds (≥15 mg/dL at 25-48 hours, ≥18 mg/dL at 49-72 hours, ≥20 mg/dL after 72 hours) 3
Exchange transfusion: This is considered a medical emergency when TSB ≥25 mg/dL, as these levels significantly increase the risk of bilirubin crossing the BBB 3
Conclusion
The clinical importance of understanding bilirubin transport across the BBB cannot be overstated. Since unconjugated (indirect) bilirubin is the form that crosses the BBB and causes neurotoxicity, clinical management focuses on preventing excessive levels of unbound unconjugated bilirubin in circulation, particularly in vulnerable populations like neonates.