Kernicterus - Mechanisms
Kernicterus
Mechanisms
In order for bilirubin to cause brain damage, it must first gain entry into the brain. The factors that govern this process are:
- serum concentrations of bilirubin and albumin
- bilirubin binding by albumin
- status of the blood-brain barrier
- susceptibility of the CNS
It is also clear that bilirubin is produced in situ in the brain, by the same heme degradation reactions as elsewhere. Recent animal studies have identified a bilirubin oxidase system in the brain. This may be important in protecting the brain from in situ bilirubin production. Normally, this locally produced bilirubin is metabolized or transported out of the brain. However damage to these mechanisms, leading to elevated brain bilirubin levels, may play a role in the development of kernicterus in some patients. Additionally, heme degradation in the brain produces, along with bilirubin, carbon monoxide which may act locally as a neurotoxin in some patients.While the exact cellular mechanism of neuronal injury by bilirubin is unknown, animal studies show extensive impairment of cellular function in bilirubin toxicity. Especially important seems to be injury to cellular membranes. A proposed sequence of events is as follows: unconjugated or "free" bilirubin binds to phospholipids on the cell membrane. The bilirubin anion takes up hydrogen ions and forms aggregates of bilirubin acid, still bound to the cell membrane. This bilirubin acid is highly toxic to the membrane and injury to it enhances entry of bilirubin into the cell. Once in the cell, bilirubin binds to membrane phospholipids of subcellular organelles, such as mitochondria and endoplasmic reticulum. There a similar process leads to membrane damage, organelle injury and enzyme system dysfunction.Return to top of page