Bilirubin is a yellow-orange compound that forms as a natural byproduct of the body’s process of breaking down old red blood cells. This process occurs in the spleen, where hemoglobin from these cells is converted into bilirubin. At this stage, it is known as unconjugated bilirubin, a substance that is not water-soluble.
To be transported through the bloodstream, this unconjugated bilirubin binds to a protein called albumin. This complex is then carried to the liver for metabolism. Inside the liver, an enzyme transforms it into conjugated bilirubin, a water-soluble form that allows the body to excrete it.
The conjugated bilirubin is secreted from the liver into the bile and travels to the small intestine. In the colon, gut bacteria convert it into pigments, primarily stercobilin, which gives feces its brown color. A small amount is reabsorbed and excreted in the urine as urobilin, contributing to urine’s yellow color. This system ensures bilirubin is safely removed, but high levels can become a concern for the brain.
The Pathway of Bilirubin to the Brain
The brain is protected by the blood-brain barrier (BBB), a selective network of blood vessels and cells that regulates the passage of substances from the bloodstream into brain tissue. Unconjugated bilirubin, which is soluble in lipids rather than water, can diffuse across the cellular membranes that constitute the BBB.
If the concentration of unconjugated bilirubin becomes too high, it can overwhelm albumin’s binding capacity. This results in an increase in “free” bilirubin that can more readily enter the brain.
The risk of bilirubin crossing the BBB is magnified by conditions that compromise the barrier’s integrity, such as systemic infections, acidosis, hypoxia, and hyperosmolality. These conditions weaken the barrier’s cellular connections, increasing its permeability.
Newborns, and particularly premature infants, are uniquely vulnerable to this process. Their BBB is not yet fully mature, making it more permeable than an adult’s. Their livers are also less efficient at conjugating bilirubin, and a rapid turnover of red blood cells after birth releases large amounts of bilirubin.
Neurological Impact of Excess Bilirubin
Once unconjugated bilirubin crosses the blood-brain barrier, it can damage brain cells, including neurons and glial cells. Bilirubin is neurotoxic in several ways. It disrupts the function of mitochondria, leading to a failure in the cell’s energy supply, and triggers oxidative stress, which damages cellular components.
The presence of bilirubin in the brain incites an inflammatory response and can lead to excitotoxicity, where nerve cells are damaged by overstimulation. These events can culminate in apoptosis, or programmed cell death, causing irreversible loss of brain cells. This spectrum of brain injury is termed bilirubin-induced neurologic dysfunction (BIND).
This dysfunction manifests in two primary forms. Acute Bilirubin Encephalopathy (ABE) is the acute illness that occurs in the initial stages of toxicity. If untreated, ABE can lead to Chronic Bilirubin Encephalopathy, or kernicterus, a permanent condition with specific patterns of brain damage. Certain brain regions are particularly susceptible, including the basal ganglia, cerebellum, hippocampus, and auditory nuclei in the brainstem.
Recognizing Bilirubin-Induced Brain Injury
The clinical signs of bilirubin-induced brain injury evolve as the condition progresses. The initial phase of Acute Bilirubin Encephalopathy (ABE) is marked by subtle symptoms, including significant lethargy, difficulty with feeding, a weak suck, reduced muscle tone (hypotonia), and a high-pitched cry.
Without intervention, the infant may enter an intermediate phase. During this stage, the infant becomes more irritable and develops hypertonia, where muscles become rigid. This can lead to arching of the back (opisthotonus) and neck (retrocollis), often accompanied by a fever. The advanced stage of ABE has severe symptoms, including seizures, apnea (periods where breathing stops), and progression into a comatose state.
Untreated toxicity can lead to the chronic neurological impairments of kernicterus. The damage results in a set of lasting issues, including:
- Motor problems such as athetoid cerebral palsy, characterized by involuntary writhing movements, and dystonia, which involves sustained muscle contractions.
- Auditory dysfunction, ranging from sensorineural hearing loss to auditory neuropathy spectrum disorder.
- Oculomotor impairments, particularly a paralysis of upward gaze.
- Dental enamel dysplasia, the abnormal development of the enamel on the baby teeth.
To assess the risk and confirm the diagnosis, clinicians monitor serum bilirubin levels and perform neurological exams. Specific tests like the Brainstem Auditory Evoked Response (BAER) check the auditory pathway. An MRI can reveal characteristic changes in the brain’s deep gray matter.
Strategies for Treatment and Prevention
The goal of management is to quickly reduce blood bilirubin levels to prevent brain damage. The most common treatment for neonatal jaundice is phototherapy. This procedure exposes the infant’s skin to specific wavelengths of blue light, which converts bilirubin into water-soluble isomers that can be excreted without needing liver conjugation.
In cases where bilirubin levels are dangerously high or rising rapidly despite phototherapy, an exchange transfusion may be required. This procedure replaces small amounts of the infant’s blood with donor blood. This process directly removes bilirubin and also eliminates antibodies that may be causing excessive breakdown of red blood cells.
Intravenous immunoglobulin (IVIG) can be administered in cases of Rh or ABO blood group incompatibility between the mother and infant. IVIG is thought to work by blocking the antibody receptors on red blood cells, thereby reducing their destruction.
Prevention focuses on systematic screening of all newborns for jaundice before they are discharged from the hospital. Early identification allows for prompt monitoring and timely treatment, preventing bilirubin from reaching neurotoxic levels.