| disease | Neonatal Bilirubin Encephalopathy |
| alias | Bilirubin Encephalopathy, Kernicterus |
Bilirubin encephalopathy refers to pathological damage to brain tissue caused by bilirubin. The condition affects not only the basal ganglia, subthalamic nuclei, and globus pallidus, which become stained yellow, but also extends to the cerebral cortex, brain membranes, and vascular membranes. The term "jaundice" was previously used but is now considered insufficiently comprehensive. If prevention and treatment are inadequate, it may lead to sequelae or death.
bubble_chart Etiology
The onset of the disease is related to the chemical properties of bilirubin.
Unconjugated bilirubin not bound to albumin exists in a free state, with a small molecular weight that allows it to cross the blood-brain barrier (BBB). Once it enters brain cells, it can disrupt the coupling of mitochondrial oxidative phosphorylation, known as uncoupling. As a result, energy production in brain cells is inhibited, leading to cellular damage. Mirra et al. found that the permeability of the BBB increases with rising serum bilirubin levels. Bilirubin may reduce cell surface tension and exert toxic effects on the endothelial cell walls of cerebral capillaries, thereby increasing BBB permeability.
Unconjugated bilirubin bound to albumin forms a lipophilic albumin complex with a large molecular weight, which cannot pass through the BBB or cell membranes. However, recent studies suggest that under conditions such as hypoxia, infection, dehydration, hypoglycemia, acidosis, or hypertonic fluid infusion, the BBB may temporarily open, allowing large-molecule unconjugated bilirubin bound to albumin to enter brain tissue and affect broader areas. When the concentration of anions in the blood increases or pH decreases, it can also dissociate into free bilirubin, crossing cell membranes and entering phospholipid-rich nerve cells, leading to bilirubin encephalopathy.
Bilirubin conjugated with glucuronic acid in hepatocytes becomes water-soluble and can be excreted through the liver and kidneys, without causing bilirubin encephalopathy.Bilirubin encephalopathy almost exclusively occurs in the neonatal period, primarily due to the following factors:
1. Immature enzyme systems: Hepatocytes cannot effectively conjugate unconjugated bilirubin into conjugated bilirubin.
2. Severe hyperbilirubinemia: More commonly seen in conditions such as neonatal hemolytic disease, congenital non-hemolytic jaundice (Crigler-Najjar syndrome), and drug poisoning (e.g., vitamin K3), all of which can increase unconjugated bilirubin levels.
3. Poor BBB function: Unconjugated bilirubin easily crosses the BBB and binds to brain tissue, with preterm infants being even more vulnerable. Infections, asphyxia, and hypoxia can compromise the integrity of the BBB's barrier function.
4. Low plasma albumin levels: Limited capacity to bind unconjugated bilirubin.
5. Acidosis: Neonates are prone to acidosis, which can promote BBB opening and increase cellular uptake of bilirubin.
6. Displacement of albumin-bound bilirubin: Exogenous factors include sulfisoxazole, salicylates, sodium benzoate, novobiocin, cephalosporins, methicillin, and indomethacin. Endogenous factors include hemin, bile acids, and elevated free fatty acids due to starvation, hypoglycemia, or cold stress.
The severity of symptoms is related to factors such as serum unconjugated bilirubin concentration and postnatal age. It is generally divided into four stages:
**Warning Stage**: In younger infants, when serum bilirubin is around 256.5 μmol/L (15 mg/dl), symptoms are relatively mild, mainly manifesting as inhibitory signs such as drowsiness, refusal to feed, hypotonia, weakened or absent Moro reflex, etc. Some may also exhibit apnea or bradycardia. This stage lasts about half a day to a day before progressing to the convulsive stage.
**Stage of Convalescence**: Sucking and responsiveness gradually recover first, followed by improved breathing and reduced or resolved convulsions. This stage lasts about 2 weeks.
**Sequelae Stage**: Usually appears between 2 months and 3 years of age. Symptoms include athetosis (involuntary writhing movements), difficulty in upward gaze or strabismus, hearing impairment, and hypoplasia of tooth enamel (green or brownish teeth). The so-called "tetrad" primarily involves extrapyramidal system damage. Among 48 cases of kernicterus followed up in Shanghai from 835 cases of hemolytic disease, additional symptoms included intellectual disability, convulsions or clonus, poor head control, and drooling.
**Note**: Serum bilirubin levels may sometimes decrease when symptoms appear, possibly due to bilirubin uptake by tissues such as the central nervous system. Therefore, vigilance should not be relaxed based on this observation. Recent studies using brainstem auditory evoked potentials (BAEP) have found that some infants with serum bilirubin levels of 171–342 μmol/L (10–20 mg/dl) show no neurological symptoms but exhibit abnormalities such as the disappearance of waves IV and V or prolonged brainstem transmission time, indicating auditory nerve dysfunction. These changes disappear after bilirubin levels decline. Perlman (1988) termed this "transient subclinical bilirubin neurotoxicity," suggesting that such bilirubin-induced effects are reversible and gradually recover.
The purpose is to prevent serum unconjugated bilirubin from rising to dangerous levels. For methods, refer to the overview of jaundice. To ensure safe phototherapy, emergency measures must be taken immediately—without delay overnight—if symptoms of the warning phase of bilirubin encephalopathy or yellowing of the hands and feet are present. Early intervention is required for asphyxia, hypoxia, and acidosis, while avoiding cold exposure, hunger, and hypoglycemia. Displacing drugs should be prohibited or used with caution, and rapid intravenous injection of hypertonic drugs should be avoided. Prompt treatment of jaundice, along with phototherapy and exchange transfusion, has significantly reduced the incidence of sequelae and deaths caused by this condition in recent years.
Neonatal hyperbilirubinemia must be managed early to prevent the development of bilirubin encephalopathy.
1. Conduct prenatal examinations and health education to prevent premature labor, difficult delivery, and infections as much as possible. For those suspected of having hemolytic disease, prepare adequately for labor.
2. Postpartum: Avoid routine use of vitamin K3, sulfonamides, sodium benzoate coffee bean extract, and salicylates in newborns, especially premature infants. Jaundice detection must be taken seriously; experienced observers generally have an error margin of no more than 85.5 μmol/L (5 mg/dL). The Shanghai Neonatal Medical Engineering Professional Committee is researching a jaundice color comparison chart, which features five shades of yellow fixed on an acrylic board. By gently pressing the newborn's nose, the degree of jaundice can be assessed, enabling primary healthcare workers to detect neonatal jaundice early and roughly estimate serum bilirubin levels. It can also serve as a screening tool for hyperbilirubinemia and monitor its progression. In the absence of specialized tools, the extent of jaundice on the body surface can provide a rough estimate. Generally, mild facial jaundice is around 85.5 μmol/L (5 mg/dL), trunk jaundice about 171 μmol/L (10 mg/dL), limb jaundice approximately 256.5 μmol/L (15 mg/dL), and jaundice on the palms and soles exceeding 256.5 μmol/L. If the color shifts from apricot-yellow to golden-yellow, it often exceeds 342 μmol/L (20 mg/dL). Transcutaneous bilirubinometers are useful for dynamic observation of neonatal jaundice and screening for hyperbilirubinemia, but they are expensive and of limited value to experienced medical staff, as decisions regarding exchange transfusion still require micro-serum bilirubin measurements as the basis (Shanghai is also developing such tools).
