Kernicterus Unconjugated Bilirubin

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Hervieuxfirst described the condition in 1847, and Schmorl first used the term kernicterus as early as 1903. Regions most commonly affected include the basal ganglia; hippocampus; geniculate bodies; and cranial nerve nuclei, such as the oculomotor, vestibular, and cochlear. The cerebellum can also be affected. Bilirubin-induced neurologic dysfunction (BIND) refers to the clinical signs associated with bilirubin toxicity (ie, hypotonia followed by hypertonia and/or opisthotonus or retrocollis) and is typically divided into acute and chronic phases. The two terms are commonly used interchangeably, but this use is not technically accurate because one refers to clinical manifestations and the other to an anatomic diagnosis.

Conventional wisdom characterizes kernicterus as prevalent in the 1950s and 1960s, virtually eradicated in the 1970s and 1980s, only to reappear during the 1990s. It was speculated that early discharge of term infants (before their serum bilirubin concentration peaks) could be a factor in the reemergence of this devastating neurologic affliction, and medical research focused on developing surveillance and treatment paradigms to eliminate the condition. Whereas it is undeniable that kernicterus remains a cause of major neurologic morbidity in the infant population, population studies of children born in California between 1988 and 1997 suggest the prevalence of kernicterus has remained virtually unchanged since 1980. [2]

Much of the traditional teaching regarding hyperbilirubinemia has been questioned as more is learned about bilirubin metabolism and neurologic injury. Kernicterus is now recognized in the premature infant and, very rarely, in the term infant in the absence of profound hyperbilirubinemia [3] ; however, other problems (eg, acidosis or infection) are present in term infants without profound hyperbilirubinemia. Conversely, physiologic jaundice (sometimes to levels previously thought to be universally dangerous) has been recognized to be within the reference range in the first week of life in healthy term babies, particularly those who are breastfed. Jaundice of this type usually spontaneously resolves without sequelae.

The lack of a clear correlation between the measured bilirubin level and the development of kernicterus continues to confuse clinicians and confound preventive measures. [4] Despite the lack of a clear-cut cause-and-effect relationship between kernicterus and the degree of hyperbilirubinemia, laboratory investigations have demonstrated that bilirubin is neurotoxic at a cellular level. Other in vitro studies have shown bilirubin to have more antioxidant capability than vitamin E, which is commonly assumed to be the most potent antioxidant in the human system. [5] This possible role of bilirubin in early protection against oxidative injury, coupled with identification of multiple neonatal mechanisms to preserve and potentiate bilirubin production, has led to speculation about an as-yet-unrecognized beneficial role for bilirubin in the human neonate.

Kernicterus results from an increased concentration of indirect, or unconjugated, bilirubin. The pathophysiology depends on the underlying condition, of which the most common are Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a reduced ability to conjugate bilirubin in infants. [1]

Bilirubin staining can be noted on autopsy of fresh specimens in the regions of the basal ganglia, hippocampus, substantia nigra, and brainstem nuclei. Such staining can occur in the absence of severe hyperbilirubinemia; in this situation, factors influencing permeability of the blood-brain barrier (eg, acidosis, infection) and the amount of unbound (versus albumin-bound) bilirubin may play a role.

Characteristic patterns of neuronal necrosis leading to the clinical findings consistent with chronic bilirubin encephalopathy are also essential in the pathophysiology of this entity. Bilirubin staining of the brain without accompanying neuronal necrosis can be observed in babies who did not demonstrate clinical signs of bilirubin encephalopathy but who succumbed from other causes. This staining is thought to be a secondary phenomenon, dissimilar from the staining associated with kernicterus.

Improved brain imaging modalities, such as magnetic resonance imaging (MRI) and ultrasonography, may be emerging as instrumental tools to help clarify the complex picture of kernicterus in contrast with asymptomatic bilirubin staining of brain tissues. Bilirubin staining has been suggested to be visualized on MRI as an increased signal in the posteromedial aspect of the globus pallidus. Despite its theoretical value, however, efforts to use cranial imaging in the clinical setting have remained unsatisfying. A 2008 case series by Gkoltsiou et al reported the inexplicable conclusion that, while all children with severe cerebral palsy and a history of hyperbilirubinemia had abnormal central grey matter on later scans, the characteristic central grey matter MRI features of kernicterus were not seen in early scans. [6]

Familiarity with bilirubin metabolism leads to an understanding of the factors leading to an increased risk of kernicterus (see image below). Bilirubin is produced during the catabolism of the heme component of red blood cells (RBCs). Red cell destruction is usually increased in the immediate neonatal period; it can be pathologically elevated in the presence of immune-mediated or nonimmune-mediated hemolytic disease. The first enzyme in the catabolic cascade leading to bilirubin is heme oxygenase. A constitutive form and an inducible form are recognized and are induced by physiologic stressors. The creation of bilirubin, a potentially toxic water-insoluble compound, from biliverdin, a nontoxic water-soluble substance, consumes energy.

Because of its lipophilic nature, bilirubin must be bound to albumin to travel through the blood stream. In this state, it is not free to cross the blood-brain barrier and cause kernicterus. The albumin-bilirubin complex is carried to the liver, where bilirubin enters the hepatocyte for further metabolism. Once in the liver, bilirubin is conjugated via the action of uridine diphosphate glucuronyl transferase (UDPGT), [7] an enzyme not fully functional until 3-4 months of life.

Conjugated bilirubin is excreted into the intestinal tract via the biliary system. Beta-glucuronidase, present in the intestinal lumen of human neonates, deconjugates the conjugated bilirubin, allowing it to be reabsorbed across the intestinal lipid cell membranes back into the blood stream where it must be re-bound to albumin to repeat the cycle. This process, called enterohepatic recirculation, is a unique neonatal phenomenon and contributes significantly to physiologic jaundice. Feeding and excretion of meconium and stool interrupt the enterohepatic recirculation.

Most of the circulating bilirubin in the neonate arises from destruction of circulating RBCs. Neonates produce bilirubin at more than double the daily rate of the average adult, primarily because of the larger circulating volume of RBCs and their shorter life span. Any event resulting in increased serum bilirubin load puts the infant at risk for hyperbilirubinemia.

Prenatal factors, such as maternal smoking, maternal illness, placental insufficiency, and gestation at high altitude, can result in neonatal polycythemia. Obstetric factors, such as delayed clamping of the cord, stripping the cord, or holding the baby below the level of the introitus for a prolonged period, can result in increased RBC mass in the baby. This is particularly true for babies born in the absence of a trained birth attendant.

ABO isoimmunization, as well as minor blood group antigens, can also cause hemolytic disease in the newborn, usually of moderate severity. Infants born to mothers of blood type O negative are at greatest risk, with one series of 249 infants with severe hyperbilirubinemia reporting an odds ratio of 48.6 for infants with Rh incompatibility. [9]

Abnormalities of the red cell itself can also predispose to hemolysis. These can be grouped into membrane defects, such as hereditary spherocytosis and elliptocytosis; enzyme defects, such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and hemoglobinopathies, such as alpha and beta thalassemias.

Significant areas of bruising, such as severe cephalohematoma, subgaleal hemorrhage or peripheral ecchymoses from birth trauma, can result in an increased bilirubin load in the serum as the blood collection resolves. Internal areas of hemorrhage, such as pulmonary or intraventricular bleeds, can also be a significant occult source of serum bilirubin.

As mentioned above, heme-oxygenase-one (HO-1) is the inducible form of the first enzyme involved in the creation of bilirubin. This enzyme is activated by physiologic stressors, such as hypothermia, acidosis, hypoxia, and infection (odds ratio 20.6 in sepsis). [9]

East Asian and Native American babies produce bilirubin at higher rates than do White infants; Black infants have lower production rates than do infants of other racial groups. Male infants have higher serum bilirubin levels than females. Hyperbilirubinemia also runs in families; the etiology is unclear but may relate to genetically increased levels of beta-glucuronidase in the infant, in the mother's breast milk, or both (if the infant is breastfed).

Because of its lipophilic nature, bilirubin must be bound to carrier protein to be transported in the aqueous environment of the serum. Albumin has one primary high-affinity binding site for bilirubin and two lower-affinity sites. At physiologic pH, the amount of free bilirubin (eg, bilirubin not bound to albumin) is very low. This is important because only free bilirubin is available to cross the blood-brain barrier and cause neurotoxicity. Decreased albumin binding capacity, decreased albumin binding affinity, or both can serve to increase the amount of free serum bilirubin. Binding affinity is lower in neonates than in older infants and is lower still in premature and sick infants than in healthy term ones.

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