*1.3.3 Kernicterus*

*Update on Critical Issues on Infant and Neonatal Care*

**1.3 Neurotoxicity of bilirubin**

*1.3.2 Neurotoxicity risk factors*

ity risk factors [17].

*1.3.1 Cellular toxic effects of bilirubin*

deficiency-associated hyperbilirubinemia [11, 12]. It has been shown that inadequate conjugation capacity of the liver mainly contributes to development of neonatal jaundice in G6PD-deficient infants [12–14]. This has been proven by significantly lower total serum bilirubin level as well as mono- and di-conjugated bilirubin fractions in G6PD-deficient newborns that developed hyperbilirubinemia than the non-hyperbilirubinemic G6PD-deficient newborns [13]. Research that further supports the report that the decreased bilirubin conjugation is the main element of jaundice in G6PD-deficient newborns has shown varying shortening of red cell life span, which could only partially contribute to the jaundice [11, 13]. Moreover, the problem of jaundice is potentiated in cases of inherited UDP glucuronosyltransferase promoter polymorphism associated with Gilbert syndrome [14, 15]. The combination of the two gene mutations has been shown to significantly increase the incidence

3.And finally, the third mechanism of jaundice marked by *impaired bilirubin excretion* causes direct (conjugated) hyperbilirubinemia [2, 9, 10, 16]. Neonatal sepsis can be featured by both indirect and direct hyperbilirubinemia [2, 16].

Even though being of great clinical importance, hyperbilirubinemia neurotoxicity effects on the cellular level are not entirely understood. It has been established that the mitochondria could be the primary target of the bilirubin neurotoxicity as evidenced by uncoupling of oxidative phosphorylation. Additional effects expressed in neuronal tissue include inhibition of DNA synthesis, induction of DNA strand breakage, inhibition of protein synthesis, and changes in neurotransmitters' synthesis and function. Experiments in immature rats have shown association between hyperbilirubinemia and impaired cerebral glucose metabolism [9].

Of specific clinical importance is to recognize the risk factors associated with brain damage in newborn infants with significant hyperbilirubinemia. According to the 2009 AAP recommendation, neurotoxicity risk factors are isoimmune hemolytic disease, G6PD deficiency, asphyxia, sepsis, acidosis, and albumin <3.0 mg/dL [17]. The neurotoxicity risk factors are used in making the decision when to initiate phototherapy or perform an exchange transfusion. These interventions are recommended at a lower bilirubin threshold level in the presence of any of the neurotoxic-

Prematurity represents a well-recognized predisposition to development of jaundice. In premature newborns the rise of the total serum bilirubin tends to be slightly slower but of longer duration than term newborns [18]. There is still insufficient amount of evidence-based data to provide recommendations for treatment in this group of patients. Recommendations are mainly based on consensus agreementbased guidelines on the safe spectrum of thresholds [19, 20]. Bilirubin neurotoxicity has been associated with prematurity; however, birth weight and gestation are not the sole variables predictive of the neuronal damage. Other factors such as the presence of a concurrent neonatal disease, sepsis, cholestasis, drugs that alter the albumin-bilirubin binding, or the use of total parenteral nutrition have been found to enhance the risk of neurotoxicity. Moreover, premature newborns have similar

of hyperbilirubinemia in a dose-dependent manner [15].

**4**

This term refers to the neurologic consequences of the deposition of unconjugated bilirubin in brain tissue with subsequent damage and scarring of the basal ganglia and brainstem nuclei. Determinants of the neurotoxic effect of bilirubin are the duration of exposure and the concentration of bilirubin in the brain. Poor correlation exists between serum bilirubin level and bilirubin encephalopathy in the absence of hemolysis [9]. Other important determinants of bilirubin influx in the brain are the bilirubin-binding capacity of albumin and the integrity of the bloodbrain barrier. If the serum unconjugated bilirubin level exceeds the bilirubin-binding capacity of albumin, unbound lipid-soluble bilirubin crosses the blood-brain barrier. Conditions that alter the permeability of the blood-brain barrier such as sepsis, acidosis, hypoxia, hyperoxia, hypoperfusion, and hyperosmolality can potentiate bilirubin entry in the brain [2, 9]. Differentiating neurons are particularly sensitive to bilirubin-related injury; therefore, premature newborns are more susceptible to the effects of bilirubin deposition in the brain [9]. For the purpose of greater consistency when defining bilirubin-induced neurological damage, it has been recommended to separate the terms "acute bilirubin encephalopathy" and "kernicterus." The former is used to describe the acute manifestations of bilirubin toxicity in the first weeks of life, whereas the latter is reserved for the chronic and permanent clinical sequelae of bilirubin toxicity [4]. The exact bilirubin concentration associated with kernicterus in the healthy term infant is unpredictable. Toxicity levels may vary among ethnic groups, also with maturation of an infant, and in the presence of hemolytic disease. The clinician's concerns of possible bilirubin toxicity should rise in the presence of bilirubin >25 mg/dL (428 μmol/L) in the term newborn without hemolysis and > 20 mg/dL (342 μmol/L) in the term newborn with hemolysis [2]. The early phase of acute bilirubin encephalopathy is characterized by lethargy, hypotonia, and poor sucking. In the intermediate phase, irritability and hypertonia develop. The infant may develop a fever and high-pitched cry, which may alternate with drowsiness and hypotonia [4, 24]. The hypertonia is demonstrated by backward arching of the neck (retrocollis) and trunk (opisthotonos). The advanced phase is characterized by pronounced hypertonia, apnea, and fever, deep stupor to coma, sometimes seizures, and death. Features of chronic bilirubin encephalopathy (kernicterus) include athetoid cerebral palsy, hearing loss, visual and dental problems, and moreover intellectual and other handicaps [1, 2, 4, 5, 9, 10].
