Elsevier

Pediatric Neurology

Volume 29, Issue 5, November 2003, Pages 410-421
Pediatric Neurology

Bilirubin toxicity in the developing nervous system

https://doi.org/10.1016/j.pediatrneurol.2003.09.011Get rights and content

Abstract

Bilirubin toxicity remains a significant problem despite recent advances in the care of jaundiced (hyperbilirubinemic) neonates. A recent surge in reported cases of classical kernicterus, due in part to earlier hospital discharge and relaxation of treatment criteria for hyperbilirubinemia, and new reports of hyperbilirubinemia-induced auditory dysfunction using evoked potential based infant testing and hearing screening, underscore the need to better understand how hyperbilirubinemia causes brain damage in some infants, especially because the damage is preventable. Recent progress in understanding bilirubin binding and neurotoxicity resulting from unbound or “free” unconjugated bilirubin, how bilirubin affects the central nervous system in vivo and in vitro, and the use of new clinical tools in neonates, for example magnetic resonance imaging revealing bilateral lesions in globus pallidus and subthalamus, and abnormal brainstem auditory evoked potentials with normal inner ear function, may lead to improved detection and prevention of neurologic dysfunction and damage from bilirubin. Finally, the concern is raised that partial or isolated neurologic sequelae, for example auditory neuropathy and other central auditory processing disorders, may result from excessive amount and duration of exposure to free, unconjugated bilirubin at different stages of neurodevelopment.

Introduction

It is a pleasure to participate in this Festschrift for Dr. Michael J. Painter. I trained in Child Neurology with Dr. Painter from 1978 to 1981. By his guidance and support of my interest in medical research, including support for an additional fellowship year of basic research, I began a career in developmental neuroscience. With Dr. Painter's continued encouragement and advice, I have been fortunate to be able to study the effects of bilirubin neurotoxicity on the developing nervous system for the past 20 years, primarily using the classical animal model of bilirubin encephalopathy, the jaundiced Gunn rat, characterizing electrophysiologic changes in the model and comparing these to anatomic, biochemical, and immunohistochemical measures.

Bilirubin toxicity remains a significant problem of human infants despite recent advances in the care of jaundiced (hyperbilirubinemic) neonates. A recent surge in reported cases of classical kernicterus in the United States and other countries [1], [2], [3], [4], [5], [6] and new reports of auditory neuropathy resulting from hyperbilirubinemia without other classical signs of kernicterus [7], [8], [9], [10], [11] underscore the need for models to provide a better understanding of how jaundice, present in 60% of newborn infants, causes permanent brain damage in some, especially because with better understanding, the damage is preventable. The localization of sites of central nervous system dysfunction, the determinants of vulnerability and reversibility, and the pathogenesis are still only partially understood despite decades of study.

Most of the “classical” literature on kernicterus was developed during an era when the therapeutic options for treatment of fetomaternal isoimmune (Rh) disease were limited. The resulting acute “kernicteric” syndrome was dramatic, and central nervous system symptoms were the most clinically apparent: lethargy, ophthalmoplegia, high-pitched cry, opisthotonus, and seizures. Both the basal ganglia and auditory pathways were recognized as being particularly vulnerable. Preventative prenatal therapy could obviate these signs and symptoms, and specific therapeutic criteria were developed for the treatment of jaundice. The level of bilirubin that is regarded as safe in human infants, particularly those who are premature and have low birth weight, is unknown. Mollison and Cutbush [12] associated kernicterus with maximum serum bilirubin concentrations in term infants with Rh hemolytic disease. Kernicterus occurred in 1/13 (8%), 4/12 (33%), and 8/11 (73%) of term infants with bilirubin of 19-24, 25-29, and 30-40 mg/dL, respectively, although the definition of kernicterus and the criteria used to make the diagnosis were not clearly documented.

With the virtual elimination of Rh disease, concern for the developmental consequences of elevated bilirubin diminished despite warnings that previously established treatment criteria might not be adequate [3], [13], [14]. Classical kernicterus has recently reemerged, in part owing to earlier hospital discharge, before the natural peak of bilirubin in the infant, and in part as a result of relaxation of treatment criteria [1], [3], [4]. Coupled with recent trends toward the early hospital discharge of infants, for whom hyperbilirubinemia has become the main reason for hospital readmission [6], [15], [16], there is a growing concern regarding the “safe” level of bilirubin and the pathogenesis of hyperbilirubinemic cellular damage [1]. In 2001, warnings on the danger of kernicterus were issued by the Joint Commission on Accreditation of Healthcare Organizations [17] and the Centers for Disease Control [18]. Most children have no identified etiology other than a combination of factors known to be associated with higher risk of bilirubin injury, for example prematurity, dehydration, infection, genetic deficiencies, or breast-feeding with inadequate intake. Factors such as glucose-6-phosphate dehydrogenase deficiency [19] that increase bilirubin production from hemoglobin, or genetic variations in hepatic uridine diphosphate–glucuronosyltransferase (UDPGT) activity (e.g., Crigler-Najjar or Gilbert syndromes) that decrease hepatic elimination of bilirubin have been found alone or in combination [20] in cases of otherwise unexplained severe hyperbilirubinemia. Pathologic factors, for example fetomaternal blood group incompatibilities (Rh or ABO), are well known underlying causes of excessive jaundice [21]. Irrespective of physiologic or pathologic etiology, elevated levels of unconjugated (indirect) bilirubin place infants at risk for the development of bilirubin encephalopathy or kernicterus, which is one of the few causes of brain damage occurring in the infant period that is preventable with current diagnostic and treatment regimens. A systematic approach with universal screening and the use of an hour-specific bilirubin nomogram has been advocated [4], [22].

There is evidence that even moderate levels of elevated bilirubin place infants at risk for cognitive, perceptual, motor, and auditory disorders [23], [24], [25], [26], [27], [28], [29]. Prospective controlled studies have revealed cognitive and neurologic impairment in children with elevated levels of unbound bilirubin in the infant period [23], [25], [30]. Large statistical studies of healthy, term infants, such as the National Collaborative Perinatal Project [24], [26], have detected an association between “low levels” of hyperbilirubinemia that ordinarily would not be treated and subtle cognitive and motor neurologic sequelae. More recent clinical and pathologic studies have indicated that levels of bilirubin previously considered safe may, in fact, prove harmful. Recent literature suggests that moderate degrees of hyperbilirubinemia in healthy term neonates may not be safe for the brain [29].

Hyperbilirubinemia has recently emerged as a significant risk factor for nonsyndromic auditory neuropathy resulting from dys-synchrony in the auditory nerve or brainstem auditory pathways causing auditory processing problems or neural, not sensory, hearing loss [7], [8], [9], [11], [31], [32]. Auditory neuropathy may be more common in infants than previously suspected, affecting approximately 1 in 400 infants at risk for hearing impairment [7].

Section snippets

Pathophysiology of bilirubin

Unconjugated bilirubin (also known as indirect bilirubin because of its indirect reaction in the diazo assay used to measure bilirubin), a breakdown product of the porphyrin ring of red blood cell hemoglobin, is lipid soluble, water insoluble, and neurotoxic. Unconjugated bilirubin is conjugated in the liver by UDPGT to a water-soluble, nontoxic glucuronide, known clinically as conjugated bilirubin (also known as direct bilirubin because of its direct reaction in the diazo assay). The relative

Clinical bilirubin encephalopathy

Bilirubin neurotoxicity produces selective damage of the central nervous system. Clinical symptoms of classical, chronic bilirubin encephalopathy, also known as kernicterus, in humans correlate with specific pathologic findings. The classical sequelae of excessive neonatal hyperbilirubinemia comprise a tetrad consisting of athetoid cerebral palsy, deafness or hearing loss, impairment of upward gaze, and enamel dysplasia of the primary teeth, and correspond to pathologic lesions in the globus

The Gunn rat animal model

Just as Crigler-Najjar syndrome, by producing extremely high bilirubin levels, provides important information regarding kernicterus that occurs with hyperbilirubinemia from any cause, so the animal equivalent, the jaundiced Gunn rat, provides the opportunity to study kernicterus and bilirubin toxicity in the laboratory and to help unravel some of the mechanisms that underlie this disorder.

The classical Gunn rat model was first described in 1938 by C. K. Gunn as a mutant jaundiced rat of the

Current clinical diagnosis of bilirubin encephalopathy and kernicterus

Current concepts of the diagnosis and treatment of bilirubin encephalopathy are changing. The use of magnetic resonance imaging scans which demonstrate bilateral lesions of the globus pallidus in neonates, and brainstem auditory evoked potentials that are absent or abnormal, in combination with clinical signs of acute bilirubin encephalopathy and abnormal muscle tone in infants with significant hyperbilirubinemia, have led to much earlier diagnosis of bilirubin encephalopathy and kernicterus.

Conclusion

The traditional view that kernicterus is a disease of the past, and that bilirubin toxicity causes only the classical clinical and pathologic syndrome may be an oversimplification of the effect of bilirubin on the developing nervous system. It is likely that partial or isolated neurologic sequelae, especially auditory neuropathy and other central auditory processing disorders, may result from excessive amount and duration of exposure to free, unconjugated bilirubin at different stages of

Acknowledgements

Dr. Michael J. Painter's guidance, support, encouragement, and advice have enabled me to study the effects of bilirubin neurotoxicity on the developing nervous system since completing Pediatric Neurology training in 1981. This work was also supported in part by NIH NIDCD R01-DC00369.

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