Developmental influence of unconjugated hyperbilirubinemia and neurobehavioral disorders

Amin, Sanjiv B.; Smith, Tristram; Timler, Geralyn

doi:10.1038/s41390-018-0216-4

Cited by 32 publications

(39 citation statements)

References 124 publications

(172 reference statements)

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“…In premature infants, acute bilirubin neurotoxicity may occur without obvious clinical symptoms ( 1 ). Over time, the condition can progress to chronic symptoms including motor incoordination, learning disabilities and balance disorders ( 6 ). Despite the overwhelming incidence of hyperbilirubinemia in premature infants, rodent models have focused on term equivalent ages (e.g., postnatal day (P) 16)( 7 ).…”

Section: Introductionmentioning

confidence: 99%

A Gunn rat model of preterm hyperbilirubinemia

Waddell

Tang

et al. 2019

Pediatr Res

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Background The impact of bilirubin in preterm infants is poorly understood. An animal model would assist in improving understanding. The Gunn rat lacks uridine diphosphate-glucuronylsyl transferase 1 and can be made acutely hyperbilirubinemic by injection of sulfodimethoxine (sulfa), a drug that displaces bilirubin from albumin and thus increases free bilirubin. Methods On postnatal day (P) 5, Gunn rats either heterozygous (Nj) or homozygous (jj) for glucuronosyltransferase activity were injected with either saline or sulfa. Behavior and cerebellar weight were measured. Results Pups did not show any signs of acute bilirubin encephalopathy. Pup weight dropped significantly on P8 only in the jj-sulfa group. Behavior was affected only in the jj-sulfa group. Cerebellar weight was significantly less in the jj-sulfa group. Discussion The Gunn rat pup model may be a good model to study hyperbilirubinemia in preterm infants.

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Section: Introductionmentioning

confidence: 99%

A Gunn rat model of preterm hyperbilirubinemia

Waddell

Tang

et al. 2019

Pediatr Res

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“…Several studies have also shown toxic effects of bilirubin on synaptic functions (139,292,311,613). Bilirubin hippocampal toxicity in the newborn period may have adverse effects on synaptic plasticity and lead to memory deficits with negative effects on learning (28). Bilirubin toxicity in the auditory system, discussed elsewhere in this review, may also have negative consequences for language development.…”

Section: A Clinical Picture Of Kernicterusmentioning

confidence: 87%

“…Although kernicterus in the strict sense affects the basal parts of the brain, bilirubin toxicity may also affect cortical neurons, albeit the cortex appears less vulnerable than other areas (28,106).…”

Section: A Clinical Picture Of Kernicterusmentioning

confidence: 99%

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Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

Hansen

Wong

Stevenson

2020

Physiological Reviews

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Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.

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“…Normally, bilirubin remains in the intravascular space bound to albumin, but in neonates with HHA who have a sudden elevation of unconjugated bilirubin, it can exceed the albumin‐binding capacity and unbound bilirubin can pass through the blood‐brain barrier posing a risk of bilirubin toxicity. Although permanent bilirubin neurotoxicity, kernicterus, is rare, milder forms of neurologic dysfunction due to bilirubin are more common . In addition, hereditary defects in hepatic bilirubin conjugation can substantially increase this risk …”

Section: Introductionmentioning

confidence: 99%

Molecular diagnostic update in hereditary hemolytic anemia and neonatal hyperbilirubinemia

Rets

Clayton

Christensen

et al. 2019

Int J Lab Hematology

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Hereditary hemolytic anemia (HHA) is a group of genetically and phenotypically heterogeneous disorders characterized by premature destruction of red blood cells (RBCs) with clinical manifestations ranging from asymptomatic to marked hemolytic anemia. There are three main categories of HHA: (a) RBC membrane defects; (b) hemoglobinopathies/thalassemias; and (c) RBC enzyme deficiencies. Hyperbilirubinemia is a frequent consequence of hemolytic anemia and can lead to bilirubin‐associated neurotoxicity in neonates and to jaundice, and formation of gall stones in adults. Hyperbilirubinemia can also be caused by impaired bilirubin conjugation due to polymorphisms and mutations in genes involved in bilirubin metabolism (eg, UGT1A1). Neonates with HHA and co‐inherited variants impairing bilirubin conjugation are at increased risk of bilirubin‐associated toxicity. Prior to the advent of next‐generation sequencing (NGS), molecular diagnosis of these disorders was limited to targeted single gene Sanger sequencing. However, NGS is making its way into the standard diagnostic workup of complex and multigene disorders like HHA. This review will focus on the molecular updates of HHA with particular focus on the neonatal and pediatric population.

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Developmental influence of unconjugated hyperbilirubinemia and neurobehavioral disorders

Cited by 32 publications

References 124 publications

A Gunn rat model of preterm hyperbilirubinemia

A Gunn rat model of preterm hyperbilirubinemia

Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

Molecular diagnostic update in hereditary hemolytic anemia and neonatal hyperbilirubinemia

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