Kernicterus in Rats with an Inherited Deficiency of Glucuronyl Transferase

Johnson, Lois; Sarmiento, Felicitas; Blanc, William A.; Day, Richard L.

doi:10.1001/archpedi.1959.02070010593009

Cited by 76 publications

(71 citation statements)

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“…few days after birth [11]. The hyperbilirubinemia is a Recently, it was reported that the adult homozygous ODELL (jj) rat, in comparison with the non-jaundiced heterozygous (jj) animal, is unable to form concentrated urine and develops hyperosmolality of the extracellular fluids when thirsted [18].…”

Section: Introductionmentioning

confidence: 99%

The Response of Jaundiced and Non-Jaundiced Weanling Rats to Thirsting

Odell

1968

Pediatr Res

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ExtractLitter-mate homozygous and heterozygous weanling rats of the Gunn strain were thirsted and fasted for 24 hours. The response of the animals to thirsting was compared by analysis of solute content of serum and composition of fluid in the renal medullae. The results are given in tables I and II. When the mean values for weight loss and serum solute concentrations were compared, it was found that the jaundiced rats were able to conserve body water as well as the non-jaundiced rats and to generate equally high concentrations of total solute in the tissue water of the renal medulla. Only two of the twelve jaundiced animals showed evidence of failure to develop the expected hypertonicity of the medullary tissue water. This failure was qualitatively similar to that found in adult jaundiced rats. Despite the presence of higher concentrations of bilirubin in serum, the medullary bilirubin content of the jaundiced weanling rat was only 5 % of the concentration found in adult animals. The sodium and urea concentrations in the renal medullary fluid were correlated (p <0.001) in the homozygous jaundiced rats (table IV and fig. 1). A similar correlation was not found in the non-jaundiced heterozygous animals. This finding suggests that the normal rat kidney has at least two mechanisms for renal transport of urea, one of which is sodium dependent and the other sodium independent and that the latter mechanism is inoperative in the jaundiced weanling rat. SpeculationIn vitro studies of bilirubin have previously suggested that toxicity is exerted by its surface activity on mitochondrial membranes. The examination of renal function in the intact jaundiced animal has revealed the possibility that tubular transport systems for urea and sodium are impaired in the presence of high concentrations of bilirubin in the renal medulla. These transport systems involve the maintenance of concentration gradients of sodium and urea across tubular epithelium. Bilirubin, through its surface activity, could impair the selective permeability of the membranes involved in urea and sodium transport within the renal medulla.

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Section: Introductionmentioning

confidence: 99%

The Response of Jaundiced and Non-Jaundiced Weanling Rats to Thirsting

Odell

1968

Pediatr Res

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“…[1][2][3] The threshold at which B F produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate and study for some time. Recently, Daood and Watchko 4 calculated central nervous system (CNS) B F levels in Gunn rat pups during peak postnatal hyperbilirubinemia (day of life 15 to 19) 5,6 and correlated those levels with the cerebellar weights and neurobehavioral status of the pups. 4 The Gunn rat 7 offers an excellent model to explore this relationship in vivo, as it spontaneously develops newborn jaundice and differs from other models that rely on artificially induced hyperbilirubinemia.…”

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confidence: 99%

Calculated free bilirubin levels and neurotoxicity

2009

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Although most bilirubin in the circulation is bound to albumin, a relatively small fraction remains unbound. The concentration of this 'free' bilirubin (B F ) is believed to dictate the biologic effects of bilirubin in jaundiced newborns, including its neurotoxicity. The threshold at which B F produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate. The objective of this study was to compare calculated central nervous system (CNS) B F levels in Gunn rat pups during (i) peak postnatal hyperbilirubinemia and (ii) sulfadimethoxine-induced acute bilirubin encephalopathy (ABE) previously reported from our laboratory with those predicted in human neonates with peak total serum bilirubin (TSB) levels of 35 mg per 100 ml (599 mmol l À1 ), a clinical cohort that often evidence moderate-to-severe adverse post-icteric neurodevelopmental sequelae. Homozygous j/j Gunn rat pups with neonatal hyperbilirubinemia due to a deficiency of the bilirubin conjugating enzyme uridine-diphosphate-glucuronosyl transferase 1A1 were studied along with non-jaundiced littermate heterozygous J/j controls. Sulfadimethoxine was used to displace bilirubin from albumin in hyperbilirubinemic j/j Gunn rat pups to increase their brain bilirubin content and induce ABE. Calculated Gunn rat CNS B F levels were determined as a function of genotype, sulfadimethoxine exposure and albumin-bilirubin binding constant. These data were compared with the human CNS B F predicted from the calculated serum B F in human neonates with a TSB of 35 mg per 100 ml as a function of albumin-bilirubin binding constant, albumin concentration and the assumption that at this hazardous bilirubin level there may be rapid equilibration of B F between serum and brain. There was a large gap between the upper limit of the calculated CNS B F 95% confidence interval (CI) range in non-jaundiced J/j pups (for example, 112 nM at k ¼ 9.2 l mmol À1 ) and the lower limit seen in the saline-treated hyperbilirubinemic j/j pups (556 nM at k ¼ 9.2 l mmol À1 ) as well as between the upper limit in saline-treated hyperbilirubinemic j/j pups (1110 nM at k ¼ 9.2 l mmol À1 ) and the lower limit seen in sulfadimethoxine-treated jaundiced j/j littermates (3461 nM at k ¼ 9.2 l mmol À1 ). There was considerable overlap and remarkable similarity between the predicted human CNS B F values at a TSB of 35 mg per 100 ml for a range of reported human serum bilirubin-albumin binding constants and albumin concentrations, and those calculated for saline-treated hyperbilirubinemic j/j Gunn rat pups. This exercise yielded strikingly similar apparent calculated neurotoxic B F levels for Gunn rat pups and human neonates rather than orders of magnitude differences that might have been predicted at the outset and add to a growing literature aimed at defining clinically germane neurotoxic B F thresholds.

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“…It is thus likely that any small differences in UB in clinical studies will not be detectable with standard methods, also due to differences and variations in binding capacity and TB levels both in the same infant as well as between infants. In vivo experiments of bilirubin displacement have also shown that this shift of UB into tissue compartments may actually cause a decrease in TB concentrations in plasma (16). With regard to this, it is interesting to note that in the study by Aranda et al (Aranda et al, Plasma unbound bilirubin and ibuprofen in preterms.…”

Section: Discussionmentioning

confidence: 95%

“…These drugs are able to displace bilirubin from its binding sites on albumin, thus increasing the UB concentration and toxicity. This has been demonstrated clinically by increased mortality and kernicterus in newborn infants treated with sulfisoxazole (15) as well as experimentally in vivo in Gunn rats given such treatment (16). Drugs that displace bilirubin from albumin generally have a strong binding to albumin (13).…”

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confidence: 99%

Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

2010

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Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 M by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to ϩ54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 M showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia. (Pediatr Res 67: 614-618, 2010) T he significance of unconjugated hyperbilirubinemia is the potential for development of bilirubin neurotoxicity and kernicterus. Most healthy term infants with a total serum bilirubin (TB) concentration reaching 425 to 680 M will, however, escape with no significant damage when treated with phototherapy and/or exchange transfusion according to guidelines (1). However, 8 to 9% of the kernicterus cases occur at a TB concentration Ͻ425 M. Kernicterus has also been reported at TB concentrations Ͻ340 M (2,3). In premature infants, bilirubin toxicity has been observed at even lower TB concentrations (4,5). More recently, high peak TB has been associated with poor long-term prognosis and adverse neurodevelopmental outcome in extremely low birth weight infants (6,7).The binding site of bilirubin on the albumin molecule is still uncertain, but most likely bilirubin binds to albumin at one high affinity binding site in a 1:1 molar ratio (3,8 -10). Clinical and experimental data have also suggested different secondary binding sites. However, these secondary binding sites may not be of any physiologic importance (10). At equilibrium, ϳ0.005% of bilirubin will be unbound bilirubin (UB). The albumin-bilirubin complex has a high molecular weight and cannot cross capillary walls, whereas UB is available for tissue distribution and elimination (9,11). Bilirubin is not toxic while bound to albumin (BB), and it is thought that the concentration of UB is a better predictor of toxicity than TB. The distribution and elimination of UB causes a shift in the equilibrium, and more bilirubin is released from albumin. The concentration of UB is influenced by several factors like the concentration of TB (2), albumin, and the binding capacity of albumin (5). Of clinical importance is the fact that the bindi...

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Kernicterus in Rats with an Inherited Deficiency of Glucuronyl Transferase

Cited by 76 publications

References 26 publications

The Response of Jaundiced and Non-Jaundiced Weanling Rats to Thirsting

The Response of Jaundiced and Non-Jaundiced Weanling Rats to Thirsting

Calculated free bilirubin levels and neurotoxicity

Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

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