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Robert H Tukey - One of the best experts on this subject based on the ideXlab platform.
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Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia s
2020Co-Authors: Andreia Barateiro, Robert H Tukey, Shujuan Chen, Meifei Yueh, Adelaide Fernandes, Helena Sofia Domingues, João Relvas, Olivier Barbier, Nghia Nguyen, Dora BritesAbstract:ABSTRACT Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the Neonatal period. Here we use a new mouse model that targets deletion of the Ugt1 locus and the Ugt1a1 gene in liver to promote Hyperbilirubinemiainduced seizures and central nervous system toxicity. The accumulation of TSB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histologic studies of brain tissue demonstrate that the onset of severe Neonatal Hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. Kernicterus presents as axonopathy with myelination deficits at different brain regions, including pons, medulla oblongata, and cerebellum. The excessive accumulation of TSB in the early Neonatal period (5 days after birth) promotes activation of the myelin basic protein (Mbp) gene with an accelerated loss of MBP that correlates with a lack of myelin sheath formation. These changes were accompanied by increased astroglial and microglial reactivity, possibly as a response to myelination injury. Interestingly, cerebellum was the area most affected, with greater myelination impairment and glia burden, and showing a marked loss of Purkinje cells and reduced arborization of the remaining ones. Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe Hyperbilirubinemia
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Developmental, Genetic, Dietary, and Xenobiotic Influences on Neonatal Hyperbilirubinemia
2020Co-Authors: Meifei Yueh, Shujuan Chen, Nghia Nguyen, Robert H TukeyAbstract:ABSTRACT Hyperbilirubinemia, caused by the accumulation of unconjugated bilirubin, is one of the most common clinical diagnoses in both premature and term newborns. Owing to the fact that bilirubin is metabolized solely through glucuronidation by UDPglucuronosyltransferase (UGT) 1A1, it is now known that immaturity of UGT1A1, in combination with the overproduction of bilirubin during the developmental stage, acts as a bottleneck to bilirubin elimination and predisposes the infant to high total serum bilirubin levels. Although Neonatal jaundice is mostly benign, excessively high levels of serum bilirubin in a small percentage of newborns can cause bilirubin-induced neurologic dysfunction, potentially leading to permanent brain damage, a condition known as kernicterus. Although a large portion of Hyperbilirubinemia cases in newborns are associated with hemolytic diseases, we emphasize here the impaired ability of UGT1A1 to eliminate bilirubin that contributes to Hyperbilirubinemia-induced neurotoxicity in the developmental stage. As a series of hereditary UGT1A1 mutations have been identified that are associated with UGT1A1 deficiency, new evidence has verified that delayed expression of UGT1A1 during the early stages of Neonatal development is a tightly controlled event involving coordinated intrahepatic and extrahepatic regulation. This review recapitulates the progress that has been made in recent years in understanding the causes and physiopathology of severe Hyperbilirubinemia, investigating molecular mechanisms underlying bilirubin-induced encephalopathy, and searching for potential therapies for treating pathologic Hyperbilirubinemia. Several animal models have been developed to make it possible to examine bilirubin-induced neurotoxicity from multiple directions. Moreover, environmental factors that may alleviate or worsen the condition of Hyperbilirubinemia are discussed
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humanized ugt1 mice regulation of ugt1a1 and the role of the intestinal tract in Neonatal Hyperbilirubinemia and breast milk induced jaundice
Drug Metabolism and Disposition, 2018Co-Authors: Shujuan Chen, Robert H TukeyAbstract:Neonatal Hyperbilirubinemia and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the ability to metabolize bilirubin. It is generally believed that acute Neonatal forms of Hyperbilirubinemia develop due to an inability of hepatic UGT1A1 to metabolize efficiently bilirubin for clearance through the hepatobiliary tract. Newly developed mouse models designed to study bilirubin metabolism have led to new insight into the role of the intestinal tract in controlling Neonatal Hyperbilirubinemia. Humanization of mice with the UGT1 locus (hUGT1 mice) and the UGT1A1 gene provide a unique tool to study the onset of Hyperbilirubinemia since the human UGT1A1 gene is developmentally regulated during the Neonatal period in hUGT1 mice. A new mechanism outlying developmental expression of intestinal UGT1A1 is presented and its implications in the control of Neonatal Hyperbilirubinemia discussed. New findings linking breast milk protection against necrotizing enterocolitis and intestinal control of UGT1A1 may help explain the contribution of breast milk toward the development of Neonatal Hyperbilirubinemia. Our findings outline a new model that includes an active intestinal ROS /IκB kinase/nuclear receptor corepressor 1 loop that can be applied to an understanding of breast milk-induced jaundice.
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severe Neonatal Hyperbilirubinemia in crigler najjar syndrome model mice can be reversed with zinc protoporphyrin
Hepatology Communications, 2017Co-Authors: Ryoichi Fujiwara, Tomoo Itoh, Ryo Mitsugi, Asuka Uemura, Robert H TukeyAbstract:Neurotoxic bilirubin is solely conjugated by UDP-glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological Hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced Neonatal Hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe Neonatal Hyperbilirubinemia. A mouse model that develops Neonatal Hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in Neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase-I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1−/− mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin-induced Neonatal lethality. Zinc protoporphyrin-treated Ugt1−/− mice developed normally as adults capable of reproducing, but their newborns showed even more severe Hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down-regulated in a serum bilirubin level-dependent manner. Conclusion: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin-induced toxicity. Neonatal Hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin. (Hepatology Communications 2017;1:792–802)
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intestinal ncor1 a regulator of epithelial cell maturation controls Neonatal Hyperbilirubinemia
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Shujuan Chen, Meifei Yueh, Eva Rettenmeier, Miao Liu, Miles Paszek, Johan Auwerx, Ronald M Evans, Kepeng Wang, Michael Karin, Robert H TukeyAbstract:Severe Neonatal Hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. Humanized UGT1 (hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes Hyperbilirubinemia in hUGT1 neonates because of intestinal UGT1A1 gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated in hUGT1 mice with targeted deletion of intestinal IKKβ. Physiological events during Neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and Hyperbilirubinemia.
Michael Kaplan - One of the best experts on this subject based on the ideXlab platform.
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hemolysis and glucose 6 phosphate dehydrogenase deficiency related Neonatal Hyperbilirubinemia
Neonatology, 2018Co-Authors: Michael Kaplan, Ronald J. Wong, David K. StevensonAbstract:Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme Neonatal Hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants. Objectives To explore the role of hemolysis in Neonatal Hyperbilirubinemia associated with G6PD deficiency. Methods Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition. Results Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme Hyperbilirubinemia. Conclusions Hemolysis is an important pathogenetic factor in G6PD deficiency-associated Neonatal Hyperbilirubinemia.
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the preterm infant a high risk situation for Neonatal Hyperbilirubinemia due to glucose 6 phosphate dehydrogenase deficiency
Clinics in Perinatology, 2016Co-Authors: Cathy Hammerman, Michael Kaplan, Vinod K. BhutaniAbstract:Prematurity and glucose-6-phosphate dehydrogenase (G6PD) deficiency are risk factors for Neonatal Hyperbilirubinemia. The 2 conditions may interact additively or synergistically, contributing to extreme Hyperbilirubinemia, with the potential for bilirubin neurotoxicity. This Hyperbilirubinemia is the result of sudden, unpredictable, and acute episodes of hemolysis in combination with immaturity of bilirubin elimination, primarily of conjugation. Avoidance of contact with known triggers of hemolysis in G6PD-deficient individuals will prevent some, but not all, episodes of hemolysis. All preterm infants with G6PD deficiency should be vigilantly observed for the development of jaundice both in hospital and after discharge home.
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Bilirubin and the Genome: The Hereditary Basis of Unconjugated Neonatal Hyperbilirubinemia
2013Co-Authors: Michael Kaplan, Cathy HammermanAbstract:Abstract: Severe Neonatal unconjugated Hyperbilirubinemia, with the risk of bilirubin encephalopathy or kernicterus in severe, untreated cases, occurs when bilirubin production exceeds the body's ability to eliminate it. The causes of Neonatal Hyperbilirubinemia are multifactorial and comprise increased hemolysis on the one hand, and diminished bilirubin conjugation on the other. In recent years, many of these etiologies have been found to have a genetic origin. Sometimes hereditary factors act independently, but in other circumstances, single mutations which ordinarily do not produce disease in and of themselves, may result in severe Hyperbilirubinemia as a result of interaction with other mutated genes. Of cardinal importance to this discussion is the concept of the human genome, whereby the thousands of genes of which it is comprised may interact one with the other, or with the environment, exacerbating the severity of jaundice in certain individuals, and protecting against Hyperbilirubinemia in others. Genetic interactions have been demonstrated combining increased bilirubin production with diminished bilirubin conjugation, resulting in severe Hyperbilirubinemia. Appreciation of the multiplicity of genetic interactions is of importance in our evaluation of the neonate with severe Hyperbilirubinemia, in our attempts to prevent future cases of kernicterus, and in genetic counseling of families who have had an infant with severe Neonatal Hyperbilirubinemia. Gene therapy for the most severe of these inherited defects of bilirubin conjugation, Crigler-Najjar syndrome type 1, might become a reality in future years
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Neonatal Hyperbilirubinemia in glucose 6 phosphate dehydrogenase deficient heterozygotes
Pediatrics, 1999Co-Authors: Michael Kaplan, Paul Renbaum, Ernest Beutler, Cathy Hammerman, Hendrik J. Vreman, Ephrat Levylahad, David K. StevensonAbstract:Objectives. We assessed the incidence of Hyperbilirubinemia, defined as serum total bilirubin <15 mg/dL (256 μmol/L), in a cohort of Sephardic Jewish female neonates at risk for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency with especial emphasis on the heterozygotes. We studied the roles of hemolysis by blood carboxyhemoglobin (COHb) determinations and of the variant promoter of the gene for the bilirubin-conjugating enzyme uridine 5'-diphosphate glucuronosyltransferase 1 (UGT1A1) seen in Gilbert's syndrome in the pathogenesis of the Hyperbilirubinemia. Methods. Consecutively born, healthy, term, female neonates were screened for G-6-PD deficiency and observed clinically with serum bilirubin evaluations as indicated for Hyperbilirubinemia. On day 3, blood was sampled for COHb, total hemoglobin (tHb), and a mandatory serum bilirubin determination. COHb, determined by gas chromatography, was expressed as percentage of tHb and corrected for inspired carbon monoxide (COHbc). DNA was analyzed for the G-6-PD Mediterranean 563T mutation and for the variant UGT1A1 gene. Results. The cohort included 54 G-6-PD-deficient heterozygotes, 19 deficient homozygotes, and 112 normal homozygotes. More heterozygotes (12/54, 22%; relative risk: 2.26; 95% CI: 1.07-4.80) and deficient homozygotes (5/19, 26.3%; relative risk: 2.68; 95% CI: 1.05-6.90) developed Hyperbilirubinemia, than did normal homozygotes (11/112, 9.8%). Third-day serum bilirubin values that were obtained from 144 neonates were significantly higher in both heterozygotes (11.2 ± 3.7 mg/dL [192 ± 64 μmol/L]) and G-6-PD-deficient homozygotes (12.0 ± 3.0 mg/dL [206 ± 52 μmol/L]) than in the G-6-PD normal homozygotes (9.4 ± 3.4 mg/dL [160 ± 58 μmol/L). In contrast, COHbc values were higher only in G-6-PD-deficient homozygotes (0.74% ± 0.14%) and not in heterozygotes (0.69% ± 0.19%, not statistically significant), compared with control values (0.63% ± 0.19%). High COHbc values were not a prerequisite for the development of Hyperbilirubinemia in any of the G-6-PD genotypes. A greater incidence of Hyperbilirubinemia was found among the G-6-PD-deficient heterozygotes, who also had the variant UGT1A1 gene, in both heterozygous (6/20, 30%) and homozygous (4/8, 50%) forms, than was found in their counterparts with the normal UGT1A1 gene (2/26, 7.7%). This effect was not seen in the G-6-PD normal homozygote group. A color reduction screening test for G-6-PD deficiency identified only 20.4% (11/54) of the heterozygotes. Conclusions. We showed that G-6-PD-deficient heterozygotes, categorically defined by DNA analysis, are at increased risk for Neonatal Hyperbilirubinemia. The screening test that was used was unable to detect most heterozygotes. Increased bilirubin production was not crucial to the development of Hyperbilirubinemia, but presence of the variant UGT1A1 gene did confer increased risk. Pediatrics 1999;104:68-74; bilirubin, carbon monoxide, carboxyhemoglobin, females, gas chromatography, Gilbert's syndrome, glucose-6-phosphate dehydrogenase deficiency, hemolysis, Hyperbilirubinemia, neonates, polymerase chain reaction, Sephardic Jews, screening test, uridine 5'-diphosphate glucuronosyltransferase.
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Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to Neonatal Hyperbilirubinemia.
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Michael Kaplan, Paul Renbaum, Cathy Hammerman, Amnon Lahad, Ephrat Levy-lahad, Ernest BeutlerAbstract:Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the gene for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC 2.4.1.17; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of Neonatal Hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G-6-PD deficient neonates developed serum total bilirubin >/= 257 micromol/liter, vs. 22 (9.2%) normals (P = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of Hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant UDPGT1 genotype had a higher incidence of Hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Among G-6-PD-deficient infants the incidence of Hyperbilirubinemia was greater in those with the heterozygous (31.6%, P = 0.006) or variant homozygous (50%, P = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of Hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.
Vinod K. Bhutani - One of the best experts on this subject based on the ideXlab platform.
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clinical trial of tin mesoporphyrin to prevent Neonatal Hyperbilirubinemia
Journal of Perinatology, 2016Co-Authors: Vinod K. Bhutani, Ronald L Poland, Linda Meloy, T Hegyi, Avroy A Fanaroff, M J MaiselsAbstract:To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. Masked, SnMP (4.5 mg kg−1), placebo-controlled, multicenter trial of single intramuscular injection to newborns ⩾35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP (n=87) or ‘sham’ (n=89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group (P<0.001). At age 7 to 10 days, mean TB declined 18% (P<0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent Hyperbilirubinemia.
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the preterm infant a high risk situation for Neonatal Hyperbilirubinemia due to glucose 6 phosphate dehydrogenase deficiency
Clinics in Perinatology, 2016Co-Authors: Cathy Hammerman, Michael Kaplan, Vinod K. BhutaniAbstract:Prematurity and glucose-6-phosphate dehydrogenase (G6PD) deficiency are risk factors for Neonatal Hyperbilirubinemia. The 2 conditions may interact additively or synergistically, contributing to extreme Hyperbilirubinemia, with the potential for bilirubin neurotoxicity. This Hyperbilirubinemia is the result of sudden, unpredictable, and acute episodes of hemolysis in combination with immaturity of bilirubin elimination, primarily of conjugation. Avoidance of contact with known triggers of hemolysis in G6PD-deficient individuals will prevent some, but not all, episodes of hemolysis. All preterm infants with G6PD deficiency should be vigilantly observed for the development of jaundice both in hospital and after discharge home.
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Universal bilirubin screening for severe Neonatal Hyperbilirubinemia
Journal of Perinatology, 2010Co-Authors: Vinod K. Bhutani, R J Vilms, L Hamerman-johnsonAbstract:To reduce the incidence of severe Neonatal Hyperbilirubinemia affecting newborns with jaundice in the United States and to prevent kernicterus, there is a need to implement proven prevention strategies for severe Neonatal Hyperbilirubinemia as recommended in the 2004 American Academy of Pediatrics Guidelines for newborns >35 weeks gestational age. The purpose of universal predischarge bilirubin screening is to identify infants with bilirubin levels >75th percentile for age in hours and track those with rapid rates of bilirubin rise (>0.2 mg per 100 ml per h). Early identification has been reported to predict severe Hyperbilirubinemia and allow for evidence-based targeted interventions. A systems approach is likely to reduce the preventable causes of acute bilirubin encephalopathy. To do so, highest priority should be given to (i) designating extreme Hyperbilirubinemia (total serum bilirubin >427 μmol l(-1) or >25 mg per 100 ml) as a reportable condition by laboratories and health-care providers through public health mandates; (ii) implementation of Joint Commission's Sentinel Report for kernicterus; (iii) nursing outreach to communities for education of prospective parents; (iv) development of clinical pathways to monitor, evaluate and track infants with extreme Hyperbilirubinemia; and (v) societal awareness. These efforts should be monitored by a state and national surveillance system in order to critically improve the timeliness and completeness of notifications and to allow evaluation and interventions at the policy and individual family level.
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A proposal to prevent severe Neonatal Hyperbilirubinemia and kernicterus
Journal of Perinatology, 2009Co-Authors: Vinod K. Bhutani, Lois H. JohnsonAbstract:To address systems failures and promote a safer management of newborn jaundice, we propose an 'aviation safety standard' for newborn health-care services during the first week after birth. Systems failure in newborn jaundice management has been characterized by lapses in concern, loss of continuity, and delays in care by multiple providers at multiple sites. Components for a six-step national strategy to prevent severe Neonatal Hyperbilirubinemia and possibly kernicterus are being implemented as delineated in the 2004 AAP guidelines. The clinical guidelines for safer and evidence-based practice have been characterized by both healthcare and societal communities. Professional and community organizations are optimizing outreach resources and facilitating institutionalization of these practices. Nationwide implementation at individual birthing hospitals concurrent with surveillance feedback needs to be initiated. Implementation of a 'six-sigma' approach, as proposed to the current Center for Disease Control and Prevention-initiated partnership (health-care providers, public health and community advocates) may be achieved through collaboration with state and national agencies.
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management of jaundice and prevention of severe Neonatal Hyperbilirubinemia in infants or 35 weeks gestation
Neonatology, 2008Co-Authors: Vinod K. Bhutani, M J Maisels, Ann R Stark, Giuseppe BuonocoreAbstract:Kernicterus is still occurring but should be largely preventable if health care personnel follow the recommendations listed in this guideline. These recommendations emphasize the importance of universal, systematic assessment of the risk of severe Hyperbilirubinemia, lactation support, close follow-up, and prompt intervention when necessary. A systems-based approach to prevent severe Neonatal Hyperbilirubinemia should be implemented at all birthing facilities and coordinated with continuing ambulatory care. Translational research is needed to better understand the mechanisms of bilirubin neurotoxicity and potential therapeutic interventions.
Kiyoshi Hayasaka - One of the best experts on this subject based on the ideXlab platform.
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Association of breast-fed Neonatal Hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding
Journal of Human Genetics, 2013Co-Authors: Hiroko Sato, Toshihiko Uchida, Kentaro Toyota, Miyako Kanno, Taeko Hashimoto, Masashi Watanabe, Tomohiro Nakamura, Gen Tamiya, Kuraaki Aoki, Kiyoshi HayasakaAbstract:Breastfeeding jaundice is a well-known phenomenon, but its pathogenesis is still unclear. Increased production of bilirubin, impaired hepatic uptake and metabolism of bilirubin, and increased enterohepatic circulation of bilirubin account for most cases of pathological Neonatal Hyperbilirubinemia. We previously reported that 211G>A (G71R) mutation of the UGT1A1 gene is prevalent in East Asians and is associated with the development of Neonatal Hyperbilirubinemia. Recently, significant association of G71R mutation with Hyperbilirubinemia in breast-fed neonates was reported. We enrolled 401 full-term Japanese infants, who were exclusively breast-fed without supplementation of formula before developing Hyperbilirubinemia, and classified them into two groups based on the degree of maximal body weight loss during the Neonatal period. We analyzed the sex, gestational age, delivery mode, body weight at birth, maximal body weight loss and genotypes of G71R and (TA)_7 polymorphic mutations of UGT1A1 . Statistical analysis revealed that maximal body weight loss during the Neonatal period is the only independent risk factor for the development of Neonatal Hyperbilirubinemia. The effect of G71R mutation on Neonatal Hyperbilirubinemia is significant in neonates with 5% or greater maximal body weight loss and its influence increases in parallel with the degree of maximal body weight loss. Our study indicates that G71R mutation is a risk factor for Neonatal Hyperbilirubinemia only in infants with inadequate breastfeeding and suggests that adequate breastfeeding may overcome the genetic predisposing factor, G71R mutation, for the development of Neonatal Hyperbilirubinemia.
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Neonatal Hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese
Journal of Human Genetics, 1999Co-Authors: Kazuhiro Akaba, Ayako Sasaki, Saori Tanabe, Kazuko Maki, Shogo Aikawa, Seiji Yasumura, Masahiko Hiroi, Takashi Wakabayashi, Toshiyuki Kimura, Kiyoshi HayasakaAbstract:Neonatal Hyperbilirubinemia, which is prevalent among Asian peoples, has been considered as a physiological phenomenon, and its metabolic basis has not been clearly explained. Gilbert syndrome is a common inherited disease of unconjugated Hyperbilirubinemia due to decreased bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT), and its role in Neonatal jaundice has recently been considered. We have previously reported that the Gly71Arg mutation of the B-UGT gene associated with Gilbert syndrome is prevalent in Japanese, Korean, and Chinese populations and was more frequently detected in neonates with severe Hyperbilirubinemia than in control subjects. We have studied 159 Japanese full-term neonates, evaluating the relationship between the B-UGT genotype and the severity of jaundice, as assessed with a transcutaneous bilirubinometer. The gene frequency of the Gly71Arg mutation in these neonates was 0.19, and neonates carrying the Gly71Arg mutation had significantly increased bilirubin levels on days 2-4, manifested in a gene dose-dependent manner. The frequency of the Gly71Arg mutation was 0.47 in the neonates who required phototherapy (i.e., those with more severe Hyperbilirubinemia), significantly higher than 0.16 in the neonates who did not require the therapy. The gene frequency of the TA repeat promoter polymorphism, the (TA)7 mutation, was 0.07, and neonates carrying this mutation did not have an increase in bilirubin. These results suggested that the Gly71Arg mutation contributes to the high incidence of Neonatal Hyperbilirubinemia in Japanese.
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Neonatal Hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese.
Biochemistry and molecular biology international, 1998Co-Authors: Kazuhiro Akaba, Ayako Sasaki, Tetsuo Ikegami, Hirotoshi Umeda, I Yuasa, Saori Tanabe, KENJI UMETSU, H. Chiba, M Hashimoto, Kiyoshi HayasakaAbstract:We analyzed the bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT) gene in 42 Japanese newborns with Hyperbilirubinemia and determined that 21 infants were heterozygous while 3 was homozygous for Gly71Arg. Allele frequency of Gly71Arg was 0.32 in newborns with Hyperbilirubinemia, which was significantly higher than 0.13 in healthy Japanese controls. This mutant allele is also prevalent among Korean and Chinese healthy controls with a frequency of 0.23 in both populations. However, this mutation was not detected in 50 healthy German controls. These data suggest that the high frequency of the Gly71Arg mutation of the B-UGT gene is associated with high incidence of Neonatal Hyperbilirubinemia in Japanese, Korean and Chinese populations.
David K. Stevenson - One of the best experts on this subject based on the ideXlab platform.
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hemolysis and glucose 6 phosphate dehydrogenase deficiency related Neonatal Hyperbilirubinemia
Neonatology, 2018Co-Authors: Michael Kaplan, Ronald J. Wong, David K. StevensonAbstract:Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme Neonatal Hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants. Objectives To explore the role of hemolysis in Neonatal Hyperbilirubinemia associated with G6PD deficiency. Methods Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition. Results Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme Hyperbilirubinemia. Conclusions Hemolysis is an important pathogenetic factor in G6PD deficiency-associated Neonatal Hyperbilirubinemia.
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inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model
Pediatric Research, 2016Co-Authors: Kazumichi Fujioka, Ronald J. Wong, Flora Kalish, David K. StevensonAbstract:Increased bilirubin production due to hemolysis can lead to Neonatal Hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for Neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants. After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT–PCR, respectively. After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed. ZnPP-Lipid is effective and thus has potential for treating Neonatal Hyperbilirubinemia due to hemolysis.
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association of hmox1 gene promoter polymorphisms with Hyperbilirubinemia in the early Neonatal period
Pediatrics International, 2015Co-Authors: Yoshinori Katayama, Ronald J. Wong, David K. Stevenson, Hajime Nakamura, Hui Zhao, Tomoyuki Yokota, Mariko Taniguchiikeda, Kazumoto Iijima, Ichiro MoriokaAbstract:Background Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with Neonatal Hyperbilirubinemia in a population of Japanese term neonates. Methods Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on Hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with Hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case–control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates. Results The prevalence of short alleles (<22 (GT)n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of Neonatal Hyperbilirubinemia (OR, 3.1; 95%CI: 1.03–9.53). Conclusions Infants carrying short alleles (<22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing Neonatal Hyperbilirubinemia.
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effects of light on metalloporphyrin treated newborn mice
Acta Paediatrica, 2014Co-Authors: Ronald J. Wong, Hendrik J. Vreman, Stephanie Schulz, Cecilia Espadas, Jayakumar Rajadas, David K. StevensonAbstract:UNLABELLED Zinc protoporphyrin (ZnPP) is a promising metalloporphyrin with sufficient potency, but has poor solubility and is not absorbed well orally. Intragastric administration of ZnPP microparticles (30 μmol/kg) to 3-day-old mice resulted in a twofold increase in potency and no signs of phototoxicity. CONCLUSION The use of polymeric particulate delivery systems can improve the stability and enhance intestinal absorption of ZnPP, while retaining HO inhibitory potency without photosensitising effects, and thus is potentially useful in treating Neonatal Hyperbilirubinemia.
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Pharmacology Review: Tin Mesoporphyrin for the Prevention of Severe Neonatal Hyperbilirubinemia
NeoReviews, 2007Co-Authors: Ronald J. Wong, Vinod K. Bhutani, Hendrik J. Vreman, David K. StevensonAbstract:Competitive inhibitors of heme oxygenase (HO) have been studied as interventional agents for Neonatal Hyperbilirubinemia. Several naturally occurring and synthetic metalloporphyrins have been shown to be potent inhibitors of HO activity and effective in reducing bilirubin concentrations in vitro and in vivo. Targeting HO may aid in preventing Hyperbilirubinemia in newborns. Tin mesoporphyrin (SnMP) has emerged as a potential agent for reducing total bilirubin concentrations in preterm newborns. Adverse effects associated with SnMP use include photosensitization (which complicates its use in conjunction with phototherapy), and potential inhibition of several other enzymes that have essential roles in metabolism. Clinical studies of SnMP have shown that it prevents excessive Neonatal Hyperbilirubinemia and reduces the need for Neonatal phototherapy in term and near-term infants. Because further research, specifically safety investigations, are complicated, use of SnMP should be reserved for neonates who are at especially high risk for developing bilirubin-induced neurologic dysfunction or participating in clinical trials.
