RESUMEN
The mechanisms involved in bilirubin neurotoxicity are still far from being fully elucidated. Several different events concur to damage mainly the neurons among which inflammation and alteration of the redox state play a major role. An imbalance of cellular calcium homeostasis has been recently described to be associated with toxic concentrations of bilirubin, and this disequilibrium may in turn elicit an inflammatory reaction. The different and age-dependent sensitivity to bilirubin damage must also be considered in describing the dramatic clinical picture of bilirubin-induced neurological damage (BIND) formerly known as kernicterus spectrum disorder (KSD). This review aims to critically address what is known and what is not in the molecular events of bilirubin neurotoxicity to provide hints for a better diagnosis and more successful treatments. Part of these concepts have been presented at the 38th Annual Audrey K. Brown Kernicterus Symposium of Pediatric American Society, Washington DC, May 1, 2023.
Asunto(s)
Bilirrubina , Encéfalo , Kernicterus , Humanos , Bilirrubina/metabolismo , Kernicterus/metabolismo , Kernicterus/etiología , Encéfalo/metabolismo , Recién Nacido , Neuronas/metabolismo , Animales , Calcio/metabolismo , Oxidación-ReducciónRESUMEN
Bilirubin encephalopathy is a severe complication of neonatal hyperbilirubinemia. With elevation of serum unconjugated bilirubin (UCB) levels, UCB crosses the blood-brain barrier and possibly leads to neurological dysfunction. Neuroinflammation is recognized as a prominent pathological feature in bilirubin encephalopathy. Recent studies have suggested that autophagy plays a crucial role in the inflammatory response. However, the potential effect of microglial autophagy in the pathogenesis of bilirubin encephalopathy remains uncertain. The in vitro findings verified that in primary cultured microglia, UCB significantly reduced the ratio of LC3B-II to LC3B-I and downregulated the expression of ATG5, Beclin-1, and ATG7, while increasing the expression of p62/SQSTM1. The results showed that UCB could decrease the number of mCherry-EGFP-LC3 positive puncta, even when chloroquine (CQ) was applied to block the microglial autophagy flux. Mechanistically, UCB was found to upregulate the expression of TLR4 and increase the phosphorylation levels of Akt and mammalian target of rapamycin (mTOR). Promoting microglial autophagy by treatment with Rapamycin (RAPA), an mTOR inhibitor, decreased the levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and IL-1ß, rescued microglial overactivation, and improved neurological functions. These data indicated that UCB could impact microglial autophagy via the Akt-mTOR signaling pathway and synergistically promote neuroinflammatory responses. Enhancing autophagy might disrupt the assembly of NLRP3 inflammasome, attenuate UCB-induced neuroinflammation, and improve the prognosis of model rats with bilirubin encephalopathy. In conclusion, this study implies that regulating microglial autophagy might be a promising therapeutic strategy for bilirubin encephalopathy.
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Kernicterus , Microglía , Ratas , Animales , Microglía/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Bilirrubina/farmacología , Bilirrubina/metabolismo , Kernicterus/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias , Transducción de Señal , Autofagia/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Mamíferos/metabolismoRESUMEN
There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible deep brain stimulation surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH), UK, were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the 10 commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of 39 adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired cerebral palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1 and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. 'Signature' patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalized management strategies.
Asunto(s)
Parálisis Cerebral , Distonía , Trastornos Distónicos , Kernicterus , Adulto , Recién Nacido , Humanos , Niño , Fluorodesoxiglucosa F18/metabolismo , Distonía/metabolismo , Kernicterus/complicaciones , Kernicterus/metabolismo , Encéfalo/metabolismo , Trastornos Distónicos/metabolismo , Tomografía de Emisión de Positrones/métodos , Glucosa/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
Despite the availability of successful prevention strategies to prevent excessive hyperbilirubinemia, the neurological sequelae of bilirubin neurotoxicity (BNTx) still occur throughout the world. Kernicterus, encephalopathy due to BNTx, is now understood to be a spectrum of severity and phenotypes known as kernicterus spectrum disorder (KSD). A better understanding of the selective neuropathology and molecular biology of BNTx and using consistent clinical definitions of KSDs as outcome measure can lead to more accurately predicting the risk and causes of BNTx and KSDs. In Part I of our two-part review, we will summarize current and recent advances in the understanding of the selective neuropathology and molecular biology of the disease. Herein we emphasize the role of unbound, free unconjugated bilirubin as well as genetic contributions to the susceptibility BNTx and the development of KSDs. In Part II, we focus on current and possible novel methods to prevent BNTx and ABE and treat ABE and KSDs.
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Bilirrubina/metabolismo , Hiperbilirrubinemia/complicaciones , Kernicterus/etiología , Neuronas/metabolismo , Síndromes de Neurotoxicidad/etiología , Animales , Bilirrubina/sangre , Niño , Desarrollo Infantil , Preescolar , Predisposición Genética a la Enfermedad , Humanos , Hiperbilirrubinemia/sangre , Hiperbilirrubinemia/genética , Hiperbilirrubinemia/metabolismo , Lactante , Recién Nacido , Kernicterus/genética , Kernicterus/metabolismo , Kernicterus/fisiopatología , Degeneración Nerviosa , Neurogénesis , Neuronas/patología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Fenotipo , Factores de RiesgoRESUMEN
Previously in Part I of this two-part review, we discussed the current and recent advances in the understanding of the molecular biology and neuropathology of bilirubin neurotoxicity (BNTx). Here in Part II, we summarize current treatment options available to treat the severely jaundiced infants to prevent significant brain damage and improve clinical outcomes. In addition, we review potential novel therapies that are in various stages of research and development. We will emphasize treatments for both prevention and treatment of both acute bilirubin encephalopathy (ABE) and kernicterus spectrum disorders (KSDs), highlighting the treatment of the most disabling neurological sequelae of children with mild-to-severe KSDs whose "rare disease" status often means they are overlooked by the clinical research community at large. As with other secondary dystonias, treatment of the dystonic motor symptoms in kernicterus is the greatest clinical challenge.
Asunto(s)
Bilirrubina/metabolismo , Hiperbilirrubinemia/terapia , Kernicterus/prevención & control , Neuronas/metabolismo , Síndromes de Neurotoxicidad/prevención & control , Animales , Bilirrubina/sangre , Niño , Desarrollo Infantil , Preescolar , Humanos , Hiperbilirrubinemia/sangre , Hiperbilirrubinemia/complicaciones , Hiperbilirrubinemia/metabolismo , Lactante , Recién Nacido , Kernicterus/etiología , Kernicterus/metabolismo , Kernicterus/fisiopatología , Degeneración Nerviosa , Neurogénesis , Neuronas/patología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Resultado del TratamientoRESUMEN
Our objective was to assess the relationship between hyperbilirubinemia with and without kernicterus and metabolic profile at newborn screening. Included were 1,693,658 infants divided into a training or testing subset in a ratio of 3:1. Forty-two metabolites were analyzed using logistic regression (odds ratios (ORs), area under the receiver operating characteristic curve (AUC), 95% confidence intervals (CIs)). Several metabolite patterns remained consistent across gestational age groups for hyperbilirubinemia without kernicterus. Thyroid stimulating hormone (TSH) and C-18:2 were decreased, whereas tyrosine and C-3 were increased in infants across groupings. Increased C-3 was also observed for kernicterus (OR: 3.17; 95% CI: 1.18-8.53). Thirty-one metabolites were associated with hyperbilirubinemia without kernicterus in the training set. Phenylalanine (OR: 1.91; 95% CI: 1.85-1.97), ornithine (OR: 0.76; 95% 0.74-0.77), and isoleucine + leucine (OR: 0.63; 95% CI: 0.61-0.65) were the most strongly associated. This study showed that newborn metabolic function is associated with hyperbilirubinemia with and without kernicterus.
Asunto(s)
Ictericia Neonatal/diagnóstico , Kernicterus/diagnóstico , Metaboloma , Tamizaje Neonatal/métodos , Bilirrubina/sangre , Bilirrubina/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro/sangre , Recien Nacido Prematuro/metabolismo , Isoleucina/sangre , Isoleucina/metabolismo , Ictericia Neonatal/sangre , Ictericia Neonatal/complicaciones , Ictericia Neonatal/metabolismo , Kernicterus/sangre , Kernicterus/etiología , Kernicterus/metabolismo , Leucina/sangre , Leucina/metabolismo , Masculino , Metabolómica , Ornitina/sangre , Ornitina/metabolismo , Fenilalanina/sangre , Fenilalanina/metabolismo , Estudios Retrospectivos , Tirotropina/sangre , Tirotropina/metabolismoRESUMEN
Bilirubin neurotoxicity has been studied for decades and has been shown to affect various mechanisms via significant modulation of gene expression. This suggests that vital regulatory mechanisms of gene expression, such as epigenetic mechanisms, could play a role in bilirubin neurotoxicity. Histone acetylation has recently received attention in the CNS due to its role in gene modulation for numerous biological processes, such as synaptic plasticity, learning, memory, development and differentiation. Aberrant epigenetic regulation of gene expression in psychiatric and neurodegenerative disorders has also been described. In this work, we followed the levels of histone 3 lysine 14 acetylation (H3K14Ac) in the cerebellum (Cll) of the developing (2, 9, 17 days after the birth) and adult Gunn rat, the natural model for neonatal hyperbilirubinemia and kernicterus. We observed an age-specific alteration of the H3K14Ac in the hyperbilirubinemic animals. The GeneOntology analysis of the H3K14Ac linked chromatin revealed that almost 45% of H3K14Ac ChiP-Seq TSS-promoter genes were involved in CNS development including maturation and differentiation, morphogenesis, dendritogenesis, and migration. These data suggest that the hallmark Cll hypoplasia in the Gunn rat occurs also via epigenetically controlled mechanisms during the maturation of this brain structure, unraveling a novel aspect of the bilirubin-induced neurotoxicity.
Asunto(s)
Bilirrubina/metabolismo , Cerebelo/metabolismo , Histonas/metabolismo , Kernicterus/metabolismo , Acetilación , Animales , Animales Recién Nacidos/metabolismo , Cerebelo/anomalías , Discapacidades del Desarrollo/metabolismo , Modelos Animales de Enfermedad , Malformaciones del Sistema Nervioso/metabolismo , Plasticidad Neuronal/fisiología , Ratas , Ratas GunnRESUMEN
Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.
Asunto(s)
Bilirrubina/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Pérdida Auditiva/etiología , Kernicterus/etiología , Síndromes de Neurotoxicidad/etiología , Enfermedad Aguda , Animales , Antiinflamatorios/farmacología , Ataxia/etiología , Ataxia/metabolismo , Bilirrubina/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Pérdida Auditiva/metabolismo , Pérdida Auditiva/prevención & control , Humanos , Hiperbilirrubinemia/complicaciones , Hiperbilirrubinemia/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Kernicterus/metabolismo , Lipocalina 2/deficiencia , Lipocalina 2/genética , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos CBA , Ratones Noqueados , FN-kappa B/metabolismo , Síndromes de Neurotoxicidad/metabolismoRESUMEN
INTRODUCTION: Hemolytic kernicterus, an indirect bilirubin-induced brain dysfunction, is associated with hyper-bilirubinemia in mammalian neonates. In this study, a new model of kernicterus has been developed using intra-peritoneal injections of phenyl hydrazine and subcutaneous injections of sulfisoxazole. These drugs can potentially induce kernicterus in neonatal through changes in hemolysis and hypo-albumin. METHODS: For this purpose, 7-day-old male Wistar rats (n=72; mean weight 11±1g) were used. The animals have been divided into six different groups which received the drugs alone and their combination, and the drugs' solvents and their combination. Biochemical parameters, brain iron and bilirubin, behavioural performance, auditory function and apoptosis were measured using auto-analyser instruments; atomic absorption spectroscopy, Sawasaki, footprint, auditory brainstem response (ABR) and TUNEL test, respectively. RESULT: The drug-injected groups showed a significant reduction in serum haematocrit and an increase in the concentration of brain bilirubin, total and indirect bilirubin as well as TUNEL positive cells in basal ganglia. In addition, the obtained results showed that there was a significant increase in behavioural disturbance and auditory dysfunction in the group injected with the combination of two drugs. CONCLUSION: This kernicterus-induced rat model could perfectly mimic the common conditions of the hyperbilirubinemia in human neonates. This study offers an easy technique to develop more stable models for follow-up studies.
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Bilirrubina/metabolismo , Modelos Animales de Enfermedad , Kernicterus/inducido químicamente , Kernicterus/metabolismo , Animales , Animales Recién Nacidos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Kernicterus/patología , Masculino , Fenilhidrazinas/toxicidad , Distribución Aleatoria , Ratas , Ratas Wistar , Sulfisoxazol/toxicidadRESUMEN
Total serum/plasma bilirubin (TB), the biochemical measure currently used to evaluate and manage hyperbilirubinemia, is not a useful predictor of bilirubin-induced neurotoxicity in premature infants. Altered bilirubin-albumin binding in premature infants limits the usefulness of TB in premature infants. In this article, bilirubin-albumin binding, a modifying factor for bilirubin-induced neurotoxicity, in premature infants is reviewed.
Asunto(s)
Bilirrubina/metabolismo , Hiperbilirrubinemia Neonatal/metabolismo , Unión Proteica , Albúmina Sérica/metabolismo , Humanos , Hiperbilirrubinemia Neonatal/complicaciones , Recién Nacido , Recien Nacido Prematuro , Kernicterus/etiología , Kernicterus/metabolismoRESUMEN
Bilirubin-induced neurotoxicity in preterm neonates remains a clinical concern. Multiple cellular and molecular cascades likely underlie bilirubin-induced neuronal injury, including plasma membrane perturbations, excitotoxicity, neuroinflammation, oxidative stress, and cell cycle arrest. Preterm newborns are particularly vulnerable secondary to central nervous system immaturity and concurrent adverse clinical conditions that may potentiate bilirubin toxicity. Acute bilirubin encephalopathy in preterm neonates may be subtle and manifest primarily as recurrent symptomatic apneic events. Low-bilirubin kernicterus continues to be reported in preterm neonates, and although multifactorial in nature, is often associated with marked hypoalbuminemia.
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Bilirrubina/metabolismo , Encéfalo/metabolismo , Membrana Celular/metabolismo , Hiperbilirrubinemia Neonatal/metabolismo , Kernicterus/metabolismo , Neuronas/metabolismo , Apnea/etiología , Apoptosis , Encéfalo/patología , Encéfalo/fisiopatología , Calcio/metabolismo , Ciclo Celular , Puntos de Control del Ciclo Celular , Imagen de Difusión por Resonancia Magnética , Estrés del Retículo Endoplásmico , Humanos , Hiperbilirrubinemia Neonatal/complicaciones , Recién Nacido , Recien Nacido Prematuro , Inflamación , Kernicterus/diagnóstico por imagen , Kernicterus/etiología , Kernicterus/fisiopatología , Imagen por Resonancia Magnética , Mitocondrias/metabolismo , Necrosis , Neuronas/patología , Estrés Oxidativo , Insuficiencia Respiratoria/etiologíaRESUMEN
Hyperbilirubinemia occurs frequently in newborns, and in severe cases can progress to kernicterus and permanent developmental disorders. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymopathies, is a major risk factor for hyperbilirubinemia and greatly increases the risk of kernicterus even in the developed world. Therefore, a novel treatment for kernicterus is needed, especially for G6PD-deficient newborns. Oxidative stress is a hallmark of bilirubin toxicity in the brain. We propose that the activation of G6PD via a small molecule chaperone is a potential strategy to increase endogenous defense against bilirubin-induced oxidative stress and prevent kernicterus.
Asunto(s)
Antioxidantes/uso terapéutico , Deficiencia de Glucosafosfato Deshidrogenasa/metabolismo , Hiperbilirrubinemia Neonatal/terapia , Kernicterus/prevención & control , Chaperonas Moleculares/uso terapéutico , Fototerapia , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Humanos , Hiperbilirrubinemia Neonatal/complicaciones , Hiperbilirrubinemia Neonatal/metabolismo , Recién Nacido , Kernicterus/etiología , Kernicterus/metabolismo , Kernicterus/terapiaAsunto(s)
Encéfalo/fisiopatología , Hiperbilirrubinemia Neonatal/fisiopatología , Kernicterus/fisiopatología , Bilirrubina/metabolismo , Encéfalo/metabolismo , Comorbilidad , Humanos , Hiperbilirrubinemia Neonatal/complicaciones , Hiperbilirrubinemia Neonatal/metabolismo , Recién Nacido , Recien Nacido Prematuro , Kernicterus/etiología , Kernicterus/metabolismoAsunto(s)
Hiperbilirrubinemia Neonatal/terapia , Kernicterus/prevención & control , Sordera/etiología , Deficiencia de Glucosafosfato Deshidrogenasa/metabolismo , Hemólisis , Humanos , Hiperbilirrubinemia Neonatal/complicaciones , Hiperbilirrubinemia Neonatal/metabolismo , Recién Nacido , Recien Nacido Prematuro , Kernicterus/etiología , Kernicterus/metabolismo , Fototerapia , Guías de Práctica Clínica como Asunto , Unión ProteicaRESUMEN
BACKGROUND: A novel filtered-sunlight phototherapy (FSPT) device has been demonstrated to be safe and efficacious for treating infants with neonatal jaundice in resource-constrained tropical settings. We set out to provide baseline data for evaluating the clinical impact of this device in a referral pediatric hospital. METHODS: We reviewed the medical records of infants admitted for neonatal hyperbilirubinemia in an inner-city Children's Hospital in Lagos, between January 2012 and December 2014 to determine the pattern, treatment and outcomes during the pre-intervention period. Factors associated with adverse outcomes were identified through multivariable logistic regression. RESULTS: Of the 5,229 neonatal admissions over the period, a total of 1,153 (22.1%) were admitted for neonatal hyperbilirubinemia. Complete records for 1,118 infants were available for analysis. The incidence of acute bilirubin encephalopathy (ABE) and exchange transfusion (ET) were 17.0% (95% CI: 14.9%-19.3%) and 31.5% (95% CI: 28.8%-34.3%) respectively. A total of 61 (5.5%, 95% CI: 4.3%-6.9%) of the jaundiced infants died. Weight on admission, peak total serum bilirubin (TSB), sepsis and exposure to hemolytic products were predictive of ABE, while age on admission, peak TSB, ABO incompatibility and ABE were predictive of ET. Rhesus incompatibility, asphyxia, exposure to hemolytic substances and ABE were associated with elevated mortality risk, while ET was a protective factor. Lack of routine irradiance monitoring and steady energy supply were frequent challenges for conventional blue-light phototherapy. CONCLUSIONS: Severe hyperbilirubinemia is associated with high rates of ABE and ET in this setting, and remains a significant contributor to neonatal admissions and mortality. To be impactful, FSPT, complemented with improved diagnostic facilities, should effectively curtail jaundice-related adverse outcomes in this and comparable settings.
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Helioterapia/métodos , Ictericia Neonatal/terapia , Bilirrubina/metabolismo , Incompatibilidad de Grupos Sanguíneos/metabolismo , Recambio Total de Sangre/métodos , Femenino , Helioterapia/efectos adversos , Humanos , Incidencia , Recién Nacido , Ictericia Neonatal/metabolismo , Kernicterus/metabolismo , Kernicterus/terapia , Modelos Logísticos , Masculino , Nigeria , Fototerapia/efectos adversos , Fototerapia/métodos , Luz SolarRESUMEN
BACKGROUND: Bilirubin encephalopathy (BE) is a severe neurologic sequelae induced by hyperbilirubinemia in newborns. However, the pathogenetic mechanisms underlying the clinical syndromes of BE remain ambiguous. Ex vivo (1)H nuclear magnetic resonance (NMR) spectroscopy was used to measure changes in the concentrations of cerebral metabolites in various brain areas of newborn 9-day-old rats subjected to bilirubin to explore the related mechanisms of BE. RESULTS: When measured 0.5 hr after injection of bilirubin, levels of the amino acid neurotransmitters glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) in hippocampus and occipital cortex significantly decreased, by contrast, levels of aspartate (Asp) considerably increased. In the cerebellum, Glu and Gln levels significantly decreased, while GABA, and Asp levels showed no significant differences. In BE 24 hr rats, all of the metabolic changes observed returned to normal in the hippocampus and occipital cortex; however, levels of Glu, Gln, GABA, and glycine significantly increased in the cerebellum. CONCLUSIONS: These metabolic changes for the neurotransmitters are mostly likely the result of a shift in the steady-state equilibrium of the Gln-Glu-GABA metabolic cycle between astrocytes and neurons, in a region-specific manner. Changes in energy metabolism and the tricarboxylic acid cycle may also be involved in the pathogenesis of BE.
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Encéfalo/metabolismo , Encéfalo/patología , Kernicterus/etiología , Kernicterus/metabolismo , Metaboloma , Espectroscopía de Protones por Resonancia Magnética , Animales , Animales Recién Nacidos , Bilirrubina/sangre , Análisis Discriminante , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Kernicterus/sangre , Análisis de los Mínimos Cuadrados , Análisis Multivariante , Análisis de Componente Principal , Ratas Sprague-Dawley , Extractos de TejidosRESUMEN
BACKGROUND: Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats. METHODS: On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pHâ=â8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test. RESULTS: The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (Pâ=â0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test. CONCLUSION: By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available.
Asunto(s)
Antioxidantes/efectos adversos , Bilirrubina/efectos adversos , Cisterna Magna , Modelos Animales de Enfermedad , Kernicterus , Animales , Animales Recién Nacidos , Antioxidantes/farmacología , Bilirrubina/farmacología , Cisterna Magna/metabolismo , Cisterna Magna/patología , Kernicterus/inducido químicamente , Kernicterus/metabolismo , Kernicterus/patología , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: To evaluate the usefulness of (1) H-MRS in differentiating bilirubin encephalopathy from severe hyperbilirubinemia in neonates. MATERIALS AND METHODS: There were 11 patients enrolled in the neonatal bilirubin encephalopathy (NBE) group, 8 patients in the neonatal hyperbilirubinemia (NH) group, and 9 healthy, age-matched neonates were included as controls. All patients and controls underwent (1) H-MRS and conventional magnetic resonance (MR) sequences. The spectroscopic regions of interest were the bilateral basal ganglia and the thalamus, and a spatial resolution of 1.0 cm(3) was obtained. RESULTS: Peak-area ratios of NAA/Cr and NAA/ Cho in the basal ganglia were found to be significantly lower for the NBE group compared with the NH and control groups (P < 0.05). In contrast, there was no significant difference in the NAA/Cr ratios calculated for basal ganglia of the NH and control groups. Peak-area ratios of NAA/Cr and NAA/Cho in the thalamus were decreased for the NBE group compared with the NH and control groups, but the differences were not significant (P > 0.05). There was a significant correlation between NAA/Cr ratios for basal ganglia and the total serum bilirubin (TSB) peak level in the NBE group (P < 0.05). CONCLUSION: (1) H-MRS is useful in the differential diagnosis of NBE from severe hyperbilirubinemia in neonates, especially when the symptoms of NBE are atypical (subtle) and MRI does not reveal clear abnormalities.
Asunto(s)
Ácido Aspártico/análogos & derivados , Colina/metabolismo , Creatinina/metabolismo , Hiperbilirrubinemia Neonatal/diagnóstico , Kernicterus/diagnóstico , Espectroscopía de Resonancia Magnética/métodos , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Hiperbilirrubinemia Neonatal/metabolismo , Recién Nacido , Kernicterus/metabolismo , Masculino , Protones , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Two preterm infants with athetoid cerebral palsy due to bilirubin encephalopathy were examined by magnetic resonance spectroscopic imaging at age 3 years. An increased glutamate/glutamine complex/creatine ratio was found in the basal ganglia. Chemical metabolic abnormalities of the basal ganglia were clearly demonstrated by color-coded metabolite images.