Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus.

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.

Heliotherapy for Neonatal Hyperbilirubinemia in Southwest, Nigeria: A Baseline Pre-Intervention Study.

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.

Pharmacological therapies for unconjugated hyperbilirubinemia.

Severe unconjugated hyperbilirubinemia, seen mainly in neonates, may cause kernicterus and death. Conventional treatment for severe unconjugated hyperbilirubinemia consists of phototherapy and exchange transfusion. Phototherapy, however, has several known disadvantages while exchange transfusion is associated with a significant morbidity, and even mortality. These harmful effects indicate the need to develop alternative pharmacological treatment strategies for unconjugated hyperbilirubinemia. Generally, these strategies aim to decrease the plasma concentration of unconjugated bilirubin (UCB) by inhibiting production, stimulating hepatic clearance, or interrupting the enterohepatic circulation of the pigment. To be considered for routine clinical use, an alternative treatment strategy should be less invasive and at least as effective and safe as phototherapy. Several pharmacological therapies such as metalloporhyrins, clofibrate, bile salts, laxatives and bilirubin oxidase may meet these criteria in the future, but none of them has yet been evaluated sufficiently to allow routine application. This review aims to discuss the state of the art and future perspectives in pharmacological treatment of neonatal jaundice.

Photoisomers: obfuscating factors in clinical peroxidase measurements of unbound bilirubin?

OBJECTIVES: The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic. METHODS: 4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated. RESULTS: The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of approximately 25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (<20%) in the apparent free bilirubin concentration; for bilirubin in serum, conversion of approximately 15% of the 4Z,15Z-isomer to photoisomers resulted in a much larger increase ( approximately 40%). Irradiation of bilirubin in bovine serum albumin solution generated a very different array of photoisomers than that observed in human albumin solutions. CONCLUSIONS: The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.

Studying neonatal bilirubin encephalopathy with conventional MRI, MRS, and DWI.

INTRODUCTION: The purpose of this study was to evaluate the diagnostic value of conventional magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy ((1)H-MRS), and diffusion-weighted imaging (DWI) for neonatal bilirubin encephalopathy. METHODS: We collected conventional MRI in 24 neonates with neonatal bilirubin encephalopathy. We performed (1)H-MRS and DWI sequences to nine of the 24 patients and seven age-matched healthy control subjects. Multiple-voxel (1)H-MRS data were acquired using PRESS pulse sequence with TE = 135 ms and TR = 1500 ms. The spectroscopic regions of interest were the bilateral basal ganglia and thalamus with a 1.0 mL spatial resolution. The data from DWI were collected by using a single shot-spin echo-echo planar imaging sequence with TR/TE: 2900/98, and imaging regions were also focused on the bilateral basal ganglia and thalamus. RESULTS: Nineteen of the 24 patients had abnormal T(1)-weighted image hyperintensity in the globus pallidus, but these lesions appeared as normal T(2)-weighted image intensity in the same region. Ten of the 24 patients had T(1)-weighted image high signal intensity in the subthalamic nucleus and appeared as normal intensity in the region for the T(2)-weighted images. The peak area ratios of NAA/Cho and NAA/Cr were significantly decreased (t-test, P < 0.05) in the patients compared to the controls in the basal ganglia. CONCLUSION: Conventional MR imaging and (1)H-MRS are important complementary tools in the diagnosis of neonatal bilirubin encephalopathy. The study provides important information for applying these MR modalities to evaluate neonates with bilirubin encephalopathy.

Bilirubin encephalopathy: a study of neuronal subpopulations and neurodegenerative mechanisms in 12 autopsy cases.

Bilirubin encephalopathy (BE), which includes acute (kernicterus) and chronic (postkernicteric) forms, results from severe neonatal jaundice. In order to investigate neurodegenerative mechanisms in autopsy cases of BE, we immunohistochemically examined expressions of neurotransmitters, neuropeptides, and calcium-binding proteins in the basal ganglia; and deposition of oxidative products. Expression of tyrosine hydroxylase was reduced in the putamen in cases of acute BE, and in the globus pallidus in cases of acute and chronic postkernicteric BE. Methionine-enkephalin expression was reduced in the external segment of the globus pallidus in cases of acute and chronic postkernicteric BE, and immunoreactivity for substance P was severely altered in both internal and external segments in cases of chronic postkernicteric BE. A decrease in the number of parvalbumin-immunoreactive interneurons in the external segment of the globus pallidus was observed predominantly in cases of acute BE, whereas the number of interneurons immunoreactive for calbindin-D28K was reduced in the putamen in cases of chronic postkernicteric BE. Nuclear immunoreactivity for 8-hydroxy-2'-deoxyguanosine was seen in the putamen in half of the BE cases. These findings indicated that the putamen was impaired in BE and the pallidal external segment was also damaged in the acute form of BE, suggesting that oxidative damage to DNA is implicated in lesions of the basal ganglia.

[Icterus of the newborn caused by indirect bilirubin--recent progress]. / Ujszülöttek indirekt bilirubin okozta icterusa--újabb ismeretek és szempontok.

Recently a big shift has taken place in the judgment and treatment of jaundice in newborn, caused by increased unconjugated bilirubin level. New techniques evolved for assessing the prognosis of developing jaundice. An important major discovery is the antioxidant effect of bilirubin. We have a broader range of knowledge concerning the mechanism of bilirubin toxicity and for judging the chance of developing kernicterus. The prevention techniques do not stop at prohibiting anti-D immunisation but go on to preventing hydrops foetalis, the life-threatening form of haemolytic disease. There are data about the complications of phototherapy and EPO treatment for prolonged anaemia.

[Changes in the synaptosomal membrane in the modelling of the phototherapeutic action used in bilirubin encephalopathy]. / Izmeneniia v sinaptosomal'noi membrane pri modelirovanii fototerapevticheskogo vozdeistviia, primeniaemogo pri bilirubinovoi éntsefalopatii.

Continuous irradiation of bilirubin containing (3.10(-5) M) particles of the synaptosomal membrane (pH 7.2, at 10 degrees C) with blue light for 2 hours led to decrease of the total specific activity of ATPase, specific activity of Na, K-ATPase, and (less significantly and at a slower rate) specific activity of acetilcholinesterase. Pre-irradiation argon barbotage of the aqueous suspension of the synaptosomal membrane particles or addition of tocopherol acetate to the suspension counteracted the irradiation induced decrease of the enzyme activity. A counteraction was also produced by pre-irradiation alkalization of the suspension to pH 7.8 at 10 degrees C or addition of serum albumin to the suspension; the character of the effect of this protein on the activity of the membrane enzymes in irradiation was determined by certain peculiarities of its chemical composition. The strongest counteraction to the irradiation induced decrease of enzyme activity occurred in addition of monomeric albumin, freed of organophilic ligands, when pH of the suspension was 7.8 (10 degrees C). The activity of Na, K-ATPase and acetylcholinesterase was reduced most markedly when monomeric ligand containing albumin was added to a suspension of membrane particles which was acidified to pH 6.8 (10 degrees C) before the beginning of irradiation.

The neurotoxicity of bilirubin.

Recent clinical and research findings on kernicterus and bilirubin toxicity are reviewed. Bilirubin binds to cell membranes and appears to interfere with the metabolism, depolarization, and transmitter functions of neurons. The neurobehavioral and clinical findings associated with bilirubin encephalopathy and low bilirubin kernicterus are presented and evaluated. Cardiorespiratory stabilization, avoidance of displacing drugs, and preventive use of phototherapy appear to have decreased the incidence of low bilirubin kernicterus in high-risk newborns.

Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement.

Kernicterus, the primary manifestation of neonatal bilirubin toxicity, remains an important complication of unconjugated hyperbilirubinaemia despite advances made with phototherapy and exchange transfusions. It results from the penetration of bilirubin into neuronal tissues of the CNS with subsequent damage to the mitochondrion. A number of factors may modify or potentiate bilirubin toxicity, including drugs administered to the infant. The importance of drug-bilirubin interactions in the pathogenesis of kernicterus was first realised quite inadvertently in the 1950s, and the potential risk for significant drug-bilirubin interactions has since become an important consideration in neonatal drug therapy. All drugs intended for use in newborn infants should be evaluated for their capacity to displace bilirubin. A number of techniques have been developed which have facilitated investigation of the mechanisms mediating the bilirubin-displacing effects of drugs and the pharmacokinetics of drug-bilirubin interactions. Further, the clinical risk for inducing kernicterus has been investigated for many of the drugs to which neonates may be exposed by direct administration, transplacentally, or through breast milk. This review summarises the available knowledge concerning the physicochemical properties and toxicities of bilirubin, reviews the methodologies used in evaluating drug-bilirubin interactions, and focuses on the mechanisms, pharmacokinetics and clinical significance of the bilirubin displacing effects of antibiotics, anticonvulsants, diuretics, and other important drug classes used in the treatment of neonates.

Kernicterus 1980: problems and practices viewed from the perspective of the practicing clinician.

An understanding of the pathophysiologic factors causing kernicterus, the determination of infants at greatest risk for developing kernicterus, even the cornerstone of therapy for kernicterus--controlling the bilirubin level--are in a current (and continuous) state of revision. These changing concepts are discussed in light of recent research.