UGT1A1-related Bilirubin Encephalopathy/Kernicterus in Adults

Background and Aims:Bilirubin encephalopathy/kernicterus is very rare in adults.This study is aimed to investigate the clinical manifestations and genetic features of two patients with UGT1A1-related kernicterus.Methods:Sanger sequencing analysis was performed to identify UGT1A1 gene mutations in the patients and their families.Bioinformatics analysis was used to predict the potential functional effects of novel missense mutations.Clinical manifestations and biochemical parameters were collected and analyzed.Results:Two patients with Crigler-Najjar syndrome type II(CNS2)developed kernicterus in adulthood.Sanger sequencing identified a compound heterozygous mutation in the UGT1A1 gene in patient 1,which was inherited from his mother(G71R)and his father(c.-3279T>G;S191F).Patient 2 carried three heterozygous mutations,namely G71R,R209W and M391K;among which,the M391K mutation has not been reported before.Multiple prediction software showed that the M391K mutation was pathogenic.Symptoms were relieved in the two patients after phenobarbital and artificial liver support treatment.Patient 1 also underwent liver transplantation.Conclusions:Adults with CNS2 are at risk for kernicterus.Phenobarbital treatment is beneficial for maintaining bilirubin levels and preventing kernicterus.

Management of pregnancy in Crigler Najjar syndrome type 2

Crigler Najjar syndrome is associated with indirect hyperbilirubinemia due to a deficiency of enzyme Uridine Di Phospho Glucoronosyl Transferase(UDPGT).Presented here is a case of a female in the first trimester of pregnancy,who was diagnosed to have type 2 Crigler Najjar syndrome.We also discuss the management of this rare disease especially in pregnancy.Unconjugated bilirubin can cross the placental barrier causing neuro-logical damage in the newborn.Patient was carefully monitored during pregnancy and treatment with pheno-barbitone in low doses was adjusted such that the serum bilirubin levels were below 10 mg/d L.Crigler Najjar syndrome being rare needs to be diagnosed early in pregnancy to avoid adverse fetal outcomes.Phenobarbitone being an inducer of enzyme UDPGT is used as the first line of treatment and is not teratogenic in the low doses used.Treatment protocol followed was on the basis of previous reported cases and successful perinatal outcome was achieved.

Facility-based constraints to exchange transfusions for neonatal hyperbilirubinemia in resource-limited settings

Several clinical guidelines for the management of infants with severe neonatal hyperbilirubinemia recommend immediate exchange transfusion(ET) when the risk or presence of acute bilirubin encephalopathy is established in order to prevent chronic bilirubin encephalopathy or kernicterus. However, the literature is sparse concerning the interval between the time the decision for ET is made and the actual initiation of ET, especially in low- and middle-income countries(LMICs) with significant resource constraints but high rates of ET. This paper explores the various stages and potential delays during this interval in complying with the requirement for immediate ET for the affected infants, based on the available evidence from LMICs. The vital role of intensive phototherapy, efficient laboratory and logistical support, and clinical expertise for ET are highlighted. The challenges in securing informed parental consent, especially on religious grounds, and meeting the financial burden of this emergency procedure to facilitate timely ET are examined. Secondary delays arising from posttreatment bilirubin rebound with intensive phototherapy or ET are also discussed. These potential delays can compromise the effectiveness of ET and should provide additional impetus to curtail avoidable ET in LMICs.

Percentile analysis of plasma total bilirubin—How different will the rate of phototherapy for jaundice of neonates be by different standards?

Phototherapy of a jaundiced neonate is usually started when bilirubin exceeds a threshold in the standard. There are several standards used in the developed countries even though the guideline of American Academy of Pediatrics is considered to be a global standard. Although the purpose of phototherapy is the prevention of kernicterus, nowadays the prevalence of kernicterus in otherwise healthy term neonates in the developed countries is rare. Meanwhile several potential adverse effects of phototherapy have been reported. In the present study we tried to estimate how different the rate of phototherapy for the jaundice of neonates at lower risk of kernicterus would be by different standards. For this purpose, we utilized the records of plasma total bilirubin (TB) values of 1893 healthy neonates of 38 weeks and more which were measured on day 6 for the percentile analysis. However, this database did not include the TB values of the neonates who received phototherapy by day 6. Then the database was corrected with an assumption that TB on day 6 would have been normally distributed if no phototherapy had been performed. The mean and the standard deviation (SD) of corrected database were 11.29 mg/dl (193 μmol/l) and 3.63 mg/dl (62 μmol/l), respectively. Using a standard distribution with these mean and SD, the percents of TB values which exceed 18.0, 19.0, 20.0 and 21.0 mg/dl on day 6 were estimated 3.22%, 1.70%, 0.82% and 0.35%, respectively. Results of the present report would help to estimate the relative rate of phototherapy that is performed for the neonates who are term and otherwise healthy by different standards.

Characteristics and outcome of newborn admitted with acute bilirubin encephalopathy to a tertiary neonatal intensive care unit

Background Acute bilirubin encephalopathy (ABE) still represents a significant cause of morbidity and mortality throughout the world,especially in developing countries.We aimed to determine the prevalence of ABE based on the Johnson bilirubininduced neurologic dysfunction (BIND) score and to describe the discharge outcomes.Methods We prospectively studied all newborns ≥ 35 weeks with ABE by evaluating signs of mental sensorium,muscle tone,and cry patterns over 1 year.Results 12% (81 out of 674) of the newborns admitted for neonatal hyperbilirubinemia had a BIND score > 1.Their admission age was 6 ± 4.1 days;total serum bilirubin (TSB) was 31.2± 10 mg/dL (range 17.5-75.2).Of these newborns,40.7% and 21% had evidence of haemolysis and sepsis,respectively.Overall mortality was 9.9%;58% of the newborns showed signs of mild-to-moderate BIND at discharge,while 32.1% survived with an apparently normal outcome.Admission BIND score was significantly correlated with admission TSB (r=0.476,P < 0.001).Similarly,BIND score at discharge was correlated with admission TSB (r=0.442,P < 0.001) and admission BIND score (r =0.888,P < 0.001).The regression model showed that admission TSB (P < 0.001) and maternal illiteracy (P =0.034) were predictors of the BIND score at admission,while admission BIND score was the best indicator of the discharge score (P < 0.001).Conclusions ABE is still a major problem in our community.Admission TSB and maternal illiteracy are good predictors of bilirubin encephalopathy at admission and discharge.

胆红素脑病治疗现状

胆红素脑病是新生儿高胆红素血症最主要的并发症，系胆红素直接损伤中枢神经系统特定核团产生的相应症状。听觉中枢对胆红素高度敏感，听觉障碍可作为胆红素脑病的唯一临床表现。目前，临床上针对胆红素脑病的治疗主要是采取光疗及换血以快速降低血中胆红素浓度，但存有一定几率的并发症。助听器和人工耳蜗植入是听觉损伤后的补救治疗，疗效有限。因此，寻找作用于胆红素代谢及拮抗其神经毒性的药物成为目前防治胆红素脑病的新方向。

Infants at risk of significant hyperbilirubinemia in poorly-resourced countries:evidence from a scoping review

Background:Neonatal hyperbilirubinemia is frequently associated with disproportionately high rates of bilirubin-induced mortality and long-term morbidities in low-and middle-income countries(LMICs).This scoping review aimed to identify possible et iological/risk factors for clinically significant hyperbilirubinemia in LMICs so as to guide intervention and future research priorities.Data sources:We systematically searched PubMed,Scopus,Excerpt Medica Database,Cumulative Index to Nursing and Allied Health Literature,WHO Library Database,African Index Medicus,African Journals Online,Latin American and Caribbean Health Sciences Literature,and Indian Medical Journals for reports published between January 1990 and August 2014 in LMICs with per capita income of≤US$6000.We included studies on the etiology of neonatal hyperbilirubinemia or hyperbilirubinemia as signifi cant morbidity for relevant maternal,perinatal and neonatal disorders without restriction on study design.Results:A total of 131 studies were identified in 23 LMICs from different regions of the world.The factors most frequently associated with neonatal hyperbilirubinemia(in approximately 10%of all studies)were ABO and Rhesus incompatibilities,diabetes mellitus,glucose-6-phosphate dehydrogenase defi ciency,prematurity/low birth weight,infection,birth trauma,and drug-induced labor.The role of exclusive breast-feeding and genetic factors was sparsely explored.Conclusions:Several maternal,perinatal and neonatal factors are associated with neonatal hyperbilirubinemia in LMICs.Improved research efforts and strategies to address these factors are warranted to curtail the disease burden in these countries.