Unbound Bilirubin and Acute Bilirubin Encephalopathy in Infants Born Late Preterm and Term with Significant Hyperbilirubinemia.

OBJECTIVE: To compare the association of unbound bilirubin (UB), total serum bilirubin (TSB), and bilirubin:albumin molar ratio (BAMR) with acute bilirubin encephalopathy (ABE), as assessed by bilirubin-induced neurologic dysfunction (BIND) score, in infants with significant hyperbilirubinemia (TSB ≥20 mg/dL or underwent exchange transfusion). STUDY DESIGN: In this prospective cohort study, infants ≥34 weeks of gestational age with significant hyperbilirubinemia during the first 2 postnatal weeks were eligible, unless they had craniofacial malformations, chromosomal disorders, TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus and herpes simplex) infections, surgery, or a family history of congenital deafness. TSB, serum albumin, and UB were measured at hospital admission using the colorimetric, bromocresol green, and modified peroxidase method, respectively. Infants were evaluated on admission for ABE using a standardized neurologic examination and assigned a BIND score by trained physicians. Infants with a total BIND score of 0 were deemed to not have ABE, whereas those with a score ≥1 were deemed to have ABE. RESULTS: A total of 151 infants were studied, among whom 37 (24.5%) had ABE. Of these, 19 had mild ABE (BIND score 1-3) and 18 had moderate-to-severe ABE (BIND score 4-9). On logistic regression, UB, but not TSB or BAMR, was associated with ABE (aOR 1.64; 95% CI 1.17-2.3). On ordered logistic regression, UB, but not TSB or BAMR, was associated with severity of ABE (aOR 1.76; 95% CI 1.28-2.4). CONCLUSIONS: Our findings of the association between UB and ABE indicate that BIND scoring may be useful for evaluation of ABE in infants ≥34 weeks of gestational age.

Evidence Suggests a Decrease in the Incidence of Kernicterus in California.

We identified children diagnosed with kernicterus in the California Department of Developmental Services and estimated an incidence of 0.42 per 100 000 births from 1988 to 2014, significantly decreasing to 0.04 per 100 000 births after 2009. We also examined national infant kernicterus mortality from 1979 to 2016 using CDC data. It did not decrease significantly.

Neonatal acute liver failure with pulmonary yellow hyaline membrane and kernicterus

Background Neonatal acute liver failure (NALF) is a rare and life-threatening condition. It causes bilirubin to accumulate to a dangerous level in the body, causing permanent damage to vital organs such as the brain and lungs. In many cases, the etiology of NALF remains unknown. Case presentation We described a case of an 8-day-old baby girl who presented with poor oral intake, lethargy, and jaundice. Her clinical condition rapidly deteriorated with progression to multi-organ failure, and despite intensive resuscitation efforts, she expired. At autopsy, the most significant findings were liver necrosis, yellow hyaline membrane deposition in the lungs, and bilirubin deposition in the brain (kernicterus). Conclusions NALF is a rare and potentially fatal condition necessitating prompt recognition and disease-specific treatment approaches. Toxic accumulation of bilirubin in the lungs can lead to hypoxia and precipitate further ischemic injury to the liver.

Increased Serum Expression of Inflammatory Cytokines may Serve as Potential Diagnostic Biomarker for Bilirubin Encephalopathy.

OBJECTIVES: The present study was designed to explore the roles of inflammatory cytokines interleukin-1ß (IL-1ß) and Tumor growth factor-ß (TGF-ß) in the diagnosis and treatment of neonate bilirubin encephalopathy (BE). METHODS: A total of 128 BE neonates and 128 normal neonates were included. The serum samples of the BE children and controls were collected, and the levels of IL-1ß and TGF-ß were examined. Moreover, the correlation between the level of bilirubin and serum expression of IL-1ß or TGF-ß in BE patients was analyzed. Finally, receiver operating characteristic (ROC) curves were generated to determine the diagnostic value of the cytokines. RESULTS: IL-1ß and TGF-ß levels were higher in the serum of BE patients than those in non-BE patients, and the expression of either IL-1ß or TGF-ß showed a strong positive correlation with the serum expression of bilirubin in BE patients. Moreover, the results of ROC analysis showed that either IL-1ß or TGF-ß could distinguish BE patients from healthy controls. CONCLUSION: IL-1ß and TGF-ß levels were upregulated in BE and might function as potential biomarkers or therapeutic targets for BE patients.

Mortality, morbidity and clinical care in a referral neonatal intensive care unit in Haiti.

BACKGROUND: Neonatal mortality rates in Haiti are among the highest in the Western hemisphere. Few mothers deliver with a skilled birth attendant present, and there is a significant lack of pediatricians. The neonatal intensive care unit (NICU) at St. Damien Pediatric Hospital, a national referral center, is one of only five neonatology departments in Haiti. In order to target limited resources toward improving outcomes, this study seeks to describe clinical care in the St. Damien NICU. METHODS: A retrospective medical record review was performed on available medical records on all admissions to the NICU between April 2016 and April 2017. RESULTS: 220 neonates were admitted to the NICU within the study epoch. The mortality rate was 14.5%. Death was associated with a maternal diagnosis of hypertension (p = 0.03) and neonatal diagnoses of lower gestational age (p<0.0001), lower birth weight (p<0.0001), prematurity (p = 0.002), RDS p = 0.01), sepsis (p<0.0001) and kernicterus (p = 0.04). The most common diagnoses were sepsis, chorioamnionitis, respiratory distress syndrome, jaundice, prematurity and perinatal asphyxia. CONCLUSIONS: This study demonstrates that preterm birth, sepsis, RDS and kernicterus are key contributors to neonatal mortality in a Haitian national pediatric referral center NICU and as such are promising interventional targets for reducing the neonatal mortality rate in Haiti.

Maternal Instruction About Jaundice and the Incidence of Acute Bilirubin Encephalopathy in Nigeria.

OBJECTIVE: To evaluate whether teaching mothers about neonatal jaundice will decrease the incidence of acute bilirubin encephalopathy among infants admitted for jaundice. STUDY DESIGN: This was a multicenter, before-after and cross-sectional study. Baseline incidences of encephalopathy were obtained at 4 collaborating medical centers between January 2014 and May 2015 (Phase 1). Structured jaundice instruction was then offered (May to November 2015; Phase 2) in antenatal clinics and postpartum. Descriptive statistics and logistic regression models compared 3 groups: 843 Phase 1 controls, 338 Phase 2 infants whose mothers received both antenatal and postnatal instruction (group A), and 215 Phase 2 infants whose mothers received no instruction (group B) either because the program was not offered to them or by choice. RESULTS: Acute bilirubin encephalopathy occurred in 147 of 843 (17%) Phase 1 and 85 of 659 (13%) Phase 2 admissions, which included 63 of 215 (29%) group B and 5 of 338 (1.5%) group A infants. OR for having acute bilirubin encephalopathy, comparing group A and group B infants adjusted for confounding risk factors, was 0.12 (95% CI 0.03-0.60). Delayed care-seeking (defined as an admission total bilirubin ≥18 mg/dL at age ≥48 hours) was the strongest single predictor of acute bilirubin encephalopathy (OR 11.4; 6.6-19.5). Instruction decreased delay from 49% to 17%. Other major risk factors were home births (OR 2.67; 1.69-4.22) and hemolytic disease (hematocrit ≤35% plus bilirubin ≥20 mg/dL) (OR 3.03; 1.77-5.18). The greater rate of acute bilirubin encephalopathy with home vs hospital birth disappeared if mothers received jaundice instruction. CONCLUSIONS: Providing information about jaundice to mothers was associated with a reduction in the incidence of bilirubin encephalopathy per hospital admission.

IIncreased serum expression of inflammatory cytokines may serve as potential diagnostic biomarker for bilirubin encephalopathy

OBJECTIVES: The present study was designed to explore the roles of inflammatory cytokines interleukin-1β (IL-1β) and Tumor growth factor-β (TGF-β) in the diagnosis and treatment of neonate bilirubin encephalopathy (BE). METHODS: A total of 128 BE neonates and 128 normal neonates were included. The serum samples of the BE children and controls were collected, and the levels of IL-1β and TGF-β were examined. Moreover, the correlation between the level of bilirubin and serum expression of IL-1β or TGF-β in BE patients was analyzed. Finally, receiver operating characteristic (ROC) curves were generated to determine the diagnostic value of the cytokines. RESULTS: IL-1β and TGF-β levels were higher in the serum of BE patients than those in non-BE patients, and the expression of either IL-1β or TGF-β showed a strong positive correlation with the serum expression of bilirubin in BE patients. Moreover, the results of ROC analysis showed that either IL-1β or TGF-β could distinguish BE patients from healthy controls. CONCLUSION: IL-1β and TGF-β levels were upregulated in BE and might function as potential biomarkers or therapeutic targets for BE patients.

Kernicterus in an adult dog

Background: Kernicterus or bilirubin encephalopathy is a condition rarely observed in animal characterized by a yellowish discoloration of the central nervous system. It is a potentially fatal condition due to bilirubin neurotoxic effects caused by the increase of non-conjugated bilirubin pigment, which passes blood brain barrier and has been attributed to an imbalance between albumin and bilirubin levels. Intracellular bilirubin is toxic for cells and can cause decrease in protein synthesis, specially albumin, depression of cell respiration and cellular death. This paper describes kernicterus in a 2-year-old Great Dane female dog.Case: Clinically, the animal showed apathy, lethargy, weight loss and jaundice, which progressed to vomiting and neurological signs characterized by loss of consciousness and eventually coma. Blood parameters were within normal range, except for high levels of alanine aminotransferase (523 U/L), suggesting a liver lesion. The animal was submitted to euthanasia due to the poor prognosis, and at post-mortem examination it showed dehydration and severe jaundice, especially oral, vaginal and ocular mucosas, subcutaneous tissue and blood vessels intima surface. The liver had an accentuated lobular pattern, and the stomach mucosa was reddened. Multiple petechiae were observed in the epicardium, as well as icterus in the blood vessels of the heart. Furthermore, the brain and cerebellum cortex, thalamic region and nuclei region of brainstem showed extensive icteric areas. Microscopically, the liver presented a mononuclear portal hepatitis, centrilobular necrosis and presence of yellowish pigments. The brain had neuronal necrosis, mild vacuolization of the white matter, perineuronal edema and Alzheimer type II astrocytes, while cerebellum showed Purkinje cells necrosis. Hepatic cooper measurement was within range values, and direct imunofluorescence for the detection of Leptospira sp. was negative.[...]

Kernicterus in an adult dog

Background: Kernicterus or bilirubin encephalopathy is a condition rarely observed in animal characterized by a yellowish discoloration of the central nervous system. It is a potentially fatal condition due to bilirubin neurotoxic effects caused by the increase of non-conjugated bilirubin pigment, which passes blood brain barrier and has been attributed to an imbalance between albumin and bilirubin levels. Intracellular bilirubin is toxic for cells and can cause decrease in protein synthesis, specially albumin, depression of cell respiration and cellular death. This paper describes kernicterus in a 2-year-old Great Dane female dog.Case: Clinically, the animal showed apathy, lethargy, weight loss and jaundice, which progressed to vomiting and neurological signs characterized by loss of consciousness and eventually coma. Blood parameters were within normal range, except for high levels of alanine aminotransferase (523 U/L), suggesting a liver lesion. The animal was submitted to euthanasia due to the poor prognosis, and at post-mortem examination it showed dehydration and severe jaundice, especially oral, vaginal and ocular mucosas, subcutaneous tissue and blood vessels intima surface. The liver had an accentuated lobular pattern, and the stomach mucosa was reddened. Multiple petechiae were observed in the epicardium, as well as icterus in the blood vessels of the heart. Furthermore, the brain and cerebellum cortex, thalamic region and nuclei region of brainstem showed extensive icteric areas. Microscopically, the liver presented a mononuclear portal hepatitis, centrilobular necrosis and presence of yellowish pigments. The brain had neuronal necrosis, mild vacuolization of the white matter, perineuronal edema and Alzheimer type II astrocytes, while cerebellum showed Purkinje cells necrosis. Hepatic cooper measurement was within range values, and direct imunofluorescence for the detection of Leptospira sp. was negative.[...](AU)

Kernicterus in a boy with ornithine transcarbamylase deficiency: A case report.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle defect associated with severe and usually fatal hyperammonemia. This study describes a patient with early onset lethal OTCD due to a known pathogenic variant (c.298+1G>A), as well as the novel autopsy finding of kernicterus with relatively low blood concentration of unconjugated bilirubin (UCB) (11.55 mg/dL). The patient was a full-term male with a family history of two previous male siblings who died as newborns after acute neurologic deterioration. The patient's symptoms began at 24 h of life with lethargy that rapidly progressed to coma upon admission to the neonatal intensive care unit. Although hyperammonemia and hyperbilirubinemia were documented, hemofiltration could not be performed. OTCD diagnosis was biochemically established. Despite nutritional intervention and treatment for hyperammonemia, the patient died on the sixth day of life. At autopsy, external brain examination revealed a marked yellow pigmentation typical of kernicterus that included gray matter, particularly the thalamus and basal ganglia; dentate nuclei of the cerebellum and brain stem gray matter were also affected. Microscopic findings were consistent with the classical description of tissue damage in OTCD, including the presence of Alzheimer type II astrocytes in basal ganglia, necrosis, neuronal loss with spongiform degeneration and macrophage infiltration surrounded by astroglia. This condition may be an important comorbidity in newborns with hyperammonemia.

Prediction of 3- to 5-Month Outcomes from Signs of Acute Bilirubin Toxicity in Newborn Infants.

OBJECTIVE: To evaluate the ability of the bilirubin-induced neurologic dysfunction (BIND) score to predict residual neurologic and auditory disability and to document the relationship of BIND score to total serum bilirubin (TSB) concentration. STUDY DESIGN: The BIND score (assessing mental status, muscle tone, and cry patterns) was obtained serially at 6- to 8-hour intervals in 220 near-term and full-term infants with severe hyperbilirubinemia. Neurologic and/or auditory outcomes at 3-5 months of age were correlated with the highest calculated BIND score. The BIND score was also correlated with TSB. RESULTS: Follow-up neurologic and auditory examinations were performed for 145/202 (72%) surviving infants. All infants with severe acute bilirubin encephalopathy (BIND scores 7-9) either died or suffered residual neurologic and auditory impairment. Of 24 cases with moderate encephalopathy (BIND 4-6), 15 (62.5%) resolved following aggressive intervention and were normal at follow-up. Three of 73 infants with mild encephalopathy (BIND scores 1-3) but severe jaundice (TSB ranging 33.5-38 mg/dL; 573-650 µmol/L) had residual neurologic and/or auditory impairment. A BIND score ≥4 had a specificity of 87.3% and a sensitivity of 97.4% for predicting poor neurologic outcomes (receiver operating characteristic analysis). BIND scores trended higher with severe hyperbilirubinemia (r2 = 0.54, P < .005), but 5/39 (13%) infants with TSB ≥36.5 mg/dL (624 µmol/L) had BIND scores ≤3, and normal outcomes at 3-5 months. CONCLUSIONS: The BIND score can be used to evaluate the severity of acute bilirubin encephalopathy and predict residual neurologic and hearing dysfunction.

Magnetic Resonance Imaging Abnormalities in Advanced Acute Bilirubin Encephalopathy Highlight Dentato-Thalamo-Cortical Pathways.

A distinct pattern of acute restricted diffusion on magnetic resonance imaging localized to key regions within the dentato-thalamo-cortical pathway was observed early in a term newborn during advanced stages of acute bilirubin encephalopathy. These findings demonstrate that vulnerability to bilirubin toxicity extends across specific neuroanatomic tracts.

Prospective Surveillance of Extreme Neonatal Hyperbilirubinemia in Australia.

OBJECTIVES: To determine the incidence, causes, associated factors, and short-term outcomes of extreme neonatal hyperbilirubinemia in Australia in order to identify opportunities for prevention. STUDY DESIGN: This was a prospective population-based surveillance study in collaboration with the Australian Pediatric Surveillance Unit between April 1, 2010, and March 31, 2013. Case definition was: infants >34 weeks gestation with a peak total serum bilirubin ≥450 µmol/L and or clinical evidence of bilirubin encephalopathy. Clinicians completed questionnaires detailing demographic and clinical data including: peak serum bilirubin, signs of bilirubin encephalopathy, etiology, associated pathology, management, and short-term outcomes. RESULTS: The questionnaire return rate was 95%, and 87 infants met the case definition. The Australian incidence of extreme neonatal hyperbilirubinemia is estimated to be 9.4/100,000 live births. Main etiologies were: idiopathic ABO blood group incompatibility, glucose-6-phosphate dehydrogenase deficiency, and Rhesus isoimmunization. There were no significant differences in short-term outcomes between inpatient and outpatient cases. Cases with a hemolytic etiology were significantly more likely to have extremely high levels of hyperbilirubinemia (P < .002). CONCLUSION: The incidence of extreme neonatal hyperbilirubinemia in Australia is comparable with previous studies. Robust pre- and post-discharge assessment and management strategies of neonatal hyperbilirubinemia are essential to prevent neurodisability. Universal glucose-6-phosphate dehydrogenase screening and serial bilirubin monitoring may optimize preventative strategies.