Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn
- Ronald J Wong, BA
Ronald J Wong, BA
- Senior Research Scientist
- Stanford University School of Medicine
- Vinod K Bhutani, MD, FAAP
Vinod K Bhutani, MD, FAAP
- Professor of Pediatrics
- Stanford University School of Medicine
- Section Editors
- Steven A Abrams, MD
Steven A Abrams, MD
- Section Editor — Neonatology
- Professor, Department of Pediatrics
- Dell Medical School at the University of Texas at Austin
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Professor of Pediatrics
- University of Pennsylvania School of Medicine
Almost all newborn infants develop a total serum or plasma bilirubin (TB) level greater than 1 mg/dL (17 micromol/L), which is the upper limit of normal for adults. As the TB increases, it produces neonatal jaundice, the yellowish discoloration of the skin and/or conjunctiva caused by bilirubin deposition . Neonates with severe hyperbilirubinemia (defined as a TB >25 mg/dL [428 micromol/L]) are at risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue
The pathogenesis and etiology of neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical features, evaluation, prevention, and treatment of this disorder are discussed separately. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)
●Severe neonatal hyperbilirubinemia is defined as a TB >25 mg/dL (428 micromol/L). It is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)
●Acute bilirubin encephalopathy (ABE) is used to describe the acute manifestations of BIND. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.)
- Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001; 344:581.
- American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297.
- Maisels MJ. Neonatal hyperbilirubinemia. In: Care of the High-Risk Neonate, 5th ed, Klaus MH, Fanaroff AA (Eds), WB Saunders, Philadelphia 2001. p.324.
- Kawade N, Onishi S. The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochem J 1981; 196:257.
- Kaplan M, Wong RJ, Sibley E, Stevenson DK. Neonatal jaundice and liver disease. In: Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 9th ed, Martin RJ, Fanaroff AA, Walsh MC (Eds), Elsevier Mosby, St. Louis 2011. Vol 2, p.1443.
- Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998; 95:8170.
- Akaba K, Kimura T, Sasaki A, et al. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int 1998; 46:21.
- Long J, Zhang S, Fang X, et al. Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence. Acta Paediatr 2011; 100:966.
- Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999; 103:6.
- Fawaz R, Baumann U, Ekong U, et al. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2017; 64:154.
- MacDonald MG. Hidden risks: early discharge and bilirubin toxicity due to glucose 6-phosphate dehydrogenase deficiency. Pediatrics 1995; 96:734.
- Slusher TM, Vreman HJ, McLaren DW, et al. Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants. J Pediatr 1995; 126:102.
- Johnson JD, Angelus P, Aldrich M, Skipper BJ. Exaggerated jaundice in Navajo neonates. The role of bilirubin production. Am J Dis Child 1986; 140:889.
- Fischer AF, Nakamura H, Uetani Y, et al. Comparison of bilirubin production in Japanese and Caucasian infants. J Pediatr Gastroenterol Nutr 1988; 7:27.
- Watchko JF, Lin Z, Clark RH, et al. Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics 2009; 124:e868.
- Kaplan M, Hammerman C, Vreman HJ, et al. Direct antiglobulin titer strength and hyperbilirubinemia. Pediatrics 2014; 134:e1340.
- Riskin A, Gery N, Kugelman A, et al. Glucose-6-phosphate dehydrogenase deficiency and borderline deficiency: association with neonatal hyperbilirubinemia. J Pediatr 2012; 161:191.
- Skierka JM, Kotzer KE, Lagerstedt SA, et al. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr 2013; 162:1146.
- Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333:1171.
- Kadakol A, Sappal BS, Ghosh SS, et al. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet 2001; 38:244.
- Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998; 132:656.
- Chang PF, Lin YC, Liu K, et al. Prolonged unconjugated hyperbiliriubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase. J Pediatr 2009; 155:860.
- Travan L, Lega S, Crovella S, et al. Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism. J Pediatr 2014; 165:42.
- Petersen JP, Henriksen TB, Hollegaard MV, et al. Extreme neonatal hyperbilirubinemia and a specific genotype: a population-based case-control study. Pediatrics 2014; 134:510.
- Kaplan M, Renbaum P, Levy-Lahad E, et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 1997; 94:12128.
- Kaplan M, Renbaum P, Vreman HJ, et al. (TA)n UGT 1A1 promoter polymorphism: a crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates. Pediatr Res 2007; 61:727.
- Watchko JF. Vigintiphobia revisited. Pediatrics 2005; 115:1747.
- Huang MJ, Kua KE, Teng HC, et al. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56:682.
- Stevenson DK, Ostrander CR, Hopper AO, et al. Pulmonary excretion of carbon monoxide as an index of bilirubin production. IIa. Evidence for possible delayed clearance of bilirubin in infants of diabetic mothers. J Pediatr 1981; 98:822.
- Grunebaum E, Amir J, Merlob P, et al. Breast mild jaundice: natural history, familial incidence and late neurodevelopmental outcome of the infant. Eur J Pediatr 1991; 150:267.
- Maisels MJ, Clune S, Coleman K, et al. The natural history of jaundice in predominantly breastfed infants. Pediatrics 2014; 134:e340.
- Preer GL, Philipp BL. Understanding and managing breast milk jaundice. Arch Dis Child Fetal Neonatal Ed 2011; 96:F461.
- Gourley GR, Arend RA. beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. Lancet 1986; 1:644.
- Gourley GR, Li Z, Kreamer BL, Kosorok MR. A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics 2005; 116:385.
- Maruo Y, Morioka Y, Fujito H, et al. Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 2014; 165:36.
- Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002; 140:396.
- Maisels MJ, Gifford K. Normal serum bilirubin levels in the newborn and the effect of breast-feeding. Pediatrics 1986; 78:837.
- Gourley GR, Kreamer B, Arend R. The effect of diet on feces and jaundice during the first 3 weeks of life. Gastroenterology 1992; 103:660.
- Johnson L, Bhutani VK, Karp K, et al. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol 2009; 29 Suppl 1:S25.
- American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Neonatal complications and management of high-risk infants. In: Guidelines for Perinatal Care, 7th ed, Riley LE, Stark AR (Eds), American Academy of Pediatrics, Elk Grove Village 2012.
- BILIRUBIN METABOLISM
- Bilirubin production
- Bilirubin clearance and excretion
- NEONATAL JAUNDICE
- Ethnic variation in conjugation ability
- CAUSES OF HYPERBILIRUBINEMIA
- Increased production
- Decreased clearance
- - Crigler-Najjar syndrome
- - Gilbert syndrome
- - OATP-2 polymorphism
- - Other causes
- Increased enterohepatic circulation
- - Breast milk jaundice
- - Intestinal obstruction
- Breastfeeding failure jaundice
- - Prevention
- Severe hyperbilirubinemia
- INFORMATION FOR PATIENTS