Core Concepts: Bilirubin Metabolism Thor Willy Ruud Hansen NeoReviews 2010;11;e316-e322 DOI: 10.1542/neo.


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NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 2000. NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Online ISSN: 1526-9906.

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bilirubin is transferred into the hepatocytes.Sognsvannsveien. The Table summarizes some key concepts of neonatal bilirubin metabolism. MD. where it is bound to ligandin. readers should be able to: Recognize the different steps in bilirubin metabolism. Explain why bilirubin accumulates in the For simplicity. is binding of bilirubin to glucuronic acid (conjugation) through the enzyme uridine diphosphate glucuronyl transferase (UDPGT). 4. physiologic jaundice may be said to be present when bilirubin production is increased and excretion capacity is low as part of a normal transitional process. Explain why the enterohepatic circulation of bilirubin may influence the course of neonatal jaundice. bilirubin is excreted into the bile and transported through the gut with food and further broken down. This distinction is useful didactically but often not possible clinically. Objectives 1. Norway. Some of the steps in bilirubin metabolism can be influenced by drugs or feeding.11 No. Both ligandin and UDPGT have very low concentrations and activities in the fetus. The predominant bilirubin isomer in humans is IX-alpha (Z. which is why clinicians worry about jaundice in newborns. Increased enterohepatic circulation is believed to contribute to prolonged jaundice in some newborns and may be partially responsible for human milk-associated jaundice. Such visual detection is possible when the TSB exceeds 5 to 6 mg/dL (85 to 100 mcmol/L) and varies between observers and lighting conditions. 3. a process known as enterohepatic circulation. this characteristic permits passage of bilirubin through the placenta into the maternal organism for excretion. bilirubin accumulates. Oslo University Hospital . In fetal life. Nonphysiologic jaundice may be said to be present when bilirubin production is exaggerated beyond normal or bilirubin excretion is reduced below normal for the newborn period.6 June 2010 Downloaded from http://neoreviews. during the time required to increase these enzyme activities. 2011 . Bilirubin Metabolism Abstract Bilirubin is formed in the reticuloendothelial system as the end product of heme catabolism through a series of oxidation-reduction reactions. Definition Neonatal jaundice occurs when the concentration of bilirubin in serum (TSB) increases to the point where the accumulation of bilirubin in skin becomes visible to the unaided eye in daylight conditions (or similar-quality artificial light). Postpartum. PhD* Author Disclosure Dr Hansen has disclosed no financial relationships relevant to this article. Deconjugation and reabsorption of bilirubin can occur in the bowel. After completing this article. An important factor in this process is increased bilirubin production through the breakdown of fetal erythrocytes. *Department of Neonatal Intensive Care Medicine. Describe how the isomers of bilirubin may be relevant to its distribution in the body. When the bilirubin-albumin complex reaches the liver. A distinction often is made between physiologic and nonphysiologic jaundice. Provided by Health Internetwork on February 15. Women’s and Children’s Clinic. However. which occurs inside the hepatocyte. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device. Describe how bilirubin metabolism changes from fetal to postnatal life. contributing to the color of stool. Bilirubin is transported in serum bound to albumin. because of its lipophilic nature. e316 NeoReviews Vol. Oslo. Once conjugated in the liver.core concepts Core Concepts: Thor Willy Ruud Hansen.Z). 5. this same characteristic enables passage of bilirubin across the blood-brain barrier. can cross phospholipid membranes. The next step. 2. but activity increases greatly after birth. which.

Schematic illustration of bilirubin metabolism in fetal and neonatal life. Modified from Hansen.aappublications. fractures. UDPGT catabolizes the conversion of bilirubin to a water-soluble form through binding to one or two molecules of glucuronic acid. inadequate nutrition [“breast feeding jaundice”]) –Increased deconjugation of bilirubin in the bowel (eg. neonatal hepatitis. Crigler-Najjar. but a minor fraction is unbound (“free”) and can cross the blood-brain barrier or (in the fetus) the placental barrier. these conjugates subsequently are transformed to urobilinoids through bacterial action. Excreted in the bile. necrotizing enterocolitis. Arias type 2. forming bilirubin conjugates. (4) The first step in heme catabolism (Figure) involves heme oxygenase. Bilirubin is formed in the reticuloendothelial system from heme through reactions catabolized by heme oxygenase and biliverdin reductase. Conjugated bilirubin also may undergo deconjugation.5 mg/kg per day. (3) Bilirubin production in the neonate has been estimated to be about 8. breast milk jaundice) Nonphysiologic Jaundice ● ● ● Bilirubin Metabolism Production The life span of red cells in the newborn is about 1. myoglobin from muscle. Bilirubin is transported into the cell and bound to ligandin. Physiologic Jaundice in the Newborn ● ● Catabolism of heme –From breakdown of fetal erythrocytes –From myoglobin. approximately double the rate of 4 mg/kg per day in adults. The Figure. and the unconjugated bilirubin can be reabsorbed into the circulation (enterohepatic circulation). intracranial hemorrhages) Decreased bilirubin conjugation and excretion –Genetic defects in UDGPT (eg. Rhesus and ABO incompatibility) –Extravasation of blood (bruising. Fe iron. the intracellular binding protein –Low neonatal activity of uridine diphosphate glucuronyl transferase (UDPGT) Increased heme catabolism –Congenital hemolytic anemias (eg. B bilirubin. glucose-6phosphate dehydrogenase deficiency. Carbon monoxide is a byproduct of this process and can be measured in exhaled breath. catalase Decreased uptake into and excretion from liver cells –Low neonatal concentration of ligandin. catalyzed by biliverdin reductase. intra. CO carbon monoxide.German for “together”). (8) A more detailed review recently was published in NeoReviews. an enzyme that is found in the reticuloendothelial system but also in other tissues. and enzymes such as cytochromes and catalases leads to production of bilirubin.and extrahepatic biliary atresia) Increased enterohepatic circulation of bilirubin –Decreased bowel passage (eg. Provided by Health Internetwork on February 15. (6)(7) Reduction of biliverdin IX-alpha to bilirubin IX-alpha takes place in the cytosol. cytochromes.11 No.15Z) isomer. (5) apparent lipophilic nature of this bilirubin isomer can be explained by the intramolecular hydrogen bonds between the side groups (Z zusammen . (8) Bilirubin IX-alpha in the serum of humans occurs almost exclusively as the (4Z. 2011 . (1) Degradation of heme from red cells. (2) Biliverdin is formed as an intermediate step. Gilbert) –Hepatic and biliary disease ( June 2010 e317 Downloaded from http://neoreviews.core concepts bilirubin metabolism Mechanisms of Neonatal Hyperbilirubinemia Table. intestinal atresias. providing an estimate of bilirubin production. (9) NeoReviews Vol. fasting. Bilirubin is transported in serum bound to albumin. spherocytosis) –Immunologically mediated hemolysis (eg.5 to 3 months. UDPGT uridine diphosphate glucuronyl transferase.

bilirubin is transported into the cell. Unconjugated bilirubin then can be reabsorbed into the circulation. bilirubinIX-alpha is the primary isomer. may contribute to increased enterohepatic circulation in so-called human milk-associated jaundice. (11) If the molar concentration of bilirubin exceeds that of albumin. (15) Bilirubin also can bind to other proteins (eg. there is evidence that hemin. reaching adult values by 1 to 2 months of age.17) catalyzes the binding of glucuronic acid to bilirubin. alphafetoprotein and ligandin). (25) Phenobarbital has been used both before and after birth to prevent or treat neonatal jaundice.4. (28) Biliverdin also can be excreted in bile. which prolongs intestinal transit time. activates hepatic CYP1A1 gene expression. about 60% of bilirubin is found in the cytosol and about 25% in microsomes. Bilirubin in the Fetus Bilirubin appears in the human fetus at 14 weeks of gestation. (21) Excretion of conjugated bilirubin into bile occurs against a concentration gradient. Uptake.6 June 2010 Glucuronyl transferase activity increases 100-fold after birth. Clearance of bilirubin from the hepatocyte is a saturable process. This cycle of conjugation. administering phenobarbital to pregnant women increases conjugation in the neonate. Conjugation. a secondary binding site has a lower affinity. This process may be carrier-mediated. The biologic puzzle of why humans do not excrete nontoxic biliverdin but process this one step further to potentially toxic bilirubin may have a partial answer in the discovery that bilirubin is a free radical quencher. Thus. (22) The monomer can convert unconjugated bilirubin to monoglucuronide. which have not been unequivocally identified. lipoproteins.11 No. (23) In the first days after birth. However. such as barbiturates.aappublications. excretion.core concepts bilirubin metabolism Transport and Protein Binding Unconjugated bilirubin is transported in plasma bound to albumin. When bilirubin enters the bowel. it also is believed that factors in human milk in some mother-infant dyads. (16) Glucuronyl transferase (UDP glucuronate betaglucuronosyl transferase EC 2. (17) Ligandin. Thus. making it a process that requires energy. (27) and this is a therapy for neonatal jaundice that is undergoing testing. (16) Ligandin concentrations in the liver are low at birth but appear to reach adult values within 1 to 2 weeks of age. Heme oxygenase can be inhibited through the use of metal meso. (26) Dexamethasone and clofibrate also increase bilirubin conjugation. Enterohepatic circulation may be significant in the newborn.and protoporphyrins. and Excretion When the bilirubin-albumin complex comes into contact with hepatocytes. (18) Uptake of bilirubin into hepatocytes increases with increasing concentrations of ligandin. less than half of the estimated 50% in adults. (20) e318 NeoReviews Vol. (16) Inside the liver cells. In addition. concentrations of free (“unbound”) bilirubin are in the low nanomolar range. a glutathione S-transferase. and reabsorption is called enterohepatic circulation. biliverdin. is responsible for binding bilirubin inside the cells. with a high binding affinity at the primary binding site. conjugated bilirubin constitutes less than 2% of total bile pigment in serum. whereas biliverdin would have needed a transporter. (29) Umbilical vein blood samples show total bilirubin concentrations in- Downloaded from http://neoreviews. (12) The binding of bilirubin to albumin increases with postnatal age (13) but is reduced in sick infants (14) and in the presence of exogenous or endogenous binding competitors such as certain drugs. (24) Diconjugates make up about 20% of the total conjugated fraction in babies. deconjugation. and free bilirubin concentrations increase. Heme can be excreted directly in bile. (30) Whether such pathways play any role in human infants currently is not known. mediated by betaglucuronidases in the brush border. Alternate pathways for bilirubin disposition through the liver also may exist. (31) At 16 weeks. but the tetramer is needed for formation of the diglucuronide. bilirubin can diffuse through the placental membranes from fetus to mother. but this is accompanied by the loss of iron. By 38 weeks’ gestation. The excretory transport maximum can be increased by drugs that stimulate bile flow. (29) Also. Provided by Health Internetwork on February 15. in turn. (20) formation of the diglucuronide probably occurs at the cell membrane. and bilirubin can induce such pathways by activating the aryl hydrocarbon receptor that. and erythrocytes. This converts the essentially water-insoluble unconjugated bilirubin to a more polar form that can be excreted in the bile. (21) Bilirubin-UDP-glucuronyl transferase in humans is a tetramer. in part due to limited nutrient intake in the first postnatal days. Because bilirubin is tightly bound to albumin. 2011 (24) Glucuronyl transferase is inducible. the primary binding site is saturated. even in babies who exhibit significant jaundice. and after the first postnatal week appears to be the rate-limiting step in bilirubin excretion. deconjugation may occur in the small intestine. (19) The concentration of ligandin in hepatocytes can be increased by pharmacologic agents such as phenobarbital. Bilirubin monoglucuronide is formed initially in the endoplasmic reticulum of microsomes. unconjugated bilirubin-IXalpha appears in bile.

Because amniotic fluid is primarily a product from the fetus.1 mg/dL (70 mcmol/L) at 32 weeks’ gestation. Thus. Some of the bilirubin is conjugated and cannot cross the placenta. followed by a decline that initially is rapid and subsequently tapers. the fetus has a hemoglobin that is structurally different from the one formed in postnatal life as well as a higher hemoglobin concentration. The incidence of significant neonatal jaundice varies among populations and geographic locations. Breakdown of fetal red cells.5 g/dL) at 20 weeks of gestation to 30 mcmol/L (1. 82% had serum bilirubin concentrations that exceeded the 97. Mechanisms of Physiologic and Nonphysiologic Jaundice Most newborns develop a serum unconjugated bilirubin value greater than 1. it follows that the placenta has a limited capacity for transfer of bilirubin and that this capacity is exceeded in fetal hemolytic disease. but the major fraction is unconjugated. For example. Unconjugated bilirubin in the fetus can be disposed of either by crossing the placenta into the maternal circulation or by passing through the fetal liver and being excreted into fetal bile. may be increased in congenital hemolytic anemias. Bilirubin in Fetal Hemolytic Disease When hemolysis occurs in the fetus in maternal alloimmunization. the concentration of TSB may increase from approximately 1. Conjugation.5th percentile. The term physiologic jaundice should be applied to jaundice in newborns due to the normal occurrences of increased breakdown of red cells in the presence of a low capacity for uptake. which have a placenta structurally very similar to that in humans.core concepts bilirubin metabolism creasing from about 25 mcmol/L (1. but nonpolar compounds such as unconjugated bilirubin can diffuse across the membranes. (33) The umbilical artery contains bilirubin in a concentration nearly twice that of the umbilical vein. Bilirubin in the Amniotic Fluid Although bilirubin has been found in amniotic fluid in early gestation. (37) and the concentrations of bilirubin in amniotic fluid have been Decreased Hepatic Uptake. Provided by Health Internetwork on February 15. However. and due to drugs or toxins. normally there is no bilirubin in amniotic fluid near term. conjugation. There is no evidence that NeoReviews Vol. neonatal jaundice is more prevalent in populations living at high altitudes. Noninvasive bilirubin measurements on 490 term and near-term infants from a racially diverse background showed that 80% had bilirubin concentrations greater than 5 mg/dL (85 mcmol/L). (26) Bilirubin metabolism is different in the fetus compared with the neonate. most fetal bilirubin production must be handled differently. Jaundice is a very common phenomenon in neonates and a frequent reason for clinical concern and investigation. and Excretion of Bilirubin The neonate is deficient in ligandin. Thus. (34) shown to correlate with the degree of fetal effects. bilirubin in amniotic fluid probably comes from the fetus itself. the hepatocellular binding protein for bilirubin. (36) Therefore. found that more than 50% of bilirubin infused into the fetus was transferred intact across the placenta and excreted in maternal bile. the normally occurring mechanisms that produce hyperbilirubinemia may be exaggerated by both endogenous and exogenous factors. in immunologic conditions such as maternal-fetal blood group incompatibilities. although bilirubin can pass the placenta. (19) However. The course of hyperbilirubinemia in neonates is characterized by a peak between the second and fourth postnatal days.11 No. showing that bilirubin is cleared from fetal blood when it passes through the placenta. 2011 . Infections or bruising/hematomas also can shorten red cell survival.30]). Bilirubin initially was found in the amniotic fluid in cases of Rhesus immunization. resulting in production of bilirubin.5 mg/dL (25 mcmol/L) at 20 weeks of gestation to approximately 4. These compensatory mechanisms are not needed after birth. and excretion of bilirubin in the liver. In a study of fetuses that developed anemia (hematocrit 30% [0. A study in rhesus monkeys.8 g/dL) at term. To compensate for this. hemolytic disease in the fetus causes some hyperbilirubinemia. Conjugation and excretion into bile is associated with accumulation of a quantity of bilirubin in meconium corresponding to 5 to 10 times daily production. (35) The increase in serum bilirubin was detectable weeks before anemia developed. (32) Bilirubin also is transferred rapidly into and removed from the amniotic fluid. likely due to increased red cell mass. Placental membranes are essentially impermeable to polar compounds such as biliverdin and bilirubin conjugates.aappublications.8 mg/dL (30 mcmol/L) during the first postnatal week.6 June 2010 e319 Downloaded from http://neoreviews. (38) approximately the value at which the human eye can detect jaundice in the with only 3% to 6% found in fetal bile. the distinction between physiologic and nonphysiologic jaundice in newborns often is not clear. Increased Heme Catabolism The fetus lives in an oxygen-poor environment.

The Impact of Bilirubin Isomers Isomers of bilirubin differ in their polarity. Conclusion Bilirubin metabolism undergoes significant changes during fetal and neonatal life in terms of the balance of isomers. This can happen in intestinal atresias. However. Genetics and Bilirubin Metabolism It is increasingly recognized that the risk for neonatal jaundice may be modulated by genetics. Several steps in the process that causes neonatal jaundice can be modulated both by endogenous and exogenous compounds. including its solubility and tissue distribution. (43) These watere320 NeoReviews Vol. (42) Accordingly. and OATP1B1). Oski FA. • Know the factors. 2011 . the presence of P-glycoprotein in the blood-brain barrier appears to block bilirubin entry to some extent. • Know bilirubin physiology.6 June 2010 References 1. but the isomers that arise when bilirubin is exposed to light. including those that affect the enterohepatic circulation of It has been speculated that the more polar bilirubin photoisomers should be less able to diffuse across the blood-brain barrier. (40) Recently. and Gilbert syndrome is caused by mutations in the promoter sequence. Enterohepatic circulation contributes to neonatal jaundice and is amenable to therapeutic intervention by formula feedings or other bilirubin binding or degrading agents. binding and conjugation inside the hepatocyte. accounting for the therapeutic effect of phototherapy. Drugs that limit bilirubin production by inhibiting heme oxygenase are undergoing trials. are more polar and more soluble in water.Z) can enter the brain. • Know the factors associated with a decrease in neonatal serum bilirubin excretion. including the enzymatic reactions involved in production. Crigler-Najjar syndrome is caused by a stop or nonsense mutation in the gene for UDP-GT1A1. However.aappublications. (44) so the concentration of bilirubin in brain is less than might be expected. By virtue of its lipophilic nature. 1993:18 – 43 Downloaded from http://neoreviews. no experimental evidence to date supports this theoretically based hypothesis.Z) isomer is almost insoluble in water.11 No. However. deficiency of UDPGT occurs in several hereditary disorders. The erythrocyte and its disorders. coexpression of two or more of these genes was common. in infants in whom oral feedings are held for reasons of severe illness. In a recent study across three genes that had an impact on bilirubin metabolism (G6PD. and excretion into the bile. bilirubin IX-alpha (Z. genetic polymorphisms probably are important in explaining some of the clinically observed variability in the course and degree of neonatal jaundice. American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications • Know the factors that affect the biological properties of bilirubin. in the fetus and in the term and preterm neonate. The predominant IX-alpha (Z. Crigler-Najjar syndrome and Arias syndrome are well-recognized causes of extreme jaundice in neonates. (39) soluble isomers can be excreted in bile and urine without conjugation. In: Nathan DG. primarily IX-alpha (Z. eds. given its solubility characteristics. Philadelphia. Increased Enterohepatic Circulation Enterohepatic circulation occurs in the presence of delayed or interrupted passage of intestinal contents. (41) Glucose6-phosphate dehydrogenase deficiency and other hereditary hemolytic anemias also are associated with increased risk of neonatal jaundice. including genetic and increased red cell destruction. Arias syndrome is due to a missense mutation in the same gene. It is also possible that increased enterohepatic circulation is involved in so-called human milk jaundice. Drugs that increase the concentration of ligandin or the activity of bilirubin UDPGT are well documented but appear not to be used widely. and in infants receiving inadequate nutrition due to difficulties in establishing lactation (“lack-of-breast-milk jaundice”). Oski FA.E) and lumirubin. but their eventual place in the routine management of neonatal jaundice remains to be determined. the processes involved in uptake into the hepatocyte. (20) On the other hand. Hematology of Infancy and Childhood. by increasing the frequency of feeding. Provided by Health Internetwork on February 15. associated with an increase in bilirubin production.core concepts bilirubin metabolism deficiency of ligandin beyond the physiologic degree is implicated in nonphysiologic jaundice. enterohepatic circulation is reduced following the successful establishment of enteral nutrition. Pa: WB Saunders Co. genetic polymorphism for the organic anion transporter protein OATP-2 was shown to be associated with a threefold increased risk for developing marked neonatal jaundice. and following supplementation with human milk substitutes. UGT1A1. The impact of Gilbert syndrome on jaundice in the newborn also has become apparent.

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11.Core Concepts: Bilirubin Metabolism Thor Willy Ruud Hansen NeoReviews s.shtml Information about ordering reprints can be found online: 2011 .11-6-e316 Updated Information & Services Permissions & Licensing including high-resolution figures.e316-e322 DOI: 10.11/6/e316 Information about reproducing this article in parts (figures. can be found at: Reprints Downloaded from http://neoreviews. tables) or in its entirety can be found online at: Provided by Health Internetwork on February 15.