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

11-6-e316

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The predominant bilirubin isomer in humans is IX-alpha (Z. 4. However.aappublications.11 No. A distinction often is made between physiologic and nonphysiologic jaundice. Bilirubin is transported in serum bound to albumin. 2011 . Both ligandin and UDPGT have very low concentrations and activities in the fetus. bilirubin is transferred into the hepatocytes. Explain why the enterohepatic circulation of bilirubin may influence the course of neonatal jaundice. readers should be able to: Recognize the different steps in bilirubin metabolism. which occurs inside the hepatocyte. 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. Oslo. a process known as enterohepatic circulation. Describe how bilirubin metabolism changes from fetal to postnatal life. this same characteristic enables passage of bilirubin across the blood-brain barrier. during the time required to increase these enzyme activities. *Department of Neonatal Intensive Care Medicine. The Table summarizes some key concepts of neonatal bilirubin metabolism. For simplicity. When the bilirubin-albumin complex reaches the liver. e316 NeoReviews Vol. 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. where it is bound to ligandin. 5. An important factor in this process is increased bilirubin production through the breakdown of fetal erythrocytes. Norway.Sognsvannsveien. MD.org by Jennifer Rael on April 6. is binding of bilirubin to glucuronic acid (conjugation) through the enzyme uridine diphosphate glucuronyl transferase (UDPGT). This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.core concepts Core Concepts: Thor Willy Ruud Hansen. 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).6 June 2010 Downloaded from http://neoreviews. Objectives 1. Women’s and Children’s Clinic. In fetal life. which. Postpartum. PhD* Author Disclosure Dr Hansen has disclosed no financial relationships relevant to this article. This distinction is useful didactically but often not possible clinically. Some of the steps in bilirubin metabolism can be influenced by drugs or feeding. because of its lipophilic nature. The next step. Once conjugated in the liver. Oslo University Hospital . 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. bilirubin accumulates. bilirubin is excreted into the bile and transported through the gut with food and further broken down. Describe how the isomers of bilirubin may be relevant to its distribution in the body. but activity increases greatly after birth. Bilirubin Metabolism Abstract Bilirubin is formed in the reticuloendothelial system as the end product of heme catabolism through a series of oxidation-reduction reactions. contributing to the color of stool. Explain why bilirubin accumulates in the newborn. this characteristic permits passage of bilirubin through the placenta into the maternal organism for excretion. After completing this article. 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. can cross phospholipid membranes. 3. Deconjugation and reabsorption of bilirubin can occur in the bowel.Z). 2.

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

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

Increased Heme Catabolism The fetus lives in an oxygen-poor environment. the distinction between physiologic and nonphysiologic jaundice in newborns often is not clear. Bilirubin initially was found in the amniotic fluid in cases of Rhesus immunization. (36) Therefore. For example. showing that bilirubin is cleared from fetal blood when it passes through the placenta. may be increased in congenital hemolytic anemias. The course of hyperbilirubinemia in neonates is characterized by a peak between the second and fourth postnatal days. Breakdown of fetal red cells. Jaundice is a very common phenomenon in neonates and a frequent reason for clinical concern and investigation. the fetus has a hemoglobin that is structurally different from the one formed in postnatal life as well as a higher hemoglobin concentration. There is no evidence that NeoReviews Vol. 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). Because amniotic fluid is primarily a product from the fetus. and due to drugs or toxins.5th percentile. and excretion of bilirubin in the liver. found that more than 50% of bilirubin infused into the fetus was transferred intact across the placenta and excreted in maternal bile. it follows that the placenta has a limited capacity for transfer of bilirubin and that this capacity is exceeded in fetal hemolytic disease. Conjugation and excretion into bile is associated with accumulation of a quantity of bilirubin in meconium corresponding to 5 to 10 times daily production. although bilirubin can pass the placenta. A study in rhesus monkeys. in immunologic conditions such as maternal-fetal blood group incompatibilities. 82% had serum bilirubin concentrations that exceeded the 97. Bilirubin in the Amniotic Fluid Although bilirubin has been found in amniotic fluid in early gestation. These compensatory mechanisms are not needed after birth. (26) Bilirubin metabolism is different in the fetus compared with the neonate. 2011 . Conjugation. The incidence of significant neonatal jaundice varies among populations and geographic locations. likely due to increased red cell mass. Bilirubin in Fetal Hemolytic Disease When hemolysis occurs in the fetus in maternal alloimmunization. followed by a decline that initially is rapid and subsequently tapers. the hepatocellular binding protein for bilirubin. which have a placenta structurally very similar to that in humans.5 mg/dL (25 mcmol/L) at 20 weeks of gestation to approximately 4. 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. Thus. neonatal jaundice is more prevalent in populations living at high altitudes. (38) approximately the value at which the human eye can detect jaundice in the skin. but the major fraction is unconjugated. Mechanisms of Physiologic and Nonphysiologic Jaundice Most newborns develop a serum unconjugated bilirubin value greater than 1.aappublications. 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.8 g/dL) at term.5 g/dL) at 20 weeks of gestation to 30 mcmol/L (1.8 mg/dL (30 mcmol/L) during the first postnatal week. To compensate for this. the normally occurring mechanisms that produce hyperbilirubinemia may be exaggerated by both endogenous and exogenous factors.core concepts bilirubin metabolism creasing from about 25 mcmol/L (1. (35) The increase in serum bilirubin was detectable weeks before anemia developed. conjugation. (34) shown to correlate with the degree of fetal effects. but nonpolar compounds such as unconjugated bilirubin can diffuse across the membranes. hemolytic disease in the fetus causes some hyperbilirubinemia.1 mg/dL (70 mcmol/L) at 32 weeks’ gestation.11 No. Placental membranes are essentially impermeable to polar compounds such as biliverdin and bilirubin conjugates. Infections or bruising/hematomas also can shorten red cell survival. However. with only 3% to 6% found in fetal bile.6 June 2010 e319 Downloaded from http://neoreviews. the concentration of TSB may increase from approximately 1.org by Jennifer Rael on April 6. bilirubin in amniotic fluid probably comes from the fetus itself. resulting in production of bilirubin.30]). normally there is no bilirubin in amniotic fluid near term. Thus. (33) The umbilical artery contains bilirubin in a concentration nearly twice that of the umbilical vein. (37) and the concentrations of bilirubin in amniotic fluid have been Decreased Hepatic Uptake. and Excretion of Bilirubin The neonate is deficient in ligandin. (32) Bilirubin also is transferred rapidly into and removed from the amniotic fluid. In a study of fetuses that developed anemia (hematocrit 30% [0. (19) However. Some of the bilirubin is conjugated and cannot cross the placenta. most fetal bilirubin production must be handled differently.

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

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