Core Concepts: Bilirubin Metabolism

Thor Willy Ruud Hansen

Neoreviews 2010;11;e316
DOI: 10.1542/neo.11-6-e316

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 core concepts

Core Concepts: Bilirubin Metabolism

Thor Willy Ruud Hansen,
MD, PhD* Abstract
Bilirubin is formed in the reticuloendothelial system as the end product of heme
catabolism through a series of oxidation-reduction reactions. The predominant
Author Disclosure bilirubin isomer in humans is IX-alpha (Z,Z), which, because of its lipophilic nature,
Dr Hansen has can cross phospholipid membranes. In fetal life, this characteristic permits passage of
bilirubin through the placenta into the maternal organism for excretion. Postpartum,
disclosed no financial
this same characteristic enables passage of bilirubin across the blood-brain barrier,
relationships relevant
which is why clinicians worry about jaundice in newborns. Bilirubin is transported in
to this article. This serum bound to albumin. When the bilirubin-albumin complex reaches the liver,
commentary does not bilirubin is transferred into the hepatocytes, where it is bound to ligandin. The next
contain a discussion step, which occurs inside the hepatocyte, is binding of bilirubin to glucuronic acid
of an unapproved/ (conjugation) through the enzyme uridine diphosphate glucuronyl transferase
(UDPGT). Both ligandin and UDPGT have very low concentrations and activities in
investigative use of a
the fetus, but activity increases greatly after birth. However, during the time required
commercial product/
to increase these enzyme activities, bilirubin accumulates. An important factor in this
device. process is increased bilirubin production through the breakdown of fetal erythrocytes.
Once conjugated in the liver, bilirubin is excreted into the bile and transported
through the gut with food and further broken down, contributing to the color of
stool. Deconjugation and reabsorption of bilirubin can occur in the bowel, a process
known as enterohepatic circulation. Increased enterohepatic circulation is believed to
contribute to prolonged jaundice in some newborns and may be partially responsible
for human milk-associated jaundice. Some of the steps in bilirubin metabolism can be
influenced by drugs or feeding.

Objectives After completing this article, readers should be able to:

1. Recognize the different steps in bilirubin metabolism.

2. Describe how bilirubin metabolism changes from fetal to postnatal life.
3. Explain why bilirubin accumulates in the newborn.
4. Describe how the isomers of bilirubin may be relevant to its distribution in the body.
5. Explain why the enterohepatic circulation of bilirubin may influence the course of
neonatal jaundice.

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). 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. A distinction often is made between physiologic and nonphysi-
ologic jaundice. This distinction is useful didactically but often not possible clinically. For
simplicity, 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. Nonphysi-
ologic 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. The Table
summarizes some key concepts of neonatal bilirubin metabolism.

*Department of Neonatal Intensive Care Medicine, Women’s and Children’s Clinic, Oslo University Hospital - Sognsvannsveien,
Oslo, Norway.

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 core concepts bilirubin metabolism

Mechanisms of Neonatal
Table.

Hyperbilirubinemia
Physiologic Jaundice in the Newborn
● Catabolism of heme
–From breakdown of fetal erythrocytes
–From myoglobin, cytochromes, catalase
● Decreased uptake into and excretion from liver cells
–Low neonatal concentration of ligandin, the
intracellular binding protein
–Low neonatal activity of uridine diphosphate
glucuronyl transferase (UDPGT)
Nonphysiologic Jaundice
● Increased heme catabolism
–Congenital hemolytic anemias (eg, glucose-6-
phosphate dehydrogenase deficiency, spherocytosis)
–Immunologically mediated hemolysis (eg, Rhesus
and ABO incompatibility)
–Extravasation of blood (bruising, fractures,
intracranial hemorrhages)
● Decreased bilirubin conjugation and excretion
–Genetic defects in UDGPT (eg, Crigler-Najjar, Arias
type 2, Gilbert)
–Hepatic and biliary disease (eg, neonatal hepatitis,
intra- and extrahepatic biliary atresia)
● Increased enterohepatic circulation of bilirubin
–Decreased bowel passage (eg, intestinal atresias,
necrotizing enterocolitis, fasting, inadequate
nutrition [“breast feeding jaundice”])
–Increased deconjugation of bilirubin in the bowel
(eg, breast milk jaundice)
Figure. Schematic illustration of bilirubin metabolism in fetal
and neonatal life. Bilirubin is formed in the reticuloendothelial
system from heme through reactions catabolized by heme
oxygenase and biliverdin reductase. Bilirubin is transported in
Bilirubin Metabolism serum bound to albumin, but a minor fraction is unbound
Production (“free”) and can cross the blood-brain barrier or (in the fetus)
The life span of red cells in the newborn is about 1.5 to 3 the placental barrier. Bilirubin is transported into the cell and
months. (1) Degradation of heme from red cells, myo- bound to ligandin. UDPGT catabolizes the conversion of
globin from muscle, and enzymes such as cytochromes bilirubin to a water-soluble form through binding to one or
and catalases leads to production of bilirubin. (2) Bili- two molecules of glucuronic acid, forming bilirubin conju-
gates. Excreted in the bile, these conjugates subsequently
verdin is formed as an intermediate step. Carbon mon-
are transformed to urobilinoids through bacterial action.
oxide is a byproduct of this process and can be measured Conjugated bilirubin also may undergo deconjugation, and the
in exhaled breath, providing an estimate of bilirubin unconjugated bilirubin can be reabsorbed into the circulation
production. (3) Bilirubin production in the neonate has (enterohepatic circulation). Bⴝbilirubin, Feⴝiron, COⴝcarbon
been estimated to be about 8.5 mg/kg per day, approx- monoxide, UDPGTⴝuridine diphosphate glucuronyl trans-
imately double the rate of 4 mg/kg per day in adults. (4) ferase. Modified from Hansen. (5)
The first step in heme catabolism (Figure) involves
heme oxygenase, an enzyme that is found in the reticu-
loendothelial system but also in other tissues. (6)(7) apparent lipophilic nature of this bilirubin isomer can be
Reduction of biliverdin IX-alpha to bilirubin IX-alpha explained by the intramolecular hydrogen bonds be-
takes place in the cytosol, catalyzed by biliverdin reduc- tween the side groups (Z⫽zusammen - German for
tase. (8) Bilirubin IX-alpha in the serum of humans “together”). (8) A more detailed review recently was
occurs almost exclusively as the (4Z,15Z) isomer. The published in NeoReviews. (9)

NeoReviews Vol.11 No.6 June 2010 e317

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core concepts bilirubin metabolism
Transport and Protein Binding
Unconjugated bilirubin is transported in plasma bound
to albumin, with a high binding affinity at the primary
binding site. In addition, a secondary binding site has a
lower affinity. Because bilirubin is tightly bound to albu-
min, concentrations of free (“unbound”) bilirubin are in
the low nanomolar range, even in babies who exhibit
significant jaundice. (11) If the molar concentration of
bilirubin exceeds that of albumin, the primary binding
site is saturated, and free bilirubin concentrations in-
crease. (12) The binding of bilirubin to albumin in-
creases with postnatal age (13) but is reduced in sick
infants (14) and in the presence of exogenous or endog-
enous binding competitors such as certain drugs. (15)
Bilirubin also can bind to other proteins (eg, alpha-
fetoprotein and ligandin), lipoproteins, and erythrocytes.
Uptake, Conjugation, and Excretion
When the bilirubin-albumin complex comes into contact
with hepatocytes, bilirubin is transported into the cell.
This process may be carrier-mediated. (16) Inside the
liver cells, about 60% of bilirubin is found in the cytosol
and about 25% in microsomes. (17) Ligandin, a glutathi-
one S-transferase, is responsible for binding bilirubin
inside the cells. (18) Uptake of bilirubin into hepatocytes
increases with increasing concentrations of ligandin. (16)
Ligandin concentrations in the liver are low at birth but
appear to reach adult values within 1 to 2 weeks of age.
(19) The concentration of ligandin in hepatocytes can
be increased by pharmacologic agents such as phenobar-
bital. (16)
Glucuronyl transferase (UDP glucuronate beta-
glucuronosyl transferase EC 2.4.1.17) catalyzes the
binding of glucuronic acid to bilirubin. This converts the
essentially water-insoluble unconjugated bilirubin to a
more polar form that can be excreted in the bile. Biliru-
bin monoglucuronide is formed initially in the endoplas-
mic reticulum of microsomes; (20) formation of the
diglucuronide probably occurs at the cell membrane.
(21) Bilirubin-UDP-glucuronyl transferase in humans is
a tetramer. (22) The monomer can convert unconju-
gated bilirubin to monoglucuronide, but the tetramer is
needed for formation of the diglucuronide. (21)
Excretion of conjugated bilirubin into bile occurs
against a concentration gradient, making it a process that
requires energy. Clearance of bilirubin from the hepato-
cyte is a saturable process, and after the first postnatal
week appears to be the rate-limiting step in bilirubin
excretion. The excretory transport maximum can be
increased by drugs that stimulate bile flow, such as bar-
biturates. (20)
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Glucuronyl transferase activity increases 100-fold af-
ter birth, reaching adult values by 1 to 2 months of age.
(23) In the first days after birth, conjugated bilirubin
constitutes less than 2% of total bile pigment in serum.
(24) Diconjugates make up about 20% of the total con-
jugated fraction in babies, less than half of the estimated
50%⫹ in adults. (24) Glucuronyl transferase is inducible.
Thus, administering phenobarbital to pregnant women
increases conjugation in the neonate. (25) Phenobarbital
has been used both before and after birth to prevent or
treat neonatal jaundice. (26) Dexamethasone and clofi-
brate also increase bilirubin conjugation.
Heme can be excreted directly in bile, but this is
accompanied by the loss of iron. Heme oxygenase can be
inhibited through the use of metal meso- and protopor-
phyrins, (27) and this is a therapy for neonatal jaundice
that is undergoing testing. (28) Biliverdin also can be
excreted in 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. (29) Also, bilirubin can diffuse through the
placental membranes from fetus to mother, whereas
biliverdin would have needed a transporter.
Alternate pathways for bilirubin disposition through
the liver also may exist. Thus, there is evidence that
hemin, biliverdin, and bilirubin can induce such path-
ways by activating the aryl hydrocarbon receptor that,
in turn, activates hepatic CYP1A1 gene expression. (30)
Whether such pathways play any role in human infants
currently is not known.
When bilirubin enters the bowel, deconjugation
may occur in the small intestine, mediated by beta-
glucuronidases in the brush border. Unconjugated bili-
rubin then can be reabsorbed into the circulation. This
cycle of conjugation, excretion, deconjugation, and re-
absorption is called enterohepatic circulation. Entero-
hepatic circulation may be significant in the newborn, in
part due to limited nutrient intake in the first postnatal
days, which prolongs intestinal transit time. However, it
also is believed that factors in human milk in some
mother-infant dyads, which have not been unequivocally
identified, may contribute to increased enterohepatic
circulation in so-called human milk-associated jaundice.
Bilirubin in the Fetus
Bilirubin appears in the human fetus at 14 weeks of
gestation. (31) At 16 weeks, unconjugated bilirubin-IX-
alpha appears in bile. By 38 weeks’ gestation, bilirubin-
IX-alpha is the primary isomer. (29) Umbilical vein
blood samples show total bilirubin concentrations in-

creasing from about 25 mcmol/L (1.5 g/dL) at
20 weeks of gestation to 30 mcmol/L (1.8 g/dL) at
term. (26)
Bilirubin metabolism is different in the fetus com-
pared with the neonate. 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. Conjugation
and excretion into bile is associated with accumulation of
a quantity of bilirubin in meconium corresponding to
5 to 10 times daily production. (19) However, most fetal
bilirubin production must be handled differently.
Placental membranes are essentially impermeable to
polar compounds such as biliverdin and bilirubin conju-
gates, but nonpolar compounds such as unconjugated
bilirubin can diffuse across the membranes. A study in
rhesus monkeys, which have a placenta structurally very
similar to that in humans, found that more than 50% of
bilirubin infused into the fetus was transferred intact
across the placenta and excreted in maternal bile, with
only 3% to 6% found in fetal bile. (32) Bilirubin also is
transferred rapidly into and removed from the amniotic
fluid. (33) The umbilical artery contains bilirubin in a
concentration nearly twice that of the umbilical vein,
showing that bilirubin is cleared from fetal blood when it
passes through the placenta. (34)
Bilirubin in Fetal Hemolytic Disease
When hemolysis occurs in the fetus in maternal alloim-
munization, the concentration of TSB may increase from
approximately 1.5 mg/dL (25 mcmol/L) at 20 weeks of
gestation to approximately 4.1 mg/dL (70 mcmol/L) at
32 weeks’ gestation. In a study of fetuses that developed
anemia (hematocrit ⬍30% [0.30]), 82% had serum bili-
rubin concentrations that exceeded the 97.5th percen-
tile. (35) The increase in serum bilirubin was detectable
weeks before anemia developed. Thus, although biliru-
bin can pass the placenta, hemolytic disease in the fetus
causes some hyperbilirubinemia. Some of the bilirubin is
conjugated and cannot cross the placenta, but the major
fraction is unconjugated. (36) Therefore, it follows that
the placenta has a limited capacity for transfer of bilirubin
and that this capacity is exceeded in fetal hemolytic
disease.
Bilirubin in the Amniotic Fluid
Although bilirubin has been found in amniotic fluid in
early gestation, normally there is no bilirubin in amniotic
fluid near term. Bilirubin initially was found in the amni-
otic fluid in cases of Rhesus immunization, (37) and the
concentrations of bilirubin in amniotic fluid have been
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core concepts bilirubin metabolism
shown to correlate with the degree of fetal effects. Be-
cause amniotic fluid is primarily a product from the fetus,
bilirubin in amniotic fluid probably comes from the fetus
itself.
Mechanisms of Physiologic and
Nonphysiologic Jaundice
Most newborns develop a serum unconjugated bilirubin
value greater than 1.8 mg/dL (30 mcmol/L) during the
first postnatal week. The incidence of significant neonatal
jaundice varies among populations and geographic loca-
tions. For example, neonatal jaundice is more prevalent
in populations living at high altitudes, likely due to
increased red cell mass. Noninvasive bilirubin measure-
ments on 490 term and near-term infants from a racially
diverse background showed that 80% had bilirubin con-
centrations greater than 5 mg/dL (85 mcmol/L), (38)
approximately the value at which the human eye can
detect jaundice in the skin. The course of hyperbiliru-
binemia in neonates is characterized by a peak between
the second and fourth postnatal days, followed by a
decline that initially is rapid and subsequently tapers.
Jaundice is a very common phenomenon in neonates and
a frequent reason for clinical concern and investigation.
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, conjugation, and excretion of biliru-
bin in the liver. However, the distinction between phys-
iologic and nonphysiologic jaundice in newborns often is
not clear. Thus, the normally occurring mechanisms that
produce hyperbilirubinemia may be exaggerated by both
endogenous and exogenous factors.
Increased Heme Catabolism
The fetus lives in an oxygen-poor environment. To com-
pensate for this, the fetus has a hemoglobin that is
structurally different from the one formed in postnatal
life as well as a higher hemoglobin concentration. These
compensatory mechanisms are not needed after birth.
Breakdown of fetal red cells, resulting in production of
bilirubin, may be increased in congenital hemolytic ane-
mias, in immunologic conditions such as maternal-fetal
blood group incompatibilities, and due to drugs or tox-
ins. Infections or bruising/hematomas also can shorten
red cell survival.
Decreased Hepatic Uptake, Conjugation, and
Excretion of Bilirubin
The neonate is deficient in ligandin, the hepatocellular
binding protein for bilirubin. There is no evidence that
NeoReviews Vol.11 No.6 June 2010 e319
core concepts bilirubin metabolism
deficiency of ligandin beyond the physiologic degree is
implicated in nonphysiologic jaundice. However, defi-
ciency of UDPGT occurs in several hereditary disorders.
Increased Enterohepatic Circulation
Enterohepatic circulation occurs in the presence of de-
layed or interrupted passage of intestinal contents. This
can happen in intestinal atresias, in infants in whom oral
feedings are held for reasons of severe illness, and in
infants receiving inadequate nutrition due to difficulties
in establishing lactation (“lack-of-breast-milk jaun-
dice”). It is also possible that increased enterohepatic
circulation is involved in so-called human milk jaundice.
(20) On the other hand, enterohepatic circulation is
reduced following the successful establishment of enteral
nutrition, by increasing the frequency of feeding, and
following supplementation with human milk substitutes.
(39)
Genetics and Bilirubin Metabolism
It is increasingly recognized that the risk for neonatal
jaundice may be modulated by genetics. Crigler-Najjar
syndrome and Arias syndrome are well-recognized
causes of extreme jaundice in neonates. The impact of
Gilbert syndrome on jaundice in the newborn also has
become apparent. Crigler-Najjar syndrome is caused by a
stop or nonsense mutation in the gene for UDP-GT1A1,
Arias syndrome is due to a missense mutation in the same
gene, and Gilbert syndrome is caused by mutations in the
promoter sequence. (40) Recently, genetic polymor-
phism for the organic anion transporter protein OATP-2
was shown to be associated with a threefold increased risk
for developing marked neonatal jaundice. (41) Glucose-
6-phosphate dehydrogenase deficiency and other he-
reditary hemolytic anemias also are associated with in-
creased risk of neonatal jaundice. In a recent study across
three genes that had an impact on bilirubin metabolism
(G6PD, UGT1A1, and OATP1B1), coexpression of two
or more of these genes was common. (42) Accordingly,
genetic polymorphisms probably are important in ex-
plaining some of the clinically observed variability in the
course and degree of neonatal jaundice.
The Impact of Bilirubin Isomers
Isomers of bilirubin differ in their polarity. The predom-
inant IX-alpha (Z,Z) isomer is almost insoluble in water,
but the isomers that arise when bilirubin is exposed to
light, primarily IX-alpha (Z,E) and lumirubin, are more
polar and more soluble in water. (43) These water-
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soluble isomers can be excreted in bile and urine without
conjugation, accounting for the therapeutic effect of
phototherapy. By virtue of its lipophilic nature, bilirubin
IX-alpha (Z,Z) can enter the brain. However, the pres-
ence of P-glycoprotein in the blood-brain barrier appears
to block bilirubin entry to some extent, (44) so the
concentration of bilirubin in brain is less than might be
expected, given its solubility characteristics. It has been
speculated that the more polar bilirubin photoisomers
should be less able to diffuse across the blood-brain
barrier. However, no experimental evidence to date sup-
ports this theoretically based hypothesis.
Conclusion
Bilirubin metabolism undergoes significant changes dur-
ing fetal and neonatal life in terms of the balance of
isomers, the processes involved in uptake into the hepa-
tocyte, binding and conjugation inside the hepatocyte,
and excretion into the bile. Several steps in the process
that causes neonatal jaundice can be modulated both by
endogenous and exogenous compounds. Drugs that in-
crease the concentration of ligandin or the activity of
bilirubin UDPGT are well documented but appear not
to be used widely. Drugs that limit bilirubin production
by inhibiting heme oxygenase are undergoing trials, but
their eventual place in the routine management of neo-
natal jaundice remains to be determined. Enterohepatic
circulation contributes to neonatal jaundice and is ame-
nable to therapeutic intervention by formula feedings or
other bilirubin binding or degrading agents.
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specifications
• Know the factors that affect the biological
properties of bilirubin, including its
solubility and tissue distribution.
• Know bilirubin physiology, including the
enzymatic reactions involved in production,
in the fetus and in the term and preterm neonate.
• Know the factors, including genetic and increased red cell
destruction, associated with an increase in bilirubin
production.
• Know the factors associated with a decrease in neonatal
serum bilirubin excretion, including those that affect the
enterohepatic circulation of bilirubin.
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 Core Concepts: Bilirubin Metabolism
Thor Willy Ruud Hansen
Neoreviews 2010;11;e316
DOI: 10.1542/neo.11-6-e316

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