BILIRUBIN

 Non-polar, water insoluble compound

requiring conjugation with glucuronic acid
to form a water soluble product that can be
excreted.
 It circulates to the liver reversibly bound
to albumin
 BILIRUBIN PHYSIOLOGY
 Increased production in neonate due to larger red
cell volume, which produces bilirubin as cells
are broken down and shorter RBC life span, so
broken down faster.
 Heme is catabolized within the
reticuloendothelial system by heme oxygenase to
form biliverdin.
 Biliverdin is metabolized to bilirubin in the
presence of biliverdin reductase
BILIRUBIN PHYSIOLOGY

Heme oxygenase Biliverdin

Heme

Biliverdin reductase

Bilirubin
 Bilirubin Physiology

 Ligandins responsible for transport from

plasma membrane to endoplasmic
reticulum.
 Bilirubin conjugated in presence of
UDPGT (uridine diphosphate glucuronyl
transferase) to mono and diglucoronides,
which are then excreted into bile
canaliculi.
Enterohepatic Circulation
 Meconium contains 100-200mg of conjugated
bilirubin at birth.
 Conjugated bilirubin is unstable and easily
hydrolyzed to unconjugated bilirubin.
 This process occurs non-enzymatically in the
duodenum and jejunum and also occurs in the
presence of beta-glucuronidase, an enteric
mucosal enzyme, which is found in high
concentration in newborn infants and in human
milk.
 Conjugation
 Since conjugated bilirubin crosses the placenta
very little, conjugation is not active in the fetus
with levels of UDPGT about 1% of adult levels
at 30 - 40 weeks gestation
 After birth, the levels of UDPGT rise rapidly but
do not reach adult levels until 4-6 weeks of age.
 Ligandins, which are necessary for intracellular
transport of bilirubin, are also low at birth and
reach adult levels by 3-5 days.
 CONJUGATED VS
UNCONJUNCATED
HYPERBILI
 Conjugated hyperbilirubinemia is always
pathologic
 When the total bili is quite high, the conjugated
fraction can rise to as high as 20% of the total,
although it usually stays under 1.0.
 Always check a total and direct, so that you can
be sure you are excluding conjugated
hyperbilirubinemia, which has totally different
etiologies and treatments.
 KERNICTERUS
 Why we care about indirect hyperbilirubinemia
 Staining of the brain by bilirubin
 Early symptoms-acute bilirubin encephalopathy-
poor feeding, abnormal cry, hypotonia,
 Intermediate phase-stupor, irritability,
hypertonia
 Late – shrill cry, no feeding, opisthotonus,
apnea, seizures, coma, death
 KERNICTERUS
 Late sequelae can include
gaze abnormalities
feeding difficulties
dystonia
incoordination
choreoathetosis
sensorineural hearing loss
painful muscle spasms
 KERNICTERUS
 Incidence of bilirubin levels>30 1/10,000
 Over 120 cases kernicterus documented since
1990
 Overwhelming majority term, breastfed
 Majority of those had levels in high 30s to 40s.
 Lowest level recorded in case series of 111 from
1991-2002 was 20.7, but the mean was 38.
 Many cases had no planned follow up and had
been discharged early (<48 hours).
KERNICTERUS AND FREE
BILIRUBIN
 An article published this year in Pediatrics
makes the case for establishing free bilirubin
levels rather than total serum bilirubin levels to
monitor jaundice and assess risk for kernicterus.
 Since bilirubin travels bound to albumin
predominantly, the free bilirubin is inversely
proportional to the albumin concentration.
 ALBUMIN
 A low albumin level could possibly be the
reason behind kernicterus occurring in some
infants at relatively low bilirubin levels.
 There was a report of a 29 week infant whose
peak bilirubin level was only 15.7 and yet
developed classic kernicterus with spasticity,
dystonia, ballismus, and gaze abnormalities.
 Her bilirubin/albumin molar ratio was 0.67. It
has been suggested that a ratio of >0.5 might be
a threshold in sick preterm infants.
 ALBUMIN
 Wenneberg et. al. suggest that an infant with an
albumin level of 2 would be at the same risk for
kernicterus with a bilirubin of 15 as an infant
with a bilirubin of 30 and an albumin level of 4.
 We do not have data on albumin levels in
healthy term infants, but most likely,
hypoalbuminemia is a concern in extremely
preterm or otherwise sick infants.
 RISK FACTORS FOR
SIGNIFICANT JAUNDICE
 Gestational Age
 Race
 Family history of jaundice requiring
phototherapy
 Hemolysis (ABO or other)
 Severe bruising
 Breastfeeding
 TIME COURSE OF
JAUNDICE

 Pathologic by definition if significant

in first 24 hours
 Usually begins to peak by 48 hours
and continues until 96 hours
 In Asian infants and preterm infants,
peak can continue out to 5-7 days.
 RISK FACTORS-RACE
 Asians-highest risk
Levels peak at 16-18 as opposed to average
Caucasian levels of 6-8. There is also a later
peak which can occur at 5-7 days.

 Black infants have a lower peak, rarely

exceeding 12. (but they have a much higher
incidence of G6PD deficiency)

 Caucasians are in the middle.

 RISK FACTORS-
GESTATIONAL AGE
 The younger the gestation, the higher the risk
of jaundice.
 37 weeks more prone to jaundice than 40
weeker who is more prone than a 42 weeker.
 35 and below is much more prone
 Extreme preemies also more prone to
kernicterus and are treated at much lower
levels.
 RISK FACTORS-FAMILY
HX
 A child whose sibling needed
phototherapy is 12 times more likely to
also have significant jaundice.

 Frequently peak bilirubin levels correlate

between siblings.
 RISK FACTORS-
HEMOLYSIS
 ABO Incompatibility is the most common cause of
hemolysis causing jaundice.
 Only 10-20% of infants with ABO mismatch develop
significant jaundice.
 Some of these infants, however, develop very
significant jaundice quickly.
 Coombs positive ABO is more likely to cause
hemolysis, but many babies will be asymptomatic.
Conversely, Coombs negative ABO mismatch does
occasionally cause significant hemolysis, but this is
rather rare.
 RISK FACTORS-
PATHOLOGIC
 G6PD Deficiency
 Hereditary Spherocytosis
 Glucuronyl Transferase Deficiency Type 1
(Crigler Najar Syndrome)
 GT deficiency Type 2 (Arias Syndrome)
 Polycythemia
BREASTMILK/BREASTFEEDING
JAUNDICE
 Breastfeeding jaundice occurs early
 It is due to the lack of breast milk
 It is often associated with poor passage of
meconium.
 Treatment should be aimed at supporting
breastfeeding while supplementing as
needed to avoid extreme weight loss,
dehydration, and worsening jaundice.
BREASTMILK/BREASTFEEDING
JAUNDICE
 Breast milk jaundice is a different, more benign entity,
which tends to occur late in the first week or afterwards.
 It is actually due to something in the breast milk which
tends to prolong jaundice.
 Usually weight gain is good, and the baby is otherwise
well.
 Jaundice might persist as late as 3-4 weeks, but usually
will peak by 2 weeks.
 Textbook treatment is to interrupt breastfeeding (I
usually do not do this).
 ASSESSING THE RISK OF
JAUNDICE BY THE NUMBERS
Bhutani curve
 ASSESSING THE RISK OF
JAUNDICE BY THE NUMBERS
 Maisels’ and Kring’s study showed that
not all early higher TcB will continue
going up.
 They divided the rate of rise to be
concerned with into
 6-24hr >0.22/hr
 24-48 >0.15/hr
 48+ >0.06/hr
 Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316

Copyright ©2004 American Academy of Pediatrics

 THERAPIES-
PHOTOTHERAPY
 Phototherapy has been the mainstay of treating
hyperbilirubinemia since the 1960s.
 Phototherapy causes structural isomerization,
forming lumirubin, which is then excreted in the
bile and urine.
 Since photoisomers are water soluble, they
should not be able to cross the blood-brain
barrier, so starting phototherapy should decrease
the risk of kernicterus by turning 20-25% of
bilirubin into a form unable to cross, even before
the level has lowered significantly.
 THERAPIES-
PHOTOTHERAPY

 Bilirubin absorbs light best at 450 nm, but

longer wavelenths penetrate skin better.
 Make sure skin is as exposed as possible
and that light is not too far from baby.
 Fiberoptic light (bili blanket) is much less
efficacious on its own.
 THERAPIES-EXCHANGE
TRANSFUSION
 Double volume exchange transfusion was
a common procedure prior to advent of
Rhogam and phototherapy.
 Now fortunately a rare occurrence
 Used for bilirubin >25 in a term infant and
not decreasing despite phototherapy
 THERAPIES-Sn
Mesoporphyrin
 SnMP is a structural analog of heme
 It blocks the site on heme oxygenase where
conversion of heme to bilirubin occurs.
 Still under investigation (why?)
 Administered parenterally in a small dose (6
micromoles/kg)
 In term infants, obviated need for phototherapy
 Some preterm infants still needed phototherapy
but none needed exchange transfusion
 Virtually 100% efficacy
 THERAPIES-Sn
Mesoporphyrin
 Can also be used repeatedly for patients with
Crigler-Najar (effects last several days).
 Stanate®-currently being patented
 Ongoing study at Children’s Hospital of
Columbus in newborns at risk of exchange
transfusion
 Accepting patients until September, 2006
 Richard McCleod, MD, Principal Investigator
 614-722-2718
 MANAGING JAUNDICE-
TAKE HOME POINTS
 Consider the risk factors, particularly
prematurity and hemolysis
 Follow up is key!
 Consider how well baby is feeding, parents’
ability to return, reliability, etc
 The higher the number of risk factors, the lower
the level at which to intervene
 Sometimes, you will be surprised. We can’t
always prevent hyperbilirubinemia, but we
should always prevent kernicterus.