2. Neonatal Bilirubin Metabolism
• Bilirubin derived from heme
– 75% from catabolism of circulating RBC
– 25% from ineffective erythropoesis and turnover of
heme protein and free heme
• No known physiologic function, possible
antioxidant function
• Heme iron + carbon monoxide + biliverdin
bilirubin
– Heme oxygenase converts heme to biliverdin
– Biliverdin reductase converts biliverdin to bilirubin
3. Neonatal Bilirubin Metabolism
• Bilirubin is carried bound to albumin to the liver, where
in presence of the enzyme uridyldiphosphoglucuronyl
transferase (UDPGT), it is taken up by the hepatocyte
and conjugated with two glucuronide molecules
• The conjugated bilirubin is then excreted through the
bile to the intestine
• In the presence of normal intestinal flora, the conjugated
bilirubin is metabolized further to stercobilins and
excreted in the stool
4. Neonatal Bilirubin Metabolism
• Enterohepatic circulation
– In the absence of gut flora and with slow
intestinal motility/delayed feeding (as in the
first days of life) - the conjugated bilirubin
remains in the intestinal lumen, where a
mucosal enzyme (β-glucuronidase) can cleave off
the glucuronide molecules, leaving
unconjugated bilirubin to be reabsorbed
5. Bilirubin Forms
• Unconjugated bilirubin
– Bound to albumin
• Does not cross blood-brain-barier (BBB)
• Distruption of this bond by certain drugs (sulfa drugs,
ceftriaxone, free fatty acids), hypothermia, hypoxia,
acidosis
– Free unconjugated bilirubin
• Amount of bilirubin exceeds the available binding sites
on albumin
• Readily crosses the BBB
• Conjugated bilirubin
– Bilirubin glucuronide
6. Physiologic Jaundice
• Clinical jaundice develops in 50%-65% of all
newborns
– Jaundice appears after 24 hrs of age
– Total bilirubin rises by less than 5 mg/dl (86 mmol/l)
per day
• Contributing factors
– UDPGT inactivity at birth
– Relatively high RBC mass
– Absence of intestinal flora
– Slow intestinal motility leading to an active
enterohepatic circulation
7. Physiologic Jaundice
• Full term infants
– Peak bilirubin occurs at age 3 to 5 days with total
bilirubin of no more than 15 mg/dl (258 mmol/l)
– Only 3% develop serum bilirubin levels > 15 mg/dl
– Jaundice is resolved by 1 week
• Premature infants
– Higher bilirubin levels with later peak (6-7 days)
– Jaundice is resolved by 2 weeks of age
8. Exaggerated Physiologic Jaundice
• Factors that may enhance or worsen normal
physiologic jaundice
– Prematurity
• Poor enteral intake
• Delayed stooling
• Increased enterohepatic circulation
– Sequestrated blood,
– Delayed establishment of feedings
– Maternal drugs
• Oxytocin, diazepam ,promethazine
– Delayed cord clamping
9. Breast Feeding Jaundice
• Also known as “lack of breast milk jaundice”
– Occurs 1st week of life
– Breast fed infants are more likely to have bilirubin
>15 mg/dl than formula fed infants: 2% versus
0.3%
• The pathogenesis appears to be
– decreased enteral intake and increased
enterohepatic circulation
– No increase in bilirubirubin production is seen
10. Breast Feeding Jaundice
• Jaundice should be considered a possible sign of
failure to establish an adequate milk supply and
should prompt specific inquires into this
possibilty
– Weight loss >10% from birth
– Fewer than 6 wet diapers by day 3-4
– Fewer than 4 stools per day
– Nursing fewer than 8 times per 24 hrs for at least 10
min each feed
• If intake is inadequate, the infant should receive
supplementation with formula, and mother
should be instructed to nurse more frequently
11. Breast Milk Jaundice
• Incidence 1/200
• Reason unknown
– Believed to be caused by a prolonged increased
enterohepatic circulation of bilirubin
– Inhibition of hepatic glucuronyl transferase
• Metabolite of progesterone (pregnone-3-alpha-20-
beta-diol)
• Free fatty acids
• Lipoprotein lipase
12. Breast Milk Jaundice
• High levels of unconjugated bilirubin over
longer period of time
– Can reach 20 mg/dl (344 mmol/l) by age 2 weeks
and then begin to fall and normalize over age 8 to
12 weeks
– Presence of unconjugated hyperbilirubinemia for
6-8 weeks in thriving breast fed infant without
evidence of hemolysis, hypothyroidism or other
disease strongly suggest this diagnosis
13. Pathologic Jaundice
• Characteristics
– Onset before age 24 hours
– Rate of increase > 0.5 mg/dl/hr (8.6
mmol/l/hr)
– Evidence of underlying illness
• Gastrointestinal
• Hematologic
• Infectious
– Jaundice that persists greater than 8 days
in term infants and 14 days in preterm
infants
14. Pathologic Jaundice - Causes
• Overproduction of bilirubin
• Elevated reticulocyte count
– Increased rate of hemolysis
• Patients with a positive Coombs test
– ABO/Rh blood group incompatibility
• Patients with a negative Coombs test
– Abnormal RBC shapes – spherocytosis
– RBC enzyme abnormalities – G6PD
– Infants with bacterial or viral sepsis (increased
hemolysis, decreased uptake, decreased excretion
16. Pathologic Jaundice - Causes
• Deceased rate of conjugation
– Crigler-Najjar syndrome – UDPGT deficiency
• Type I – complete deficiency; autosomal recessive
– Severe hyperbilirubinemia, bilirubin encephalopathy, and death
withour therapy
• Type II – partial defficiency; autosomal dominant
– The enzyme can be induced with phenobarbital, which may
lower bilirubin levels by 30-80%
– Gilbert syndrome
• Mild autosomal dominant disorder
• Decreased hepatic UDPGT levels
17. Pathologic Jaundice - Causes
• Other
– UTI
• mixed hyperbilirubinemia
• Mechanism for the liver impairment – inhibitory action on bile
secretion of bacterial products (endotoxines) and inflamatory
cytokines
– Congenital hypothyroidism
– Inborn error of metabolism
– Hepatitis (A, B, C, autoimmune, TORCH)
– Liver failure
– Prolonged TPN
– Neonatal hypoxic-ischemic event
• Hypoperfusion of GI tract
– Biliary atresia
18. Bilirubin Toxicity
• Three phases
– Jaundice, hypotonia, lethargy, poor
feeding, poor suck
– After few days: hypertonia, opisthotonus,
high-pitched cry, fever, seizures
– After about one week: hypertonia replaced
by hypotonia, long-term neuronal injury
19. Bilirubin Toxicity
• Surviving children develop
– Extrapyramidal disturbances (choreoathetosis)
– Hearing loss
– Limitation of upward gaze
– Dental dysplasia
– Mild intellectual deficits
23. Studies
• Bilirubin level
– Total and direct
• Infant’s blood type and direct Coombs test
• Mothers blood type and antibody screening
• Peripheral smear for RBC morphology
• Hematocrit level (polycythemia or anemia)
• Reticulocyte count
• Others depending on course
– LFTs, sepsis evaluation
24. Management
• Phototherapy
– Used most commonly
– Relatively noninvasive and safe
– Unconjugated bilirubin in the skin is coverted to a
stereoisomer lumirubin, that is water-soluble and
excreted in bile without conjugation
– Wavelength of 425 to 475 nanometers (blue light) is
most effective
– Intensity – a minimum 10-14 µW/cm2 irradiance is
required
• Intensive phototherapy is defined as 30 µW/cm2
25. Management
• Phototherapy – Possible Side
Effects
– Increased insensible water loss
– Dehydration
– Watery stools
– Retinal damage
– Skin rash (increased skin perfusion)
– Mutation DNA strand breaks (cover
gonads)
– “Bronze Baby” syndrome
• High direct bilirubin level
26. Management
• Exchange transfusion
– Double volume exchange transfusion
(approximately 160-200 ml/kg body weight)
remains necessary in some cases of hemolysis
resulting from Rh isoimmunization, ABO
incompatibility, or hereditary spherocytosis
– In addition to decreasing the bilirubin level by
approximately 50% acutely, the exchange
transfusion also removes nearly 80% of the
sensitized or abnormal RBC and offending
antibodies so that ongoing hemolysis will be
deceased
27. Management
• Exchange transfusion
– Procedure is invasive and not without risk
– The risk of mortality is 1-5%
• Risk is greatest in the smallest, most immature,
and otherwise unstable infants, but sudden
death during the procedure can occur in any
infant
– Risk of serious complications such as NEC,
infection, electolyte disturbances, or
thrombocytopenia is 5-10%
28. Management
• Exchange transfusion
– Fresh irradiated whole blood, with
hematocrit of replacement blood should
equal 40% to 50%
– Performed in 5ml to 20 ml aliquots
• Monitor HR, BP, pH, glucose, potassium,
calcium, magnesium
29. Management
• Experimental pharmacotherapy
– Phenobarbital
• Increases concentration of ligandin, increasing
uptake
• Increases bile flow
– IVIG
• In severe Rh hemolytic disease
