Neonatal Jaundice.pdf

A condition that is so common in paediatrics.

1. PAEDIATRICS AND CHILD HEALTH
•NEONATOLOGY
•Neonatal Jaundice
Dr.ChongoTimothy Shapi(BSc.HB, MBChB)
-Medical Doctor.
2/21/2013 Dr. ChongoShapi, BSc.HB, MBChB, CUZ. 1

2. What is Jaundice?
•Hyperbilirubinaemia, clinically
manifesting as yellowing of the:
•Sclera
•Skin
•Mucous membranes
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3. HaemMetabolism
•In the reticulo-endothelial system (RES) e.g.
spleen, phagocytes destroy old and effete RBCs and
this releases hemoglobinwhich is converted to
haemand globin
•The globinpart is turned into amino acids
•The haempart is converted to biliverdinby haem
oxygenaseenzyme
•The biliverdinreductase converts biliverdinto free
unconjugated bilirubin which is NOT soluble in
water due to intramolecular hydrogen bonding
•Hence, it is bound to albumin and transported to
the hepatocytes
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4. HaemMetabolism
•In the hepatocytes, it is released from albumin and combined
with GLUCURONIC ACID to form BILIRUBIN GLUCURONIDE by
the enzyme called uridinediphosphoglucuronosyltransferase
(UGT-1)
•This conjugation produces CONJUGATED BILIRUBIN (Direct
Bilirubin by the Van den Bergh reaction) which is soluble in
water
•The conjugated bilirubin is then excreted via active transport
into the biliary canaliculito mix with other components of bile
and into the intestines at the major duodenal papilla of Vaterin
the 2
nd
part of the duodenum
•95% of the conjugated bilirubin in the intestines is deconjugated
by the beta glucuronidaseenzymeon the brush border of the
small intestine to the unconjugated lipid soluble bilirubin for
reabsorption at the terminal ileum back into the portal
circulation to the liver where it is resecreted(enterohepatic
circulation)
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5. HaemMetabolism
•The remaining 5% goes to the colon
•50% of the 5% of conjugated bilirubin in the colon is acted
upon by intestinal normal bacterial flora
•The bacteria degrade it to UROBILINOGEN (water soluble)
•Fate of urobilinogen:
a.95% is reabsorbed back into portal circulation for the
enterohepaticcirculation, but 5% of the 95% is oxidized to
urobilin(water soluble) and excreted in urine giving the
yellow colourof urine
b.5% is oxidized to stercobilin(water soluble) and excreted
in faecesgiving the yellow colourof faeces
NB: Bilirubin is NOT supposed to appear in urine (dark urine).
If it does, then that is water soluble bilirubin (direct bilirubin)
accumulating in blood as a result of obstruction to already
conjugated bilirubin in the liver
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6. Jaundice and Hyperbilirubinemiain the Newborn
•Hyperbilirubinemiais a common and, in most
cases, benign problem in neonates
•Jaundice in 1st wkof life is approximately:
-60% of term infants and
-80% of preterm infants
•The yellow colour usually results from the
accumulation of unconjugated, nonpolar, lipid-
solublebilirubin pigment in the skin
•This unconjugated bilirubin (designated indirect
actingby nature of the Van den Bergh reaction) is
an end product of haem-protein catabolism
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7. •It may also be due in part to deposition of
pigment from water soluble, conjugatedbilirubin
(direct bilirubin)
•Although bilirubin may have a physiologic role as
an antioxidant, elevated levels of indirect,
unconjugated bilirubin are potentially neurotoxic
•Even though the conjugated form is not
neurotoxic, direct hyperbilirubinemiaindicates
potentially serious hepatic disorders or systemic
illnesses
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8. Aetiology
•During the neonatal period, metabolism of
bilirubin is in transition from the fetalstage to
adult stage
•In the fetalstage, the placenta is the principal
route of elimination of the lipid-soluble,
unconjugated bilirubin which goes to the
maternal liver for degradation
•In the adult stage, the water-soluble conjugated
form is excreted from hepatic cells into the biliary
system and GIT
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9. •Unconjugated hyperbilirubinemiamay be caused or
increased by any factor that:
1. Increases the load of bilirubin to be metabolized
by the liver
-Haemolytic anaemias
-Polycythaemia
-Shortened RBC life as a result of immaturity or
transfused cells
-Increased entero-hepatic circulation
-Infection
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10. 2. Damages or reduces the activity of the
transferaseenzyme or other related enzymes
-Genetic deficiency
-Hypoxia
-Infection
-Thyroid deficiency
3. Competes for or blocks the transferaseenzyme
(drugs and other substances requiring glucuronic
acid conjugation)
4. Leads to an absence or decreased amounts of
the enzyme or to reduction of bilirubin uptake by
liver cells (genetic defect, and prematurity)
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11. •The toxic effects of elevated serum levels of
unconjugated bilirubin are increased by factors that
reduce the retention of bilirubin in the circulation
•These include:
-Hypoproteinemia
-Displacement of bilirubin from its binding sites on
albumin by competitive binding of drugs such as
sulfonamides
-Acidosis
-Increased free fatty acid concentration secondary to
hypoglycemia
-Starvation
-Hypothermia
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12. •Neurotoxic effects are directly related to:
-The permeability of the blood-brain barrier
-Permeability of the nerve cell membranes
-Neuronal susceptibility to injury
•All of these are adversely influenced by asphyxia,
prematurity, hyperosmolality, and infection
•Early and frequent feeding decreases whereas
breast-feeding and dehydration increase serum
levels of bilirubin
•Delay in passage of meconium, which contains 1 mg
bilirubin/dL, may contribute to jaundice by
enterohepaticcirculation after deconjugationby
intestinal glucuronidase
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13. Risk factors for Hyperbilirubinemia
Acronym = JAUNDICE:
•Jaundice visible on the 1st day of life
•Asibling with neonatal jaundice or anemia
•Unrecognized hemolysis(ABO, Rh, other blood group,
incompatibility); UDP-glucuronosyltransferasedeficiency
(Crigler-Najjar, Gilbert’s disease)
•Non-optimal feeding (formula or breast-feeding)
•Deficiency of glucose-6-phosphate dehydrogenase (G6PD)
•Infection (viral, bacterial). Infant of diabetic mother
(macrosomic). Immaturity (prematurity)
•Cephalohematomaor bruising. Central hematocrit>65%
(polycythemia)
•East Asian, Mediterranean, Native American heritage
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14. Other risk factors:
•Gestational age 35–36 wk(major risk)
•Gestational age 37–38 wk(minor risk)
•Maternal age ≥25 yr
•Male gender
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15. Decreased risk
•Low TSB
•Gestational age ≥41 wk
•Exclusive bottle feeding
•Black race
•Discharge from hospital after 72 hr
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16. Clinical Manifestations
•Depending on the aetiology, jaundice may be present at
birth or may appear at any time during the neonatal
period
•Is usually apparent in a cephalocaudalprogression starting
on the face and progressing to the abdomen and then
feet, as serum levels increase
•Dermal pressure may reveal the anatomic progression of
jaundice, called Kramer’s rule
•The rule is basically a clinical method of assessing the
degree of jaundice present before investigations are
undertaken
•The technique depends on blanching of the infant’s skin
with the examiner’s finger at standard zones (1-5) and
observing the colour in the blanched area
•The zones of jaundice reflect the downward progression of
dermal icterus
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17. Zones of Kramer’s rule
•Zone 1: jaundice limited to head and neck
-Serum indirect bilirubin: 100umol/L
•Zone 2: over upper trunk
-Serum indirect bilirubin: 150umol/L
•Zone 3: over lower trunk, thighs
-Serum indirect bilirubin: 200umol/L
•Zone 4: over arms, forearm, legs
-Serum indirect bilirubin: 250umol/L
•Zone 5: hands and feet
-Serum indirect bilirubin: > 250umol/L
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18. •Jaundice from deposition of indirect bilirubin in
the skin tends to appear bright yellow or orange
•Jaundice of the obstructive type (direct
bilirubin) has a greenish or muddy yellow cast
•Signs of kernicterus include:
-Lethargy
-Poor feeding and, without treatment
-Progresses to acute bilirubin encephalopathy
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19. Differential diagnosis
•On the 1
st
day (24 hrs) of life
-Haemolytic disease of the newborn(HDNB) or
erythroblastosisfetalis. Remember, with haemolysis the
rise in bilirubin is very fast
-Concealed haemorrhage (cephalohaematoma)
-Neonatal sepsis
-Congenital infections (TORCHES)
•On the 2
nd
-3
rd
day of life
-Physiologic jaundice
-Familial non-hemolyticicterus (CrigglerNajjar, Gilbert’s)
-Breast feeding jaundice
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20. Differential diagnosis
•After the 3
rd
day and appearing within the 1
st
week of life
-Bacterial sepsis
-TORCHES
-Polycythaemia
-Cephalohaematoma
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21. •After 1
st
week of life
-Breast milk jaundice (is not the same as breast feeding
jaundice)
-Septicaemia
-Congenital biliary atresia (CBA)
-Hepatitis
-Galactosaemia(galactose-1-phosphate uridyltransferase=
GALT). The enzyme is deficient
-Congenital hypothyroidism (this cause low BMR, hence
slows down the conjugation process in the liver)
-Congenital haemolytic anaemia crises related to RBC
morphology and enzyme deficiencies e.g. G6PD,
hereditary spherocytosis
-Cystic fibrosis (CF): meconium ileus and also thick bile
secretions block the bile ducts
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22. •Persistent jaundice during the 1
st
month of life
-Hyperalimentationassociated with cholestasis
-Hepatitis
-Cytomegalic inclusion disease
-TORCHES
-Familial non-haemolytic icterus e.g. CriglerNajjar
syndrome or Gilbert’s disease
-Congenital biliary atresia
-Galactosemia
-Inspissatedbile syndrome (IBS) following HDNB
-Rarely physiologic jaundice in a patient with
hypothyroidism or pyloric stenosis
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23. •Full-term, low-risk, asymptomatic infants may be
evaluated by monitoring total serum bilirubin (TSB)
levels
•Patients with significant hyperbilirubinemiaand
symptomatic require a complete diagnostic
evaluation:
-Determination of direct and indirect bilirubin
fractions
-Haemoglobin
-Reticulocyte count
-Blood type
-Coombs test
-Examination of a peripheral blood smear
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24. •Haemolysis may be suggested by:
-Indirect hyperbilirubinemia
-Reticulocytosis
-Evidence of RBC destruction on peripheral smear
•In the absence of blood group incompatibility,
non–immunologically induced haemolysis should
be considered
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25. •Direct hyperbilirubinemia:
-Hepatitis
-Congenital bile duct disorders e.g. atresia
-Cholestasis
-Inborn errors of metabolism e.g. galactosaemia
-CF
-Sepsis
•Indirect hyperbilirubinemia:
-If the reticulocyte count, Coombs test, and direct
bilirubin are normal
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26. Differential Diagnosis
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27. Remember, jaundice can be:
a. Physiologic or
b. Pathologic
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28. Physiologic Jaundice (Icterus Neonatorum)
•Normal level of indirect-reacting bilirubin in umbilical
cord serum is 1–3 mg/dL
•This rises at a rate of <5 mg/dL/24 hr
•Thus, jaundice becomes visible on the 2nd–3rd day
•Usually peaks between day 2 and 4 at 5–6 mg/dL
•It then decreases to below 2 mg/dLbetween the 5th
and 7th days of life
•Jaundice associated with these changes is designated
physiologicjaundice (Icterus Neonatorum)
•Is due to breakdown of fetalRBCs combined with
inability to conjugate bilirubin by the immature
neonatal liver
•Remember, neonates have more RBCs and hence a
higher Hbthan adults
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29. •Diagnosis of physiologic jaundice in term or preterm
infants can be established only by excluding known
causes of jaundice based on history, clinical findings,
and laboratory data
•In general, a search to determine the cause of
jaundice should be made if:
1.It appears in the 1st 24–36 hrof life
2.Serum bilirubin is rising at a rate faster than 5
mg/dL/24 hr
3.TSB is >12 mg/dLin full-term infants or 10–14
mg/dLin preterm infants
4.Jaundice persists after 10–14 days of life
5.Direct-reacting bilirubin is >2 mg/dLat any time
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30. •Other factors suggesting a non-physiologic cause
of jaundice are:
-Family history of haemolytic disease
-Pallor
-Hepatosplenomegaly
-Failure of phototherapy to lower bilirubin
-Light-coloured stools
-Dark urine positive for bilirubin
-Signs of kernicterus
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31. Pathologic Jaundice
•Jaundice and its underlying hyperbilirubinemia
are considered pathologic if:
A. There is significant variation from that of
physiologic jaundice in:
1.Time of appearance
2.Duration
3.Pattern
B. The course is compatible with physiologic
jaundice but other reasons exist to suspect that the
infant is at special risk for neurotoxicity
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32. Pathologic Jaundice
•High unconjugated hyperbilirubinemia=
development of bilirubin-induced neurologic
dysfunction
•The development of kernicterus(bilirubin
encephalopathy)is dependent on:
1.Level of indirect bilirubin
2.Duration of exposure to elevated levels
3.Cause of jaundice
4.Infant's well-being
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33. Pathologic Jaundice
•Neurologic injury including kernicterus occurs at
lower bilirubin levels in:
1.Preterm infants
2.Presence of asphyxia
3.Intraventricularhaemorrhage
4.Haemolysis
5.Drugs that displace bilirubin from albumin e.g.
septrin
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34. Jaundice Associated with Breastfeeding
•Significant breast-milk jaundice develops in an
estimated 2% of breast-fed term infants after the
7th day of life
•Maximal concentrations as high as 10–30 mg/dL
are reached during the 2nd–3rd week
•If breast-feeding is continued, the bilirubin
gradually decreases but may persist for 3–10 wk
at lower levels
•Phototherapy may be of benefit
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35. Jaundice Associated with Breastfeeding
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36. The difference between Breastfeeding
Jaundice and Breast-Milk Jaundice
•Breastfeeding Jaundice
-Is due to lack of breast feeding the infant
-Can also be due to reduced amount of milk
intake
-This causes inadequate bowel movements to
remove bilirubin in the body and hence is a
mechanical problem resulting in accumulation of
bilirubin in the neonate (unconjugated)
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37. The difference between Breastfeeding
Jaundice and Breast-Milk Jaundice
•Breast-Milk Jaundice
-Is a biochemical problem
Factors responsible
1.Unusual metabolite of progesterone
(pregnane-3-alpha 20 beta-diol) inhibits UGT-
1 enzyme
2.The lipoprotein lipase in breast milk produces
increased concentrations of non-esterified
free fatty acids that inhibit UGT-1
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38. The difference between Breastfeeding
Jaundice and Breast-Milk Jaundice
3. Increased enterohepaticcirculation of bilirubin due
to:
a.Delayed establishment of enteric flora in breast fed
infants. Remember, that initially the GI of the
neonate is sterile with no normal flora
b.Because of lack of normal flora, the beta
glucuronidasein some breast milk deconjugatesthe
bilirubin and hence deconjugatedbilirubin is
reabsorbed and accumulates in blood
4. High epidermal growth factor in breast milk which
cause reduced GI motility and increased bilirubin
absorption and uptake
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39. Familial Non-Haemolytic Icterus
Unconjugated
1.Gilbert's syndrome
2.Crigler-Najjarsyndrome
Conjugated
1.Dubin-Johnson syndrome
2.Rotor’s syndrome
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40. Familial Non-Haemolytic Icterus
Gilbert’s syndrome
•This is the most common familial hyperbilirubinaemia
•Hepatic glucuronidationis approximately 30% of
normal
•This results in an increased proportion of bilirubin
monoglucuronidein bile
•Most patients have reduced levels of UDP-
glucuronosyltransferase(UGT-1) activity, the enzyme
that conjugates bilirubin with glucuronicacid
•Mutations occur in the gene (HUG-Br1) encoding this
enzyme
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41. Familial Non-Haemolytic Icterus
Crigler-Najjarsyndrome
•This is very rare
•There are 2 types:
-Type I: autosomal recessive, there is absence of
UGT-1. Patients do not survive into adult life
-Type II: autosomal dominant, with a decrease of
UGT-1. Patients survive into adult life
•There is mutation of the HUG-Br1gene for UGT-1
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42. Familial Non-Haemolytic Icterus
Dubin-Johnson and Rotor’s syndrome
•DJS is autosomal recessive
•Rotor'ssyndrome is possibly autosomal dominant
•Are syndromes that are due to defects in bilirubin
excretion from hepatocytes into the bile canaliculi
•The prognosis is good in both
•In the Dubin-Johnson syndrome there are mutations
in both multidrug resistance protein 2 (MRP2)
transporter genes
•In DJS, the liver is black owing to melanin deposition
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43. Congenital atresia of the bile ducts
•Jaundice persisting for more than 2 wkor
associated with acholicstools and dark urine
suggests biliary atresia
•All such infants must have an immediate
diagnostic evaluation, including determination of
direct bilirubin
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44. Galactosaemia
•Is an autosomal recessive disorder in which there is
inborn error of metabolism of galactose
•Dietary lactoseis broken down by lactase to glucose
and galactose
•In a 3 step process (LELOIR pathway), galactoseis
converted to glucose
•Enzymes involved: galactose-1-phosphate uridyl
transferase(GALT),galactosekinase, UDP galactose
epimerase
•This metabolic pathway is particularly vital for the
newborn, whose main carbohydrate source is lactose
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45. Galactosaemia
a. Type 1 (Classic galactosaemia)
-Most common variant
-There is deficiency of GALT
b. Type 2: Deficiency of galactosekinase
c. Type 3: defieiciencyof UDP galactoseepimerase
•This results in accumulation of galactose-1-
phosphate and other precursors causing damage to
many organs, tissues and cells including liver, spleen,
kidney, ocular lens, cardiac muscle, brain, gonadal
tissue and RBCs
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46. How Sepsis Causes Jaundice
•Severe conjugated hyperbilirubinemiacan be due sepsis
involving both gram-positive and gram-negative bacteria
•Gram negative are more common
•Serum alkaline phosphatase activity and cholesterol levels
are usually low
•This suggests an isolated defect in excretion of conjugated
bilirubin
•In jaundice associated with sepsis, liver pathology is
nonspecific and includes canalicularcholestasis and slight
fat accumulation
•Portal tracts may contain excess inflammatory cells and
variable bile ductuleproliferation
•Occasionally, dilated ductulesare filled with inspissatedbile
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47. Kernicterus (bilirubin encephalopathy)
•From Greek: kern = nucleus, icterus = jaundice
•Is a neurologic syndrome resulting from the
deposition of unconjugated (indirect) bilirubin in
the basal ganglia and brainstem nuclei
•Multifactorial pathogenesis
•Involves an interaction of the following:
-Unconjugated bilirubin levels
-Albumin binding
-Unbound bilirubin levels
-Passage across the BBB, and
-Neuronal susceptibility to injury
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48. Kernicterus (bilirubin encephalopathy)
•Disruption of the BBB by disease, asphyxia, and
other factors and maturational changes in BBB
permeability affect risk
•Rare in healthy term infants and in the absence
of haemolysis if the serum level is <25 mg/dL
•Has developed in healthy term infants when
bilirubin levels exceed 30 mg/dL
•Onset is usually in the 1st wkof life, but may be
delayed to the 2nd–3rd wk
•The more immature the infant is the greater the
susceptibility to kernicterus
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49. Clinical manifestations of Kernicterus
•Signs and symptoms appear:
-2–5 days after birth in term infants
-7th day in premature infants
•Hyperbilirubinemiamay lead to encephalopathy
at any time during the neonatal period
•The early signs are indistinguishable from those
of sepsis, asphyxia, hypoglycemia, intracranial
hemorrhage, and other acute systemic illnesses in
a neonate
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50. Clinical manifestations of Kernicterus
•Lethargy
•Poor feeding
•Loss of the Moro reflex
•Diminished tendon
reflexes
•Respiratory distress
•Opisthotonos
•Bulging fontanel
•Twitching of the face or
limbs
•High-pitched cry
•Convulsions
•Spasm (stiffly extending
their arms in an inward
rotation with the fists
clenched)
•Rigidity
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51. Treatment of hyperbilirubinemia
AIM: prevent kernicterus
Medical:
1. Phototherapy:
a.Conventional
b.Intensive: irradiance of light ≥ 30uW/cm2/nm
2. Exchange transfusion (ET)
3. IV immunoglobulin (IVIG) used as adjunct therapy in isoimmunehaemolytic
disease
Phototherapyand, if unsuccessful, ETremain the primary treatment modalities
used to keep the maximal TSB below the pathologic levels
NB: Haemoxygenaseinhibitors currently under research. Haemis excreted in
bile
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52. Treatment of hyperbilirubinemia
•Goal of therapy is to prevent kernicterus
•The risk of injury to the CNS from bilirubin must be
balanced against the potential risk of treatment
•There is lack of consensus regarding the exact
bilirubin level at which to initiate phototherapy
•Phototherapy requires 6–12 hrto have a measurable
effect
•Hence, must be started at bilirubin levels below those
indicated for ET
•Treat the underlying cause if identified e.g. antibiotics
for septicemiaand correction of acidosis
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53. Phototherapy
•Clinical jaundice and indirect hyperbilirubinemia
are reduced by exposure to a high intensity of
light in the visible spectrum
•Bilirubin absorbs light maximally in the blue
range (420–470 nm)
•Broad-spectrum white, blue, and special narrow-
spectrum (super) blue lights have been effective
in reducing bilirubin levels
•Bilirubin in the skin absorbs light energy, causing
several photochemical reactions
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54. Phototherapy
MOA:
1.Photo-oxidation: minimal contribution
2.Configurationalisomerization to 3 water soluble IBs:
4Z, 15Z ↔4Z, 15E (predominant); 4E, 15Z;4E, 15E.
3. Irreversible structural isomerization: lumirubin
-No consensus regarding the exact bilirubin
level at which to initiate phototherapy
-Rule of thumb:
TSB > 5 times the birth weight:
e.g.
1 kg = 5 mg/dL
2 kg = 10mg/dLand so on
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55. BhutaniGraph
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56. •Phototherapy causes a reversible photo-
isomerization reactionconverting the toxic native
unconjugated 4Z, 15Z-bilirubin into an
unconjugated configurationalisomer 4Z,15E-
bilirubin
•The product is then excreted in bile in an
unconjugated state
•The other major product from phototherapy is
lumirubin, which is an irreversible structural
isomerconverted from native bilirubin and can be
excreted by the kidneys in the unconjugated state
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57. •The therapeutic effect of phototherapy depends on:
1.The light energy emitted in the effective range of
wavelengths
2.The distance between the lights and the infant, and
3.The surface area of exposed skin
4.The rate of haemolysis and in vivo metabolism and
excretion of bilirubin
•The use of phototherapy has decreased the need for
ET in term and preterm infants with haemolytic and
non-haemolytic jaundice
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58. Precautions of Phototherapy
1. The infant's eyes should be closed and
adequately covered to prevent light exposure and
corneal damage
2. Body temperature should be monitored
3. Infant should be shielded from bulb breakage
4. Irradiance should be measured directly and
details of the exposure recorded:
-Type and age of the bulbs
-Duration of exposure
-Distance from the light source to the infant
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59. Always Shield the Eyes
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60. Complications of Phototherapy
1.Diarrhoea
2.Erythematous macular rash
3.Purpuricrash associated with transient
porphyrinemia(Phototherapy is a
contraindication in the presence of porphyria)
4.Overheating
5.Dehydration (increased insensible water loss,
diarrhoea)
6.Hypothermia from exposure
7.Bronze baby syndrome (BBS) due to
hyperbiliverdemia. Differential of BBS is graybaby
syndrome (GBS) due to chloramphenicol
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61. Exchange Transfusion (ET)
•Indications for double
volume ET:
1.Failure of phototherapy to
reduce bilirubin levels to a
safe range
2.Kernicterus at any level of
bilirubin
•Potential complications of
ET:
-Metabolic acidosis
-Electrolyte abnormalities
-Hypoglycemia
-Hypocalcemia
-Thrombocytopenia
-Volume overload
-Arrhythmias
-Necrotising enterocolitis
(NEC)
-Infection
-Graft versus host disease
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62. Exchange transfusion
Indications:
1.Failure of intensive phototherapy
2.Kernicterus
-Has more complications
than phototherapy
-Thus, intensive phototherapy
recommended before ET
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63. Intravenous immunoglobulin
•Is an adjunctive treatment for hyperbilirubinemia
due to isoimmunehaemolytic disease
•Its use is recommended when serum bilirubin is
approaching exchange levels despite maximal
interventions including phototherapy
•IV immunoglobulin (0.5–1.0 g/kg/dose; repeat in
12 hr) has been shown to reduce the need for ET
in both ABO and Rh haemolytic disease,
presumably by reducing haemolysis
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64. Thank You!
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