• PHYSIOLOGIC
JAUNDICE
JAUNDICE • PATHOLOGIC
JAUNDICE
• KERNITERUS
NEONATAL JAUNDICE
•Jaundice is observed during the 1st wk after birth
inapproximately 60% of term infants and 80% of
preterm infants.
•The yellow color usually results from the
accumulation of unconjugated bilirubin pigment in
the skin
•High bilirubin levels may be toxic to the
developing central nervous system and may cause
neurological impairment even in term newborns.
• In most cases, it is benign and no intervention is
required.
BILIRUBIN
• Bilirubin is a yellowish substance in the blood. the catabolic product of
heme metabolism. and it travels through liver, gallbladder, and digestive
tract before being excreted.
• Within physiologic range, bilirubin has cytoprotective and beneficial
metabolic effects, but in high levels it is potentially toxic.
• However, the body has developed mechanisms for its safe detoxification
and disposition.
• Jaundice can result from defects in any of the steps of bilirubin
metabolism.
BILIRUBIN METABOLISM
1) Bilirubin production- macrophages
reticuloendothelial cells take up red blood cells
and metabolize the hemoglobin into Heme
and Globin.
• Globin- Further broken down into amino acid
and subsequent recycled
• Heme- Broken down into Iron and Biliverdin
catalized by heme oxygenase
• Iron gets recycled while biliverdin is reduced to
create unconjugated bilirubin
BILIRUBIN METABOLISM
2) Bilirubin Conjugation- in hepatocyte the
enzyme UDP glucuronosyltransferase
(UGT1A1) catalize the conjugation of
bilirubin with glucuronic acid
• resulting in mostly Bilirubin diglucoronide
and some monoglucoronide that are more
water soluble than unconjugated bilirubin,
this forms conjugated bilirubin to be
excreted into the duodenum in bile
BILIRUBIN METABOLISM
3) Bilirubin excretion- once in the colon,
bacteria deconjugate bilirubin and convert it
into urobilinogen . around 80% of this is
converted into Stercobilin then excreted
through feces.
• 20% reabsorb into blood stream- through
enterohepatic circulation and is carried to the
liver
o Some is recycled for bile production
o Others into kidney oxidized further into urobilin
and exceted into urine.
STAGE PHYSIOLOGIC JAUNDICE PATHOLOGIC JAUNDICE
CA • Shortened RBC lifespan • Conditions that lead to hemolysis
US PRODUCTION •
•
Neonates have more RBC/kg
RBC production is inefficient = more immature,
o
o
Infection
Congenital abnormalities
ES •
malformed cells
Enterohepatic shunting
o
o
Rh diseases
ABO incompatibility
o Enzyme deficiencies (G6PD)
• Neonates have less albumin, especially those born • Albumin levels are even lower in malnourished infants
TRANSPOR
premature • Drugs that compete for albumin binding sites
• Hypothermia and acidosis interfere with albumin
T
binding
• Total Parenteral Nutrition
• Neonates are initially low in intracellular carrier • Hypoxemia
CONJUGATION
proteins • Hypoglycemia
• Conjugation enzyme activity is low for the first • Decreased liver perfusion
24hours after birth. This activity is even lower in • Sepsis
preterm baby • Endocrine disorders
• Enterohepatic shunting is increased due to • Any cause of gut obstruction
EXCRETIO
decreased gut flora, resulting in less conjugated • Hepatic obstruction
bilirubin converting to urobilinogen and available • Biliary stasis
N
to be cleaved to unconjugated bilirubin by B- • Saturation of protein carriers that carry the conjugated
glucuronidase bilirubin
PHYSIOLOGIC JAUNDICE
(ICTERUS NEONATORUM)
• believed to be the result of increased bilirubin production from the breakdown of fetal red
blood cells combined with transient limitation in the conjugation of bilirubin by the immature
neonatal liver.
• Normally the level of unconjugated bilirubin in umbilical cord serum is 1-3 mg/dL and rises at a
rate of <5 mg/dL/24 hr, thus:
o Visible jaundice usually appears between 1st -3rd day of age
o Peak between the 2nd and 4th days at 5-6 mg/dL
o Decreasing between the 5th and 7th days to <2 mg/ dL at birth
• TSB levels are below the designated cut-offs for phototherapy. It does not require any treatment.
diagnosis of physiologic jaundice in term or preterm infants can be
Diagnosis established only by excluding known causes of jaundice on the basis
of the history, clinical findings, and laboratory data
Diagnosis for Physiologic Jaundice
•In general, a search to determine the cause of jaundice should be made if:
1. It appears in the 1st 24-36 hr after birth
2. Serum bilirubin is rising at a rate faster than 5 mg/dL/24 hr,
[Link] bilirubin is >12 mg/dL in a full-term infant (especially in the absence of
risk factors) or 10-14 mg/dL in a preterm infant
4. Jaundice persists after 10-14 days after birth
5. Direct bilirubin fraction is >2 mg/dL at any time
PHYSIOLOGICAL PATHOLOGICAL
ONSET More than 24 hours Less than 24 hours
Term - <2 weeks Term - > 2weeks
DURATION Preterm - <3 weeks Preterm - >3 weeks
SERUM BILIRUBIN Raise <0.2mg/dl/hr or Raise >0.2mg/dl/hr or
CONCENTRATION <5mg/dl/day >5mg/dl/day
TOTAL SERUM BILIRUBIN < 15mg/dl > 15mg/dl
INVOLVEMENT OF PALMS AND
SOLES No Yes
SIGNS OF ACUTE BILIRUBIN
ENCEPHALOPATHY No Yes
CONJUGATED BILIRUBIN Less than 2mg/dl More than 2mg/dl
TREATMENT Not required Required
• Refers to elevation of TSB levels to the extent
where treatment of jaundice is more likely to
result into benefit than harm
• Jaundice is considered as pathologic if it
presents within the first 24 hours after birth
PATHOLOGIC and persistent after day 14 (2 weeks) in the
term infant or day 21 (3 weeks) in the
AL JAUNDICE preterm infant
• It can occur at any age and is usually a sign
of an underlying problem.
• Pathological jaundice can be caused by a
variety of conditions, including liver disease,
viral hepatitis, and blood disorders.
12
• Clinical Jaundice in first 24 hours of life
• Persistent jaundice
• >2weeks in Term neonates or
PATHOLOGIC • >3 weeks in Preterm
• Rapid rise in serum bilirubin
AL JAUNDICE • > 0.2mg/[Link]. or > 5mg/dl/day
CHARACTERI • Signs of illness (e.g. lethargy, apnea,
poor feeding, tachypnea,
STICS hepatosplenomegaly)
• Conjugated Hyperbilirubinemia
• Neonatal Jaundice with Encephalopathy
• Yellow staining of Palms and Soles
STAGE PHYSIOLOGIC JAUNDICE PATHOLOGIC JAUNDICE
CA • Shortened RBC lifespan • Conditions that lead to hemolysis
US PRODUCTION •
•
Neonates have more RBC/kg
RBC production is inefficient = more immature,
o
o
Infection
Congenital abnormalities
ES •
malformed cells
Enterohepatic shunting
o
o
Rh diseases
ABO incompatibility
o Enzyme deficiencies (G6PD)
• Neonates have less albumin, especially those born • Albumin levels are even lower in malnourished infants
TRANSPOR
premature • Drugs that compete for albumin binding sites
• Hypothermia and acidosis interfere with albumin
T
binding
• Total Parenteral Nutrition
• Neonates are initially low in intracellular carrier • Hypoxemia
CONJUGATION
proteins • Hypoglycemia
• Conjugation enzyme activity is low for the first • Decreased liver perfusion
24hours after birth. This activity is even lower in • Sepsis
preterm baby • Endocrine disorders
• Enterohepatic shunting is increased due to • Any cause of gut obstruction
EXCRETIO
decreased gut flora, resulting in less conjugated • Hepatic obstruction
bilirubin converting to urobilinogen and available • Biliary stasis
N
to be cleaved to unconjugated bilirubin by B- • Saturation of protein carriers that carry the conjugated
glucuronidase bilirubin
RISK FACTORS FOR • Blood group incompatibility with positive
direct antiglobulin test, other hemolytic
DEVELOPMENT OF disease
SEVERE • Previous sibling with jaundice and received
HYPERBILIRUBINE phototherapy
MIA • Cephalohematoma or significant bruising
• If breastfeeding is inadequate with excessive
weight loss
• Drug exposure (oxytocin , sulfonamides,
aspirin)
• Prematurity
• Delayed stooling
CLINICAL ASSESSMENT
MODIFIED KRAMER’S RULE
Serum Bilirubin
Zone (TSB) Average
1 5-8mg/dl 7
2 8-10mg/dl 9
3 10-12mg/dl 11
4 12-15mg/dl 13
5 >15mg/dl 15
INVESTIGATIONS
• FIRST LINE
• Total Serum Bilirubin : All cases with suspected
pathological levels
• Blood groups of mother and baby
• Peripheral smear : evidence of hemolysis
INVESTIGATI
• SECOND LINE
ONS • Direct Coombs test
• Hematocrit
• Reticulocyte count
• G6PD levels in RBC
KERNICTERUS
• Kernicterus is a bilirubin-induced brain dysfunction.
• The term was coined in 1904 by Christian Georg Schmorl.
• Bilirubin is a naturally occurring substance in the body of humans and many other animals,
• It is neurotoxic when its concentration in the blood is too high, a condition known
as hyperbilirubinemia.
• Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the central nervous
system, potentially causing irreversible neurological damage. Depending on the level of exposure,
the effects range from clinically unnoticeable to severe brain damage and even death.
• When hyperbilirubinemia increases past a mild level, it leads to jaundice, raising the risk of
progressing to kernicterus. When this happens in adults, it is usually because of liver
problems.
• Newborns are especially vulnerable to hyperbilirubinemia-induced neurological damage,
because in the earliest days of life, the still-developing liver is heavily exercised by the
breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the blood–brain
barrier is not as developed.
• Mildly elevated serum bilirubin levels are common in newborns, and neonatal jaundice is not
unusual, but bilirubin levels must be carefully monitored in case they start to climb, in which
case more aggressive therapy is needed, usually via light therapy but sometimes even
via exchange transfusion.
PATHOPHYSIOLOGY
• Physiologic hyperbilirubinemia
• Increased bilirubin production
• Decreased bilirubin conjugation
• Decreased excretion
• Average peak in full term : 5-6mg/dl
• Exaggerated physiological: 7-17 mg/dl
• Pathological hyperbilirubinemia: >17mg/dl
Classification
Acute bilirubin encephalopathy (ABE)
• ABE is an acute state of elevated bilirubin in the central nervous system. Clinically, it encompasses a wide range of
symptoms. These include
• lethargy, decreased feeding,
• Hypotonia or hypertonia
• a high-pitched cry
• Spasmodic torticollis (Cervical dystonia, also called spasmodic torticollis, is a painful condition in which your neck
muscles contract involuntarily, causing your head to twist or turn to one side.)
• Opisthotonus (spasm of the muscles causing backward arching of the head, neck, and spine, as in severe tetanus,
some kinds of meningitis, and strychnine poisoning)
• setting sun sign fever, seizures, and even death. If the bilirubin is not rapidly reduced, ABE quickly progresses to chronic
bilirubin encephalopathy.
Chronic bilirubin encephalopathy (CBE)
• CBE is a chronic state of severe bilirubin-induced neurological lesions. Reduction of bilirubin in
this state will not reverse the sequelae. Clinically, manifestations of CBE include; movement
disorders – dyskinetic CP with often spasticity. 60% have severe motor disability (unable to
walk).
• auditory dysfunction – auditory neuropathy (ANSD)
• visual/oculomotor impairments (nystagmus, strabismus, impaired upward or downward gaze,
and/or cortical visual impairment). In rare cases, decreased visual acuity(blindness) can occur.
• dental enamel hypoplasia/dysplasia of the deciduous teeth,
Chronic bilirubin encephalopathy (CBE)
• Gastroesophageal reflux
• Impaired digestive function.
• Slightly decreased intellectual function: Although most individuals (approximately 85%) with
kernicterus fall in normal or dull-normal range.
• Epilepsy is uncommon.
• These impairments are associated with lesions in the basal ganglia, auditory nuclei of
the brain stem and oculomotor nuclei of the brain stem. Cortex and white matter are subtly
involved. Cerebellum may be involved. Severe cortical involvement is uncommon.
Subtle bilirubin encephalopathy (SBE)
• SBE is a chronic state of mild bilirubin-induced neurological dysfunction
(BIND). Clinically, this may result in neurological, learning and movement
disorders, isolated hearing loss and auditory dysfunction.
Causes
• In the vast majority of cases, kernicterus is associated with unconjugated
hyperbilirubinemia during the neonatal period. The blood–brain barrier is not fully
functional in neonates and therefore bilirubin is able to cross into the central nervous
system. Moreover, neonates have much higher levels of bilirubin in their blood due to:
1. Rapid breakdown of fetal red blood cells immediately prior to birth,
2. Severe hemolytic disease of the newborn
3. Neonates have a limited ability to metabolize and excrete bilirubin.
4. Administration of aspirin to neonates and infants.
Risk factors • Premature birth
• Rh incompatibility
• Polycythemia – often present in neonates
• Sulfonamides (e.g. co-trimoxazole) –
displaces bilirubin from serum albumin
• Crigler-Najjar syndrome, type I
is a rare genetic condition that occurs
when your liver can't break down
bilirubin
• G6PD deficiency
• Bruising
• Gilbert's syndrome and G6PD deficiency
occurring together especially increases the
risk for kernicterus
Diagnostic:
• through a physical examination and knowledge of child's history of symptoms.
• Blood tests to measure your baby's bilirubin levels are also done
• Once a baby has kernicterus, brain damage has already occurred.
• In neonates with kernicterus, the Moro reflex may be absent or symmetrically reduced
TREATMENT
• PHOTOTHERAPY – the mainstay in treating
hyperbilirubinemia in neonates
• Blue-Green light
• Limitation: Cannot reverse stage 1
encephalopathy
• S/E : may cause Bronze baby syndrome
• DOUBLE VOLUME EXCHANGE TRANSFUSION
• Exchange of baby’s blood with fresh
cross matched blood
• More effective than phototherapy and
can also reverse stage 1 encephalopathy
• Currently no effective treatment exists for
kernicterus. Future therapies may include neuro
regeneration
• Patients with a certain condition have
undergone deep brain stimulation, and
experienced some benefit
Treatment • Drugs include such as;
• baclofen, clonazepam, gabapentin, and artane are
often used to manage movement disorders
associated with kernicterus.
• Proton pump inhibitors are also used to help with
reflux.
• Cochlear implants and hearing aids have also been
known to improve the hearing loss that can come
with kernicterus (auditory neuropathy – ANSD).
• Babies with serum bilirubin ≥20 mg/dl and those
who require exchange transfusion should be kept
FOLLOWU
under follow up in the high-risk clinic for
neurodevelopmental outcome.
• Hearing assessment (BERA) should be done at 3
P
months of age.
• With prompt treatment, even very elevated serum
bilirubin levels within the range of 25 to 29 mg/dl
are not likely to result in long-term adverse effects
on neurodevelopment.
• Antenatal investigation should include maternal blood grouping.
• Rh positive baby born to a Rh-negative mother is at higher risk
for hyperbilirubinemia and requires greater monitoring.
• Anti D (RhoGam) injection after first obstetrical event ensures
decreased risk of sensitization in future pregnancies.
PREVENTI • Ensuring adequate breastfeeding
ON • Parent education regarding danger signs should include
yellowish discoloration below knees and elbows or persistent
jaundice beyond 15 days as reason for immediate checkup by
health personnel.
• High risk babies such as ones with large cephalohematoma or
family history of jaundice should be followed up after 2-3 days
of discharge
• Measuring the serum bilirubin is helpful in evaluating a baby's
risk for developing kernicterus.
Kernicteru • Kernicterus is very rare in adults. The conditions that
s in adults cause it most often affect infants. It’s possible for
adults to develop high bilirubin levels, but almost
never kernicterus.
• Conditions that can cause very high bilirubin levels in
adults include:
• Crigler-Najjar syndrome: An inherited condition that
makes it harder for the body to break down bilirubin.
• Dubin-Johnson syndrome: A rare, inherited disorder
that prevents the body from effectively removing
bilirubin. This condition does not cause kernicterus.
• Gilbert’s syndrome: A condition in which the liver can’t
properly process bilirubin.
• Rotor syndrome: An inherited disorder that causes
bilirubin levels to build up in the blood. This condition
does not cause kernicterus.
