 Jaundice in the newborn is a common problem for the
general pediatrician – occurs in 2/3 of all newborn in
1st week of life
 Jaundice is defined as the presence of a yellow/yellow
green hue to the skin, sclerae and mucous membranes
due to an elevated serum bilirubin
 Jaundice usually becomes apparent at a total serum
bilirubin of 5 mg/dl
Bilirubin Production
 Bilirubin is a product of heme catabolism in the
reticuloendothelial system
 Approximately 80 to 90 percent of bilirubin is
produced during the breakdown of hemoglobin from
red blood cells or from ineffective erythropoesis
 The remaining 10 to 20 percent is derived from the
breakdown of other heme-containing proteins, such as
cytochromes and catalase
Bilirubin Production
 Bilirubin is formed in two steps
 The enzyme heme oxygenase catalyzes the breakdown
of heme, resulting in the formation of carbon monoxide
and biliverdin
 Biliverdin is then converted to unconjugated bilirubin by
the enzyme biliverdin reductase
 Unconjucated bilirubin can cross the blood brain barrier
Bilirubin clearance
 Hepatic uptake
 Circulating unconjugated bilirubin binds to albumin and
is transported to the liver
 Albumin saturation or presence of medications (ie.
Ceftriaxone, ibuprofen) can displace bilirubin
 Bilirubin dissociates from albumin and is taken up by
hepatocytes, where it is processed for excretion
Bilirubin Conjugation
 Conjugation —
 Occurs in hepatocytes
 Uridine diphosphogluconurate glucuronosyltransferase
(UGT) catalyzes the conjugation of bilirubin with
glucuronic acid
 UGT produces bilirubin diglucuronides and bilirubin
monoglucuronides
 Levels of UGT increase in the first few weeks after birth
(start at 1% of the adult levels)
 Conjugated bilirubin is more water soluble than
unconjugated bilirubin and is excreted in bile
Bilirubin Conjugation
 Conjugated bilirubin is more water soluble than
unconjugated bilirubin
 Conjugated bilirubin is excreted into bile via an active
process and then into digestive tract
 Conjugated bilirubin cannot be reabsorbed by the
intestinal epithelial cells, it is broken down in the
intestine by bacterial enzymes and then reabsorbed
Newborn Bilirubin
 At birth, infant's GI tracts are essentially sterile, therefore
very little conjugated bilirubin is reduced to urobilinogen
 Infants have beta-glucuronidase in the intestinal mucosa,
which helps deconjugate the conjugated bilirubin
 The unconjugated bilirubin is then reabsorbed through the
intestinal wall and recycled into the circulation
(enterohepatic circulation of bilirubin)
Evaluation
 Begins prenatally with maternal blood type, coombs test,
isoimmune antibodies (anti Jk, K, D); baby blood type
 Determine whether the jaundice is due to conjugated
(direct) or unconjugated (indirect) hyperbilirubinemia
 Most infants will have unconjugated hyperbilirubinemia,
usually of a benign and physiologic nature
 Elevated direct bilirubinemia
 > 1 mg/dl if TSB <5mg/dl or direct bili >20% of the TSB
 NEVER physiologic and implies a pathologic state
Differential of Unconjugated
Hyperbilirubinemia
 Increased Bilirubin Production
 Hemolytic disease
 Isoantibodies: ABO, Rh, Minor Antibodies
 Enzyme defects: G6PD, Pyruvate Kinase Deficiency,
Congenital Porphyria
 Structural defects: Spherocytosis, elliptocystosis
 Birth Trauma
 Cephalohematoma, Bruising
 Polycythemia
 Macrosomia, IDM
Differential of Unconjugated
Hyperbilirubinemia
 Impaired Bilirubin Conjugation
 Gilbert
 Crigler-Najjar, Type I & II
 Decreased Bilirubin Excretion
 Biliary obstruction- Biliary Atresia, Choledocal cyst,
Dubin Johnson Syndrome, Rotor Syndrom
Differential of Unconjugated
Hyperbilirubinemia
 Asian
 Prematurity
 Metabolic Disorders
 Hypothyroid
 Galactosemia
 IDM
 Infection
 Sepsis
 UTI
 Breastfeeding
 Drugs
Physiologic Jaundice
 Occurs after DOL 1
 Peak is at day 3-5 days
 Elevated hct and short life span of RBC increased
bilirubin production
 Deficiency of hepatic UGT poor excretion
 Increase in enterohepatic circulation of bilirubin
Physiologic Jaundice
 These normal physiologic alterations generally result in a
mild unconjugated hyperbilirubinemia that occurs in most
newborns
 In Caucasian and African-American infants, the mean peak
total bili occurs at 48 to 96 hours of life and is 7 to 9 mg/dL
(In Asian infants, mean TSB peak is 10mg/dL)
 Resolves within the first one to two weeks after birth
 Peak total bili is later in premature infants
Breastfeeding Jaundice
Breast Milk Jaundice
 Within the first week of life
 Begins 3-5 DOL
 Inadequate intake and milk
production
 Peaks within 2 weeks
 Dehydration
 Decreased bilirubin
elimination and increased
enterohepatic circulation
of bilirubin
 May take up to 12 weeks to
resolve
 Caused by an unknown
factor in human milk that
promotes an increase in
intestinal absorption of
bilirubin
ABO Incompatibility
 Major blood groups: A, B,
AB , O and Rh
 Biggest risk factor is
mother O and baby A, B
or AB
 All women should be
screened during
pregnancy
 If Rh negative, rhogam
given prenatally and
postnatally (based on
baby blood type)
 Minor blood groups: Kell,
Duffy , E
 Previous transfusion,
pregnancy or exposure
to bacteria or viruses
 Degree of hemolytic
disease varies with
antibody-may need to
monitor closely
G6PD
 Most common and clinically significant red cell
enzyme defect
 X linked defect, so males have full enzyme deficiency
 Common in Mediterranean population, but found in
11-13% of the African American population in the US
 Common cause of kernicterus in the US (~30%)
Treatment of Unconjugated
Hyperbilirubinemia
 Phototherapy
 Goal is to bypass liver conjugation
 Converts bilirubin into lumirubin (more soluble
substance than bilirubin) which is excreted without
conjugation into bile and urine
 Converts the stable 4Z,15Z bilirubin isomer to the
4Z,15E isomer, which is more polar and less toxic and
excreted into bile without conjugation
 Photo-oxidation reactions convert bilirubin to a
colorless polar compound that is excreted in urine
Nomogram for designation of risk in 2840 well newborns at ≥36 weeks’ gestational age with
birth weight of ≥2000 g or ≥35 weeks’ gestational age and birth weight of ≥2500 g based on
the hour-specific serum bilirubin values.
Maisels M J et al. Pediatrics 2009;124:1193-1198
©2009 by American Academy of Pediatrics
Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation.
Maisels M J et al. Pediatrics 2009;124:1193-1198
Use total bilirubin
Risk factors=isoimmune hemolytic disease, G6PD deficiency, asphyxia,
significant lethargy, temperature instability, sepsis, acidosis, albumin <3.0 g/dl
©2009 by American Academy of Pediatrics
 Helpful link
 www.bilitool.org
Treatment of Unconjugated
Hyperbilirubinemia
 Exchange transfusion
 Removes bilirubin from the circulation when intensive
phototherapy fails or in infants with signs of bilirubininduced neurologic dysfunction (BIND)
 Moost effective method for removing bilirubin rapidly
 Decreases the total bili by 50%
Treatment of Unconjugated
Hyperbilirubinemia
 IVIG
 IVIG can reduce the
need for exchange
transfusion in infants
with hemolytic disease
caused by Rh or ABO
incompatibility
 IVIG (dose 0.5 – 1 g/kg
over two hours); may
repeat once after 12
hours
 IVIG
 Indications: rise in total
bilirubin inspite of
intensive phototherapy
or within 2 or 3 mg/dL
of the threshold for
exchange transfusion
 Mechanism of action is
uncertain

? Block hemolysis by
blocking antibody
receptors on RBC’s
Red Flags of Neonatal Jaundice
 Jaundice in the first 24 hours of life
 Rate of total bili rise greater than 0.2 mg/dL per hour
 Jaundice in a term newborn after 2 weeks of age
 Direct (conjugated) hyperbilirubinemia
 You are evaluating a FT 4 day old infant in your
office. Birth history unremarkable. Mother reports
he has become more jaundice since discharge. He is
strictly breastfeeding, with normal stooling and urine
output. She is vigorous and exam is normal except
for jaundice. Serum bilirubin is 12mg/dL. What is
the most appropriate management





Admit for phototherapy
Continue breastfeeding
Discontinue breastfeeding for 3 days, then resume
Supplement with water
Supplement with formula
Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation.
Maisels M J et al. Pediatrics 2009;124:1193-1198
Use total bilirubin
Risk factors=isoimmune hemolytic disease, G6PD deficiency, asphyxia,
significant lethargy, temperature instability, sepsis, acidosis, albumin <3.0 g/dl
©2009 by American Academy of Pediatrics
 A 4 day old is brought to your office for evaluation of
jaundice. She was born at 37 weeks gestation. MBT
and BBT are A+. She is breastfeeding exclusively
with normal stooling and urination. She is vigorous,
has jaundice and appears well hydrated. At what
serum bilirubin would you initiate phototherapy?





10mg/dL
12mg/dL
15mg/dL
17mg/dL
20mg/dL
Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation.
Maisels M J et al. Pediatrics 2009;124:1193-1198
4 day old. 37 weeks gestation. MBT and BBT are A+. Where would you
initiate therapy?
10 mg/dL, 12mg/dL, 15mg/dL, 17mg/dL, 20mg/dL
What if she was 39 weeks old?
©2009 by American Academy of Pediatrics
Clinical Manifestations of
Unconjugated Hyperbili
 Bilirubin is a potential neurotoxin
 The brain regions most often affected include the basal
ganglia and the brainstem nuclei for oculomotor and
auditory function
Clinical Manifestations of
Unconjugated Hyperbilirubinemia
 Severe hyperbilirubinemia (Total bili >25 to 30 mg/dL) is
associated with an increased risk for bilirubin-induced
neurologic dysfunction (BIND)
 Bilirubin-Induced Neurologic Dysfunction occurs when
bilirubin crosses the blood-brain barrier and binds to brain
tissue
 Acute Bilirubin Encephalopathy (ABE) - acute
manifestations of BIND
 Kernicterus - chronic and permanent sequelae of BIND
Acute Bilirubin
Encephalopathy
 Early phase



Sleepy, lethargic, but arousable
Slight hypotonia, decreased movement
Poor suck, high pitched cry
 Intermediate phase



Less arousable, increased lethargy, Irritable
Variable tone, increasing tone; start to see retrocollis opisthotonos
Poor feeding, high pitched cry
 Advanced phase



Deep stupor to coma
Hypertonia- backward arching of the neck (retrocollis) and trunk
(opisthotonos) with stimulation
No feeding, shrill cry, inconsolable
Kernicterus
 Develops during the first year after birth
 Cognitive function is relatively spared
 The major features:
 Choreoathetoid cerebral palsy (chorea, tremor and dystonia)
 Sensorineural hearing loss commonly manifesting as auditory
neuropathy
 Gaze abnormalities, especially limitation of upward gaze
 Dental enamel dysplasia
Conjugated
Hyperbilirubinemia
 Pathologic condition of cholestasis
 Incidence of neonatal liver disease manifesting
cholestasis: 1:2500 live births
Differential of Conjugated
Hyperbilirubinemia
 Extrahepatic disorders






Biliary atresia
Choledochal cyst
Congential bile duct cyst
Spontaneous perforation of
the bile duct
Common bile duct
stone/sludge
Choledochocele (anomaly
of pancreaticobiliary
junction)
 Intrahepatic disorders





Idiopathic neonatal
hepatitis
Byler’s disease
Alagille syndrome
Sclerosing cholangitis
Anatomic disorders


Congenital hepatic
fibrosis with polycystic
kidney and liver
Caroli disease (cystic
dilation of intrahepatic
biliary tree)
Differential of Conjugated
Hyperbilirubinemia
 Infectious







Toxoplasmosis
Syphilis
Rubella
CMV
HSV
Varicella
Hepatitis B




Hepatitis C
TB
Coxsackie
Parvovirus B19
Differential of Conjugated
Hyperbilirubinemia

Toxins/drugs




Chromosomal/syndromic
abnormalities




TPN
Gram negative sepsis (UTI, NEC)
Medications (TMP-SMX,
anticonvulsants)
Trisomy 17, 18, 21
Turner syndrome
Polysplenic syndrome (heterotaxy)
Systemic disease



Post shock/asphyxia
Congestive heart failure
Hypoplastic left heart syndrome

Metabolic disorders






Disorders of carbohydrate
metabolism (galactosemia)
Disorders of lipid metabolism

Gaucher disease


Niemann-Pick,
Wolman disease
Disorders of amino acid metabolism
(tyrosinemia)
Alpha-1-antitrypsin deficiency
CF
Hypopituitary
Differential of Conjugated
Hyperbilirubinemia
 Long list of etiologies….
 Most common







Biliary atresia
Idiopathic neonatal hepatitis
Infectious/TORCH
Alpha 1 antitrypsin deficiency
Alagille syndrome
Progressive familial intrahepatic cholestasis (PFIC)
TPN
 A 2 week old infant is here for her well child visit. She
was born FT, NSVD. MBT B+, BBT O+, coombs
negative. She has been jaundiced since DOL 2, peak
bilirubin at DOL 5 was 13 mg/dL. She is strictly
breastfed. She has had normal urine output and is
stooling normally. She is gaining 30 grams daily.
 On exam all is normal except jaundice. What do you
do next?
 Fractionated bilirubin
 Hemoglobin is 13 g/dl, total bilirubin is 8.9 mg/dL
with direct fraction of 6.1mg/dL
 What is the likely cause?





Alagille Sydrome
Biliary Atresia
Physiologic Jaundice
Breastmilk Jaundice
ABO incompatibility
Biliary Atresia
 Most common disorder
causing neonatal cholestasis
 Congenital disorder
resulting in common bile
duct between the liver and
the small intestine being
blocked or absent

Etiology unknown, ? of
intrauterine viral infection
 Signs and symptoms are
indistinguishable from
physiologic jaundice to start
and usually begin to
develop at 1-6 weeks of age
 Usually thriving infant
 May present with acholic
stools, hepatomegaly,
splenomegaly
Biliary Atresia
 Labs show an elevated direct bili and may show a mild
transaminitis and elevated GGT
 An ultrasound should be done to look for an anatomic
abnormality and to attempt to view the gall bladder
 A hepatobiliary scan that does not demonstrate
excretion of tracer from the biliary tree into the small
bowel is concerning for biliary atresia and prompts
further work up
Biliary Atresia
 Liver biopsy will demonstrate interlobular bile duct
proliferation
 The gold standard for diagnosis is an intra-op
cholangiogram
 If no definitive extrahepatic bilary ducts can be
demonstrated on cholangiogram, a Kasai procedure is
proformed (hepatoportoenterostomy)
Kasai Procedure


Dissect and excise the
fibrotic remnants of the
extrahepatic bile ducts up
to the hilum of the liver
and its junction with the
hepatic parenchyma.
Jejunojejunostomy (Rouxen-y anastomosis) is
constructed and the free
limb is brought up to and
sutured to the exposed
small biliary branches
present at the resection line
in the hilum
Biliary Atresia
 If the infant has a Kasai procedure before 2 months of
age, bile flow may be established in up to 90% of
patients
 Delayed diagnosis and Kasai procedure worsens
prognosis
 57-80% of post Kasai patients will progress to liver
transplant
 A 2 week old infant is here for her well child visit. She
was born FT, NSVD. MBT B+, BBT O+, coombs
negative. PNL negative. She has been jaundiced since
DOL 2, peak bilirubin at DOL 5 was 13 mg/dL. She is
strictly breastfed. She has had normal urine output and is
stooling normally. She is gaining 30 grams daily.
 On exam all is normal except jaundice.
 Hemoglobin is 13 g/dl, total bilirubin is 8.9 mg/dL with
direct fraction of 6.1mg/dL. What would you do next?
 Direct and indirect Coombs test
 Liver Biopsy
 Abdominal ultrasound
 Referral to surgeon for exploratory laparotomy and
intraoperative cholangiography
 Serology for TORCH infections
Alagille Syndrome

Autosomal dominant disorder

Paucity of the interlobular bile
ducts

Jaundice, Extrahepatic biliary
hypoplasia, Pulmonary outflow
tract abnormalities (PPS most
common), Butterfly vertebrae,
Bone abnormalities,
Developmental delay

Characteristic facies (prominent
forehead, small pointed chin,
hypertelorism)
Alagille Syndrome
 Associated with a Jag-1 mutation
 It is important to distinguish Alagille syndrome from
biliary atresia to prevent an unnecessary surgery
 Treatment is symptomatic usually with urosodiol to
prevent pruritis and with fat soluble Vitamin supplements
 Some patients progress to cirrhosis and liver failure and
may require transplant
Alpha-1-antitrypsin
deficiency
 Most common inherited metabolic cause of neonatal
cholestasis
 Protease inhibitor (Pi) ZZ results in jaundice
 75% of patients with Alpha-1-antitrypsin deficiency will
have their jaundice resolve by 7 months of age
 Mild transaminitis usually persists
 Periodic acid schiff positive diastase resistant inclusions
accumulate within hepatocytes and cause of liver injury
Alpha-1-antitrypsin deficiency
 Alpha-1-antitrypsen deficiency is associated with chronic
obstructive pulmonary disease, specifically emphysema
 Clinical manifestations of lung disease are generally not
seen in pediatric patients
 Counseling regarding no exposure to tobacco is necessary
 There is no specific treatment for alpha-1-antitrypsin
deficiency
 A 9 month old presents with FTT since 1 month of age. Mother
states he is becoming increasingly jaundiced since his 6month
visit. His birthweight was 3.1 kg and is now 6.2kg. On exam you
note he has dysmorphic facies, broad forehead and wide spaced
eyes. He has scleral icterus. You note a soft systolic murmur on
exam. His liver edge is firm and palpated 2cm below right costal
margin. Serum bili is 6.8mg/dL with a direct fraction of 5.1
mg/dL. Which of the following is most likely?
 Alpha 1 antitrypsin deficiency
 Alagille Syndrome
 Choledocal Cyst
 Biliary Atresia
 Idiopathic Neonatal Hepatitis
Galactosemia
 Galactose is presented to the liver and the rest of the
body in several ways
 A majority of ingested galactose is found as a
component of lactose in milk (lactose is broken down
by lactose into glucose and galactose)
 Galactose is absorbed into the bloodstream and
proceeds to the liver
Galactosemia
 We’ll skip the complicated major and minor catabolic
pathways for galactose in the liver…but defects lead to
problems with glycogen synthesis
 The “classic” clinical presentation is an infant with
jaundice, hepatic dysfunction, hepatomegaly,
unconjugated hyperbili, FTT and E coli sepsis.
Cataracts may be present at birth or develop early
 Positive urine reducing substances with the above
symptoms is concerning for galactosemia
Galactosemia
 Symptoms of galactosemia may not develop until the
patient is exposed to galactose (baby initially on soy and
then gets lactose containing formula or milk at 1 year of
age)
 Galactosemia is part of the newborn screen and usually
diagnosed at birth
 Untreated galactosemia is a potential life threatening
disorder
 Treatment is a lactose and galactose free diet
Summary
 Neonatal jaundice is common
 Jaundice, lasting longer than 2 weeks make sure you
confirm unconjugaed bilirubin!!!!
 Elevated direct bili
 > 1 mg/dl if TSB <5mg/dl or direct bili >20% of the TSB
 NEVER physiologic and implies a pathologic state
 Thoughtful evaluation and work up will avoid unnecessary
tests and procedures
References

American Academy of Pediatrics Subcommitee on Hyperbilrubinemia.
Management of hyperbilirubinemia in the newborn infant 35 weeks or
more weeks of gestation. Pediatrics. 2004; 114: 297-316

Lauer BJ, Spector ND. Hyperbilirubinemia in the Newborn. Pediatrics in
Review. 2011; Vol 32: 31-349

Maisels, MJ. Neonatal Jaundice. Pediatrics in Review. 2006; Vol 27: 443452

Suchy, F. Neonatal Cholestasis. Pediatrics in Review. 2004; Vol 25: 388-396