Infant Jaundice 9/6/12 Continuity Lecture
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Transcript Infant Jaundice 9/6/12 Continuity Lecture
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