HYPERBILIRUBINEMIA

JANELLE MARGAUX M LOGRONIO, MD, DPPS, DPSNbM

August 23, 2016
Objectives

1. Discuss jaundice in the newborn

2. Differentiate physiologic from pathologic jaundice
3. Discuss pathophysiology of hyperbilirubinemia in the newborn
4. Enumerate and discuss different causes of hyperbilirubinemia
and complications if not appropriately addressed
5. Discuss management of treatment
CLINICAL SCENARIO

• JR, 7 day old male

• Presented with jaundice on 4th day of life
• Delivered via NSD, 38 weeks AOG, APGAR 9,9
• BW 3.18 kg
• Maternal Hx: 31 yo G3P3 now, good PNC, uncomplicated pregnancy
• Initial PE unremarkable; + some facial bruising noted
• Good suck with sustained breastfeeding
• Voiding and stooling well
• Discharged at 48 hrs
• Baby was OK at home, breastfeeding 10-15min each breast
• Regular bowel movement
• On DOL 5 mother thought baby look yellow and called the
Attending
• She was told to go to the hospital next day
Labs

• Maternal BT B+
• Baby’s BT B+
• Bilirubin Levels 21 mg/dl
JAUNDICE
• A visible manifestation in the skin and sclera of elevated bilirubin
concentrations
• Neonates appear jaundiced when total serum bilirubin (TSB) levels
reach 5-7 mg/dl
 PHYSIOLOGIC VS
• Jaundice >24 HOL
• Bilirubin peaks to 12-15 mg/dl
by 3rd DOL and then falls
PATHOLOGIC
• Visible jaundice <24 HOL
• Serum bilirubin inc >5mg/dl in
24 hrs
• Direct Bilirubin >1.5 to 2
mg/dl
• Jaundice >2 weeks in PT and
>3 weeks in FT
What is causes Neonatal
Hyperbilirubinemia?
What is BILIRUBIN?

• Bilirubin is the breakdown product of hemoglobin

• Lysis of red cells releases heme from Lysis of red cells releases
heme from hemoglobin
• Heme is then converted to bilirubin excreted
HYPERBILIRUBINEMIA

• Increased Bilirubin Production

• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
HYPERBILIRUBINEMIA

• Increased Bilirubin Production

• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
INCREASED SYNTHESIS

1. Increased rate of degradation

2. A shortened circulating erythrocyte life span (70-90 days versus
120 days) of an increased mass
3. A very large pool of hematopoietic tissue that ceases to function
shortly after birth resulting in heme degradation
4. An increased turnover of cytochromes (nonhemoglobin heme
proteins)
5. An increase in enterohepatic circulation
HYPERBILIRUBINEMIA

• Increased Bilirubin Production

• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
BINDING AND TRANSPORT

1. Unconjugated bilirubin is quickly bound to albumin in the serum

2. Newborns have reduced albumin concentrations and
consequently a lower plasma binding capacity for bilirubin
3. There is consequently more free bilirubin the serum
4. It is the free bilirubin that is believed to cause neurological
damage in newborns
HYPERBILIRUBINEMIA

• Increased Bilirubin Production

• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
CONJUGATION AND EXCRETION

• During fetal life, removal of bilirubin is accomplished by the

placenta
• In the newborn, bilirubin excretion requires conversion of the
nonpolar unconjugated bilirubin into a more polar water-soluble
substance, conjugated bilirubin
UDPGT

• UDPGT in the newborn liver

must be induced
• UDPGT activity is extremely
low in infants born at less than
30 weeks, 0.1% of adult levels
• This activity increases to only
1% at term
• The activity reaches adult
levels by 6-12 weeks of age
HYPERBILIRUBINEMIA

• Increased Bilirubin Production

• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
• Conjugated bilirubin is unstable and can be easily hydrolyzed back
to unconjugated bilirubin and reabsorbed through the intestinal
mucosa
• High mucosal beta-glucuronidase activity leads to increased
hydrolysis
• An alkaline environment also facilitates hydrolysis
• In the newborn, the relative lack of intestinal bacterial flora to
reduce bilirubin to urobilinogen further increases the bilirubin
pool
• PHYSIOLOGIC
• Jaundice >24 HOL
VS
• Bilirubin peaks to 12-15 mg/dl
by 3rd DOL and then falls
• PATHOLOGIC
• Visible jaundice <24 HOL
• Serum bilirubin inc >5mg/dl in
24 hrs
• Direct Bilirubin >1.5 to 2
mg/dl
• Jaundice >2 weeks in PT and
>3 weeks in FT
PATHOLOGIC UNCONJUGATED
HYPERBILIRUBINEMIA

• Pathologic hyperbilirubinemia is defined prolonged or exaggerated

• hyperbilirubinemia
• Occurs because of disorders of:
a. Production
b. Hepatic Uptake
c. Conjugation
d. Enterohepatic Circulation
DISORDERS OF PRODUCTION

• Isoimmunization
• Erythrocyte Enzymatic Defects
• Erythrocyte Structural Defects
• Infection
• Sequestration
• Polycythemia
ISOIMMUNIZATION

• Rh Incompatibility
• ABO Incompatibility
• Other Blood Group Incompatibilities
Rh INCOMPATIBILITY

• cause severe hemolytic anemia in the fetus and newborn

• The Rh antibody is produced by a Rh negative mother after being
exposed to an Rh antigen from fetal blood
• The initial response is to make IgM antibodies IgG are
produced which cross the placenta and bind to fetal red blood
cells hemolysis
• Infants do not appear jaundiced at birth, but severe anemia can
lead to hydrops and death
• After birth, infants may develop hyperbilirubinemia rapidly
• D Antigen
• RhoGAM
ABO INCOMPATIBILITY

• This is a hemolytic disease caused by a reaction of maternal anti-A

or anti-B antibodies with fetal A or B antigens
• Usually milder than Rh
• Almost exclusively in type O mothers
• Jaundice appears at 24-72 hours
• Half of infants with a positive Coombs show hemolysis and some
with a negative
 ERYTHROCYTE ENZYMATIC ERYTHROCYTE STRUCTURAL
DEFECTS DEFECTS
• Glucose-6-Phosphate • Hereditary Spherocytosis
Dehydrogenase Deficiency • Hereditary Elliptocytosis
• Pyruvate Kinase Deficiency • defects alter RBC structure
• defects may have profound and cause sequestration
effects on erythrocyte
function and life span
INFECTION

• secondary to hemolysis
• Sepsis may impair conjugation also leading leading to increased
bilirubin levels
SEQUESTRATION

• Sequestration of blood in body cavities may lead to

hyperbilirubinemia as the body metabolizes hemoglobin
• Cephalhematomas, subdural hematomas, subgaleal hematomas
• Excessive bruising
POLYCYTHEMIA

• The increase in red blood cell mass has potential to overload the
newborn hemoglobin metabolism capacities
PATHOLOGIC UNCONJUGATED
HYPERBILIRUBINEMIA

• Occurs because of disorders of:

a. Production
b. Hepatic Uptake
c. Conjugation
d. Enterohepatic Circulation
Gilberts Syndrome

• This is a benign disorder producing persistent unconjugated

hyperbilirubinemia
• There is defective hepatic uptake and decreased UDPGT activity
• It usually occurs in the second decade of life, but can present in
neonates
PATHOLOGIC UNCONJUGATED
HYPERBILIRUBINEMIA

• Occurs because of disorders of:

a. Production
b. Hepatic Uptake
c. Conjugation
d. Enterohepatic Circulation
 UDPGT
• Hypothyroidism
• Crigler Najjar
• TYPE I – absence of UDPGT
• TYPE II – decrease UDPGT
Glucuronyl Transferase
• Pyloric Stenosis -Hepatic
glucoronyl tranferase activity
is reduced
• Transient Familial Neonatal
Hyperbilirubinemia (Lucey-
Driscoll Syndrome) - high
concentrations of glucoronyl
transferase
PATHOLOGIC UNCONJUGATED
HYPERBILIRUBINEMIA

• Occurs because of disorders of:

a. Production
b. Hepatic Uptake
c. Conjugation
d. Enterohepatic Circulation
 NON-BREASTFEEDING
JAUNDICE
• Unconjugated hyperbilirubinemia is
secondary to a suboptimal
establishment of breastfeeding
• Newborns are under-hydrated and in
a state of starvation.
• They also have delayed passage of
meconium Enterohepatic reuptake of
bilirubin is consequently
• increased, leading to
hyperbilirubinemia
BREASTMILK JAUNDICE
• Occurs after 3-5 days of life,
typically at 2-3
• The etiology is unknown, but
believed to be a factor in breast milk
or an altered chemistry in breast
milk that enhances intestinal
reabsorption of bilirubin
• No need to stop breastfeeding unless
bilirubin levels are dangerously high
So why worry with HYPERBILIRUBINEMIA?
SEQUELAE

• Bilirubin may penetrate the brain cell and Bilirubin may penetrate
the brain cell and cause neuronal dysfunction or death if not
carefully managed
• Bilirubin causes staining and necrosis of Bilirubin causes staining
and necrosis of neurons in the basal ganglia, hippocampal cortex,
subthalamic nuclei, and cerebellum which is followed by gliosis
• 50%of patients with kernicterus die 50%of patients with
kernicterus di
KERNICTERUS

• Long term sequelae:

• Kernicterus
• Chorioathetoid cerebral palsy
• Sensorineural hearing loss
• Upward gaze palsy
• Dental-enamel dysplasia
• Mental retardation
…What to do???
DIAGNOSIS

• THOROUGH history, physical examination and evaluation

• EVERY newborn should be assessed especially before 72 hours of
life
• TSB or TcB before discharge and plot results on the nomogram
PHYSICAL EXAMINATION

• Detection of clinical jaundice requires digital

• pressure and the proper lighting, preferably daylight

• If clinical jaundice is detected, a total and If clinical jaundice is

detected, a total and direct serum bilirubin or transcutaneous
bilirubin (TcB) should be measured and plotted on the nomogram
When should I do more?

• A rate of rise greater than or equal to 0.5 mg/dL/hour over a 4-8

hour period
• An increase of 5 mg/dL per day 13-15 mg/dL in a term infant
10 mg/dL in a preterm infant
• If jaundice persist greater than 10 days
…and then?

• Determination of newborns blood type and Rh type

• Direct Coombs test
• Hemoglobin and Hematocrit
• Peripheral blood smear
• Reticulocyte count
• G6PD level
TREATMENT

• Phototherapy
• Hydration
• Pharmacologic
• Exchange Transfusion
Phototherapy

• The main mechanism of action: Geometric photoisomerization of

unconjugated bilirubin that can then be excreted without
conjugation
• Positioning
• Within 10 cm of the patient for fluorescent tubes Surface area
• Surface area
• The greater the surface area exposed, the more effective the phototherapy
• Wavelength
• Bilirubin absorbs light maximally in the blue range (420-500 nm), with a
peak at 460 nm for albumin-bound bilirubin and 440 nm for free bilirubin
• Special blue lamps have a spectrum between 420- 480
Nomogram for designation of risk for 35 or more weeks'
gestational age and birth weight of 2500 g or more based on the
hour-specific serum bilirubin values
TREATMENT

• Phototherapy
• Hydration
• Pharmacologic
• Exchange Transfusion
Hydration

• There is no evidence that excessive fluid administration affects

the serum bilirubin concentration
• If admitted with dehydration, babies will need to be rehydrated
and then fed
• Feeding inhibits enterohepatic circulation of bilirubin
• Important to watch fluid status for excretion Important to watch
fluid status for excretion of bilirubin
TREATMENT

• Phototherapy
• Hydration
• Pharmacologic
• Exchange Transfusion
• Phenobarbital – increase rate of conjugation
• Albumin–binds with unconjugated bilirubin to be brought to the
liver for conjugation
• Intravenous gamma-globulin
• Shown to reduce the need for exchange transfusions in isoimmune hemolytic
disease
TREATMENT

• Phototherapy
• Hydration
• Pharmacologic
• Exchange Transfusion
Exchange Transfusion

• With a exchange transfusion, 85% of erythrocytes will be replaced

• Serum bilirubin levels should decrease by 50%
• Recommended if:
1. TSB is greater than or equal to 25 mg/dL in a healthy full term
infant
2. If rate of rise is greater than or equal to 0.5mg/dL/hour
3. If there is active hemolysis or other risk factors, then an
exchange transfusion may be warranted at a lower bilirubin level
Exchange Transfusion
IN SUMMARY

• Physiologic vs Pathologic jaundice

• Causes of Hyperbilirubinemia:
• Increased Bilirubin Production
• Decreased Binding and Transport Capacity
• Limited Conjugation and Excretion Capacity
• Increased Enterohepatic Circulation of Bilirubin
• Most Common Cause of Pathologic Hyperbilirubinemia: ABO
Incompatibility (mOm is O+, Baby A+, B+, AB+)
• Management:
• Phototherapy
• Hydration
• Pharmacologic
• Exchange Transfusion
• DIRECT Hyperbilirubinemia will not be addressed with
phototherapy
REFERENCES

• Fanaroff, Martin. Neonatal-Perinatal Medicine, 7th Edition.

• Management of Hyperbilirubinemia in the Management of
Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of
Gestation, Pediatrics 2004;114;297-316 Gestation, Pediatrics
2004;114;297-316
• Taeusch, Ballard, Gleason. Avery’s Taeusch, Ballard, Gleason.
Avery’s Diseases of the Newborn, 8th Edition Diseases of the
Newborn, 8 Edition
THANK YOU !!!