Hyperbilirubinemia

West Visayas State University College of Medicine

Neonatal Intensive Care Unit
Hyperbilirubinemia
The state of excessive amount of bile pigment
bilirubin in the blood visibly manifested as
jaundice.

Jaundice
Yellowish discoloration of
the skin, sclerae, and
mucous membranes due
to accumulation of
bilirubin pigment
Hyperbilirubinemia

Unconjugated bilirubin
(Normal: 0.2 to 1.4 mg/dL or 0-5 umol/L)
- indirect bilirubin
- nonpolar
- lipid soluble (indirect reacting)
Conjugated bilirubin
(Normal: 0.1 to 0.4 mg/dL or 0-12 umol/L)
- direct bilirubin
- polar
- water soluble (direct reacting)
Hyperbilirubinemia

Incidence
Term 60%
Preterm 80%
 Bilirubin (bile pigment)
- end product of hemoglobin metabolism that is
excreted in bile.
- Neonates
75% - from catabolism of circulating
RBC
25% - from ineffective erythropoeisis
(bone marrow)
- from turnover of heme proteins
and free heme (liver)
Uptake of bilirubin by Blood Bilirubin-Albumin
hepatocytes
(facilitated transport) conjugate

Liver
Bilirubin
Conjugation 2UDP-Diglucuronide
UDP-glucuronyl 2 UDP
transferase

Secretion (active transport Bilirubin diglucuronide

MRP-2/MOAT)
(excreted)
 Conjugated bilirubin
-glucuronidases

Terminal Ileum &

Large Intestines Urobilinogen Liver
Entero-hepatic circulation

Colon Urobilins (colored cmpds)

Bilirubin Formation

When the heme portion of hemoglobin is

metabolized biliverdin is formed
When biliverdin is reduced it becomes
bilirubin, which immediately combines with
plasma protein and becomes free bilirubin
 Free bilirubin is absorbed by the hepatic cells
and is then released from the plasma protein
by glucuronide to form bilirubin glucuronide or
sulfate which forms bilirubin sulfate.
 The conjugated bilirubin is excreted in the bile
and is transformed by bacterial flora to
urobilinogen which is very soluble.
5% of reabsorbed urobilinogen is excreted in
the urine by the kidneys and the rest is re
excreted in the liver.
Hyperbilirubinemia/Jaundice

Physiologic Jaundice
Non-physiologic Jaundice
Clinical Assessment of Jaundice
Manifested as yellowing of the:

Face ~5 mg/dl
Abdomen ~15mg/dl
Soles ~20 mg/dl

Jaundice usually becomes apparent in a

cephalocaudal progression.
 Bright yellow/orange = indirect bilirubin in the
skin

Greenish/muddy yellow cast = jaundice of the

obstructive type (direct bilirubin)
Common causes of Neonatal Jaundice
 Risk Factors for Neonatal
Hyperbilirubinemia
JAUNDICE

Jaundice visible on the 1st day of life

A sibling with neonatal jaundice or anemia

Unrecognized hemolysis (ABO, Rh incompatibility); UDP-glucoronyl

transferase deficiency (Crigler-Najar, Gilbert disease)

Non-optimal feeding (formula or breast-feeding)

Deficiency of G6PD

Infection, Infant of diabetic mother, Immaturity (prematurity)

Cephalhematoma or bruising, Central hematocrit >65% (polycythemia)

East Asian, Mediterranean, Native American heritage

Physiologic Jaundice

a.k.a. ICTERUS NEONATORUM

Transient
Occurs during the 1st week of life (usually on
the 2nd and 3rd day)
A result of:
1. increased bilirubin production
2. decreased ability of the liver to clear the
bilirubin from plasma
 6-7% of full-term infants have indirect bilirubin
levels >13 mg/dL
<3% have levels >15 mg/dL
 Physiologic Jaundice

I. Increased bilirubin production

Normal bilirubin production in newborn
8-10 mg/kg/day (twice the rate of normal daily production in the
adult)
Normal level of indirect-reacting bilirubin in umbilical cord
serum = 1-3mg/dL
Rises at a rate of <5mg/dL/24hr
Peak = between 2nd and 4th days at 5-6mg/dL
Factors that result to increased
bilirubin production

1. Larger circulating red blood cell volume in the

newborn
2. Shortened RBC life span (70-90 days vs 120 days in
adult)
3. Substantial production from sources other than
senescent red cells
4. Increased enterohepatic circulation of bilirubin
Physiologic Jaundice

II. Decreased clearance of bilirubin from plasma

Factors:
1. Deficient Ligandin, a protein responsible
from binding bilirubin in the hepatocyte
2. Decreased activity of the conjugating
enzyme, UDP-glucuronyl transferase (<1%
of adult activity during the first 10 days of
life)
Non-physiologic Jaundice

A. Overproduction Hyperbilirubinemia
Blood Group Incompatibilities
Maternal-fetal or feto-fetal transfusions
Non Immune Hemolytic Anemias
Structurally Abnormal Red Cells
Extravascular Hemolysis
Non-physiologic Jaundice

B. Undersecretion Hyperbilirubinemia
Enzymatic Deficiency
Hormonal Suppression (Breastmilk Jaundice)
Inhibition of Conjugation
Hepatic Cell Injury Due to Infections
Substrate Deficiency (hypoglycemia)
Mechanical Obstruction
Over Production Bilirubinemia

A. Blood Group Incompatibilities

-Rh negative mother and Rh positive infant

-ABO incompatibilities
 Maternal antibodies are developed from the
infants antigens which results into hemolysis.

Strongly considered if there is presence of

jaundice in the first 24 hours of life.
B. Maternal-fetal or Feto-fetal Transfusion
Results into increased number of red cells, the
degradation of which the infant liver may not
be able to handle.
C. Structurally Abnormal Red Cells
Pyknocytes RBC are smaller than normal and
have irregular borders with spiny projection.
Spherocytic Anemia Sphere shaped RBC
D. Extravascular Hemolysis
Results in infants with extensive petechiae or
large hematomas which leads to severe
jaundice due to increased hemoglobin
catabolism at these sites.
Undersecretion of Bilirubin

Majority of infants with undersecretion

hyperbilirubinemia become jaundiced on the
second or third day of life.
A. Enzymatic Deficiency
Deficient Glucuronyl Transferase
no longer considered physiologic if the
duration is longer than 2 weeks and
bilirubin levels >12mg/dl in FT and 15mg/dl
in PT.
B. Hormonal Suppression
Pregnandiol (breastmilk Jaundice)
- Present in maternal breast milk which
suppresses bilirubin conjugation.
-Breast feeding may be stopped and restarted
in a period of 48 hours.
 Breastfeeding Jaundice versus
Breastmilk Jaundice
Parameters Breastfeeding Jaundice Breastmilk Jaundice

Onset 3rd-4th day of life Late- start to rise on day 4; may

reach 20-30mg/dL on day 14 then
decrease slowly, Normal by 4-12
weeks
Pathophysiology Decrease milk intake and Unknown; probably due to B-
caloric intake resulting glucuronidase and pregnanediol in
to increase breastmilk which increase
enterohepatic circulation enterohepatic circulation; Normal
Liver Function Test, (-) Hemolysis

Management Fluid and caloric If breastfeeding is stopped, rapid

supplementation decrease in bilirubin level in 48
hours, if resumed may rise to 2-
4mg/dL but not to previous level
C. Inhibition of Conjugation
Sulfonamides and Vitamin K results in
competitive conjugation inhibition of bilirubin.
Galactosemia absent or deficient galactose
1-phosphate uridyl transferase which is
needed in glucuronidation of indirect bilirubin.
D. Hepatic Cell Injury Due to Infections
-Results in the destruction of liver parenchyma
thus reducing liver mass available for bilirubin
excretion.
E. Substrate Deficiency (hypoglycemia)
Glucose is the precursor of glucuronic acid
which is involved in bilirubin conjugation.
F. Mechanical Obstruction
Biliary Atresia
- obstruction of the bile ducts
Idiopathic Neonatal Hepatitis
- giant cell transformation, increased
extramedullary hematopoiesis, and
inflammation
Diagnostic Approach to neonatal
Jaundice
Jaundice

Measure total and direct bilirubin

Jaundice not physiological

Blood types, Rh,

Coombs,
hematocrit, RBC
morphology,
Reticulocyte count
Increased direct bilirubin Increased indirect bilirubin

Intrauterine Infections
Toxoplasmosis
Rubella Coombs test Coombs test
CMV positive negative
Herpes simplex Rh
Syphilis ABO
Biliary atresia Minor blood
Paucity of intrahepatic bile group
ducts Hematocrit
Giant cell hepatitis
Sepsis
Bile Plugs
Choledochal cyst
Cystic fibrosis
Galactosemia
 Hematocrit
High
Twin-twin transfusion
Normal or low Maternal-fetal transfusion
Delayed cord clamping
Small for dates
Normal
Red cell morphology Extravascular blood
and reticulocyte count Cephalhematoma, bruising, other
hemorrhage
Increased Enterohepatic circulation
Breast feeding
Abnormal
Pyloric stenosis
Small or large bowel obstruction
Specific Non specific Swallowed blood
morphological abnormalities Metabolic-endocrine
abnormalities ABO Congenital glucuronyl transferase
Spherocytosis incompatibility deficiency
Elliptocytosis G6PD deficiency Breast milk jaundice
Stomatocytosis Pyruvate kinase Others: Infants of DM mother; inadequate
Pyknocytosis deficiency caloric intake
Alpha-thalassemia
DIC
Kernicterus

means jaundice of the kern or nuclear

region of the brain
If untreated, hyperbilirubinemia can result to
kernicterus or the deposition of bilirubin in the
brain.
Usually occurs if the bilirubin levels are
25mg/dl or higher in term infants
Toxicity starts at 8-12 mg/dl in sick or low
birth weights
 Clinical Features of Kernicterus
ACUTE FORM
Phase 1(1st 12 days):
poor sucking, stupor, hypotonia, seizures
Phase 2 (middle of 1st wk):
hypertonia of extensor muscles, opisthotonos,
retrocollis, fever
Phase 3 (after the 1st wk):
hypertonia
Kernicterus
CHRONIC FORM
First year: hypotonia, active deep
tendon reflexes, obligatory tonic
neck reflexes, delayed motor skills

After 1st yr:

Perlsteins Tetrad
Extrapyramidal abnormalities
(choreoathetosis, tremor),
upward gaze
sensorineural hearing loss
dental dysplasia
Management of Jaundice

Goal: To prevent neurotoxic effects of

hyperbilirubinemia
 Phototherapy
- Primary treatment
- infant is unclothed and is exposed to 20 watt
daylight or blue fluorescent light at 30 inches.
Principle

Bilirubin absorbs light maximally in the blue

range (420470 nm).
Phototherapy detoxifies bilirubin by converting
it to photoproducts that are less lipophilic
than bilirubin and that can then be excreted
without further metabolism
Reactions in phototherapy

1. Photo-isomerization (reversible)
- toxic native unconjugated 4Z, 15Z-bilirubin is
converted into an unconjugated
configurational isomer 4Z,15E-bilirubin
-comprises about 20% of TSB in a baby under
phototherapy
2. Structural isomerization (irreversible)
-Bilirubin becomes Lumirubin
-cleared from the serum much more rapidly
Usually continued for 5 days, the time wherein
physiologic jaundice subsides.
- Babys eyes are shielded to avoid retinal
degeneration
Complications of phototherapy

loose stools
erythematous macular rash
purpuric rash
overheating
dehydration (increased insensible water loss,
diarrhea)
Thank You!