Hyperbilirubinemia didactics at Neonatal Intensive Care Unit Source: Nelson's Textbook of Pediatrics 19th edition Most pictures were taken from Google images

1. Jackie Lou C. Acha
West Visayas State University College of Medicine
Neonatal Intensive Care Unit

2. Hyperbilirubinemia
 The state of excessive amount of bile
pigment billirubin in the blood visibly
manifested as jaundice.
Jaundice
 Yellowish discoloration of
the skin, sclerae, and
mucous membranes due
to accumulation of
bilirubin pigment

3. Hyperbilirubinemia
 Unconjugated bilirubin (Normal: 0.2 to 1.4 mg/dL)
- indirect bilirubin
- nonpolar
- lipid soluble (indirect reacting)
 Conjugated bilirubin (Normal: 0.1 to 0.4 mg/dL)
- direct bilirubin
- polar
- water soluble (direct reacting)

4. Hyperbilirubinemia
 Incidence
 Term – 60%
 Preterm – 80%

5.  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)

6. Bilirubin
production
and
metabolism

7. Bilirubin-Albumin
conjugate
Bilirubin
2UDP-Diglucuronide
2 UDP
Bilirubin diglucuronide
(excreted)
Blood
Liver
Uptake of bilirubin by
hepatocytes
(facilitated transport)
Conjugation
Secretion (active transport –
MRP-2/MOAT)
UDP-glucuronyl
transferase

8. Conjugated bilirubin
Urobilinogen Liver
Urobilins (colored cmpds)
Terminal Ileum &
Large Intestines
Β-glucuronidases
Entero-hepatic circulation
Colon

9. Bilirubin Formation
 When the heme portion of hemoglobin is
metabolized beliverdin is formed
 When beliverdin is reduced it becomes
bilirubin, which immediately combines
with plasma protein and becomes free
bilirubin

10.  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.

11.  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.

12. Hyperbilirubinemia/Jaundice
 Physiologic Jaundice
 Non-physiologic Jaundice

13. Clinical Assessment of Jaundice

14. Manifested as yellowing of the:
 Face ~5 mg/dl
 Abdomen ~15mg/dl
 Soles ~20 mg/dl
Jaundice usually becomes apparent in a
cephalocaudal progression.

15.  Bright yellow/ orange= indirect bilirubin
in the skin
 Greenish/ muddy yellow cast= jaundice
of the obstructive type (direct bilirubin)

16. Common causes of Neonatal Jaundice

17. Risk Factors for Neonatal
Hyperbilirubinemia
J A U N D I C E
 Jaundice visible on the 1st day of life
 A sibling with neonatal jaundice or anemia
 Unrecognized hemolysis (ABO, Rh incompatibility); UDP-glucoronyl
transferace deficiency (Crigler-Najjar, Gilbert disease)
 Nonoptimal 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

18. 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

19.  6-7% of full-term infants have indirect
bilirubin levels >12.9 mg/dL
 <3% have levels >15 mg/dL

20. 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

21. 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

22. 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-glucuronosyl
transferase (<1% of adult activity
during the first 10 days of life)

23. 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

24. 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

25. Over Production
Bilirubinemia
A. Blood Group Incompatibilities
-Rh negative mother and Rh positive
infant
-ABO incompatibilities

26.  Maternal antibodies are developed from
the infant’s antigens which results into
hemolysis.
 Strongly considered if there is presence
of jaundice in the first 24 hours of life.

27. 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.

28. C. Non Immune Hemolytic Anemias
 G6PD Deficieny
G6PD deficiency  dec. NADPH dec
GSH dec. protection of RBCs from
oxidants  dec. red cell integrity
hemolysis
 Excess of Vitamin K given IM

29. D. Structurally Abnormal Red Cells
 Pyknocytes –RBC are smaller than
normal and have irregular borders with
spiny projection.
 Spherocytic Anemia –Sphere shaped
RBC

30. E. Extravascular Hemolysis
 Results in infants with extensive
petechiae or large hematomas which
leads to severe jaundice due to
increased hemoglobin catabolism at
these sites.

31. Undersecretion of Bilirubin
 Majority of infants with undersecretion
hyperbilirubinemia become jaundiced on
the second or third day of life.

32. 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.

33. 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.

34. 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
resulting to increase
enterohepatic circulation
Unknown; probably due to B-
glucuronidase in breastmilk which
increase enterohepatic circulation;
Normall Liver Function Test, (-)
Hemolysis
Management Fluid and caloric
supplementation
If breastfeeding is stopped, rapid
decrease in bilirubin level in 48 hours,
if resumed may rise to 2-4mg/dL but
not to previous level

35.  Thyroxine Deficiency
-Thyroxine increases the activity of
Glucuronyl transferase which promotes
conjugation of bilirubin.

36. 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.

37. D. Hepatic Cell Injury Due to Infections
-Results in the destruction of liver
parenchyma thus reducing liver mass
available for bilirubin excretion.

38. E. Substrate Deficiency (hypoglycemia)
 Glucose is the precursor of glucuronic
acid which is involved in bilirubin
conjugation.

39. F. Mechanical Obstruction
 Biliary Atresia
- obstruction of the bile ducts
 Idiopathic Neonatal Hepatitis
- giant cell transformation, increased
extramedullary hematopoiesis, and
inflammation

40. Diagnostic Approach to neonatal
Jaundice
Jaundice
Measure total and direct bilirubin
Jaundice not physiological
Blood
types, Rh, Coombs’,
hematocrit, RBC
morphology, Reticulo
cyte count

41. Increased direct bilirubin
Intrauterine Infections
Toxoplasmosis
Rubella
CMV
Herpes simplex
Syphilis
Biliary atresia
Paucity of intrahepatic bile
ducts
Giant cell hepatitis
Alpha-antitrypsin deficiency
Sepsis
Bile Plugs
Choledochal cyst
Cystic fibrosis
Galactosemia
Tyrosinosis
Hypermethioninemia
Increased indirect bilirubin
Coombs’ test
positive
•isoimmunization
Rh
ABO
Minor blood
group
Coombs’ test
negative
Hematocrit

42. Hematocrit
Normal or low
Red cell morphology
and reticulocyte count
Abnormal
Specific
morphological
abnormalities
Spherocytosis
Elliptocytosis
Stomatocytosis
Pyknocytosis
Non specific
abnormalities
ABO incompatibility
G6PD deficiency
Pyruvate kinase
deficiency
Alpha-thalassemia
DIC
High
Twin-twin transfusion
Maternal-fetal transfusion
Delayed cord clamping
Small for dates
Normal
Extravascular blood
Cephalhematoma, bruising, other
hemorrhage
Increased Enterohepatic circulation
Breast feeding
Pyloric stenosis
Small or large bowel obstruction
Swallowed blood
Metabolic-endocrine
Congenital glucuronyl transferase
deficiency
Galactosemia
Hypothyroidism
Breast milk jaundice
Others: Infants of DM mother; inadequate

43. Kernicterus
 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

44. Clinical Features of Kernicterus
ACUTE FORM
 Phase 1(1st 1–2 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 (hypotonia in Spitzer)

45. Kernicterus
CHRONIC FORM
First year: hypotonia, active deep tendon
reflexes, obligatory tonic neck
reflexes, delayed motor skills
After 1st yr: movement disorders
(choreoathetosis, ballismus, tremor), up
ward gaze, sensorineural hearing loss

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

48. Principle
 Bilirubin absorbs light maximally in the
blue range (420–470 nm).
 Phototherapy detoxifies bilirubin by
converting it to photoproducts that are
less lipophilic than bilirubin and that can
then be excreted without further
metabolism

49. 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

50. Usually continued for 5 days, the time
wherein physiologic jaundice subsides.
- Baby’s eyes are shielded to avoid retinal
degeneration

51. Complications of phototherapy
 loose stools
 erythematous macular rash
 purpuric rash associated with transient
porphyrinemia
 overheating
 dehydration (increased insensible water
loss, diarrhea)
 bronze baby syndrome

52. Management
 Double volume exchange transfusion
-160-180 ml/kg
- the quickest way of clearing the
bilirubin from circulation.

53.  Phenobarbital given to mothers at 30-60
mg/kg/day 2 to 3 wks prior to delivery or
to infants at 5 mg/kg/day after birth is
effective in reducing neonatal jaundice.

54. Thank You!

55. Go forth and get one forth!
1. True or False
The incidence of hyperbilirubinemia is
higher in term compared to preterm
babies

56. 2. Based on clinical examination, which of
the following reflects the highest serum
concentration of bilirubin
a. Yellowing of the face
b. Yellowing of the teeth
c. Yellowing of the abdomen
d. Yellowing of the soles

57. 3-4
Give at least 2 risk factors for neonatal
hyperbilirubinemia
Clue: J A U N D I C E

58. 5. What is the level of serum bilirubin in
mg/dL that can usually cause
kernicterus

59. 6. Primary treatment for hyperbilirubinemia

60. 7. What is the life span of RBCs in
newborns?

61. A premature infant developed a grey-brown
coloration during phototherapy. The infant
had haemolytic jaundice due to Rhesus
incompatibility complicated by cholestasis
of thick bile fluid.
8. What is this condition called?
9. Should phototherapy be discontinued?
Yes/No

62. 10. What is the enzyme that catalyzes the
hepatic conjugation of bilirubin to form
bilirubin diglucoronide?
Bilirubin + 2UDP-Diglucuronide
enzyme?
Bilirubin Diglucuronide + 2UDP