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Jackie Lou C. Acha
West Visayas State University College of Medicine
Neonatal Intensive Care Unit
Hyperbilirubinemia
 The state of excessive amount of bile
pigment billirubin in the blood visibly
manifested as jaundice....
Hyperbilirubinemia
 Unconjugated bilirubin (Normal: 0.2 to 1.4 mg/dL)
- indirect bilirubin
- nonpolar
- lipid soluble (in...
Hyperbilirubinemia
 Incidence
 Term – 60%
 Preterm – 80%
 Bilirubin (bile pigment)
- end product of hemoglobin
metabolism that is excreted in bile.
- Neonates
75% - from cataboli...
Bilirubin
production
and
metabolism
Bilirubin-Albumin
conjugate
Bilirubin
2UDP-Diglucuronide
2 UDP
Bilirubin diglucuronide
(excreted)
Blood
Liver
Uptake of bi...
Conjugated bilirubin
Urobilinogen Liver
Urobilins (colored cmpds)
Terminal Ileum &
Large Intestines
Β-glucuronidases
Enter...
Bilirubin Formation
 When the heme portion of hemoglobin is
metabolized beliverdin is formed
 When beliverdin is reduced...
 Free bilirubin is absorbed by the hepatic
cells and is then released from the
plasma protein by glucuronide to form
bili...
 The conjugated bilirubin is excreted in
the bile and is transformed by bacterial
flora to urobilinogen which is very
sol...
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 ...
 Bright yellow/ orange= indirect bilirubin
in the skin
 Greenish/ muddy yellow cast= jaundice
of the obstructive type (d...
Common causes of Neonatal Jaundice
Risk Factors for Neonatal
Hyperbilirubinemia
J A U N D I C E
 Jaundice visible on the 1st day of life
 A sibling with ne...
Physiologic Jaundice
 a.k.a. ICTERUS NEONATORUM
 Transient
 Occurs during the 1st week of life
(usually on the 2nd and ...
 6-7% of full-term infants have indirect
bilirubin levels >12.9 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 ...
Factors that result to increased
bilirubin production
1. Larger circulating red blood cell volume in
the newborn
2. Short...
Physiologic Jaundice
II. Decreased clearance of bilirubin from
plasma
Factors:
1. Deficient Ligandin, a protein
responsibl...
Non-physiologic Jaundice
A. Overproduction Hyperbilirubinemia
 Blood Group Incompatibilities
 Maternal-fetal or feto-fet...
Non-physiologic Jaundice
B. Undersecretion Hyperbilirubinemia
 Enzymatic Deficiency
 Hormonal Suppression (Breastmilk
Ja...
Over Production
Bilirubinemia
A. Blood Group Incompatibilities
-Rh negative mother and Rh positive
infant
-ABO incompatibi...
 Maternal antibodies are developed from
the infant’s antigens which results into
hemolysis.
 Strongly considered if ther...
B. Maternal-fetal or Feto-fetal
Transfusion
 Results into increased number of red
cells, the degradation of which the inf...
C. Non Immune Hemolytic Anemias
 G6PD Deficieny
G6PD deficiency  dec. NADPH dec
GSH dec. protection of RBCs from
oxida...
D. Structurally Abnormal Red Cells
 Pyknocytes –RBC are smaller than
normal and have irregular borders with
spiny project...
E. Extravascular Hemolysis
 Results in infants with extensive
petechiae or large hematomas which
leads to severe jaundice...
Undersecretion of Bilirubin
 Majority of infants with undersecretion
hyperbilirubinemia become jaundiced on
the second or...
A. Enzymatic Deficiency
 Deficient Glucuronyl Transferase –
no longer considered physiologic if the
duration is longer th...
B. Hormonal Suppression
 Pregnandiol (breastmilk Jaundice)
- Present in maternal breast milk which
suppresses bilirubin c...
Breastfeeding Jaundice versus
Breastmilk Jaundice
Parameters Breastfeeding Jaundice Breastmilk Jaundice
Onset 3rd-4th day ...
 Thyroxine Deficiency
-Thyroxine increases the activity of
Glucuronyl transferase which promotes
conjugation of bilirubin.
C. Inhibition of Conjugation
 Sulfonamides and Vitamin K –results in
competitive conjugation inhibition of
bilirubin.
 G...
D. Hepatic Cell Injury Due to Infections
-Results in the destruction of liver
parenchyma thus reducing liver mass
availabl...
E. Substrate Deficiency (hypoglycemia)
 Glucose is the precursor of glucuronic
acid which is involved in bilirubin
conjug...
F. Mechanical Obstruction
 Biliary Atresia
- obstruction of the bile ducts
 Idiopathic Neonatal Hepatitis
- giant cell t...
Diagnostic Approach to neonatal
Jaundice
Jaundice
Measure total and direct bilirubin
Jaundice not physiological
Blood
type...
Increased direct bilirubin
Intrauterine Infections
Toxoplasmosis
Rubella
CMV
Herpes simplex
Syphilis
Biliary atresia
Pauci...
Hematocrit
Normal or low
Red cell morphology
and reticulocyte count
Abnormal
Specific
morphological
abnormalities
Spherocy...
Kernicterus
 If untreated, hyperbilirubinemia can
result to kernicterus or the deposition of
bilirubin in the brain.
 Us...
Clinical Features of Kernicterus
ACUTE FORM
 Phase 1(1st 1–2 days):
poor sucking, stupor, hypotonia, seizures
 Phase 2 (...
Kernicterus
CHRONIC FORM
First year: hypotonia, active deep tendon
reflexes, obligatory tonic neck
reflexes, delayed motor...
 Phototherapy
- Primary treatment
- infant is unclothed and is exposed to 20 watt
daylight or blue fluorescent light at 3...
Principle
 Bilirubin absorbs light maximally in the
blue range (420–470 nm).
 Phototherapy detoxifies bilirubin by
conve...
Reactions in phototherapy
1. Photo-isomerization (reversible)
- toxic native unconjugated 4Z, 15Z-
bilirubin is converted ...
Usually continued for 5 days, the time
wherein physiologic jaundice subsides.
- Baby’s eyes are shielded to avoid retinal
...
Complications of phototherapy
 loose stools
 erythematous macular rash
 purpuric rash associated with transient
porphyr...
Management
 Double volume exchange transfusion
-160-180 ml/kg
- the quickest way of clearing the
bilirubin from circulati...
 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 ...
Thank You!
Go forth and get one forth!
1. True or False
The incidence of hyperbilirubinemia is
higher in term compared to preterm
bab...
2. Based on clinical examination, which of
the following reflects the highest serum
concentration of bilirubin
a. Yellowin...
3-4
Give at least 2 risk factors for neonatal
hyperbilirubinemia
Clue: J A U N D I C E
5. What is the level of serum bilirubin in
mg/dL that can usually cause
kernicterus
6. Primary treatment for hyperbilirubinemia
7. What is the life span of RBCs in
newborns?
A premature infant developed a grey-brown
coloration during phototherapy. The infant
had haemolytic jaundice due to Rhesus...
10. What is the enzyme that catalyzes the
hepatic conjugation of bilirubin to form
bilirubin diglucoronide?
Bilirubin + 2U...
Hyperbilirubinemia
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Hyperbilirubinemia

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

Published in: Health & Medicine, Sports

Hyperbilirubinemia

  1. 1. Jackie Lou C. Acha West Visayas State University College of Medicine Neonatal Intensive Care Unit
  2. 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. 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. 4. Hyperbilirubinemia  Incidence  Term – 60%  Preterm – 80%
  5. 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. 6. Bilirubin production and metabolism
  7. 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. 8. Conjugated bilirubin Urobilinogen Liver Urobilins (colored cmpds) Terminal Ileum & Large Intestines Β-glucuronidases Entero-hepatic circulation Colon
  9. 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. 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. 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. 12. Hyperbilirubinemia/Jaundice  Physiologic Jaundice  Non-physiologic Jaundice
  13. 13. Clinical Assessment of Jaundice
  14. 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. 15.  Bright yellow/ orange= indirect bilirubin in the skin  Greenish/ muddy yellow cast= jaundice of the obstructive type (direct bilirubin)
  16. 16. Common causes of Neonatal Jaundice
  17. 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. 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. 19.  6-7% of full-term infants have indirect bilirubin levels >12.9 mg/dL  <3% have levels >15 mg/dL
  20. 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. 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. 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. 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. 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. 25. Over Production Bilirubinemia A. Blood Group Incompatibilities -Rh negative mother and Rh positive infant -ABO incompatibilities
  26. 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. 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. 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. 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. 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. 31. Undersecretion of Bilirubin  Majority of infants with undersecretion hyperbilirubinemia become jaundiced on the second or third day of life.
  32. 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. 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. 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. 35.  Thyroxine Deficiency -Thyroxine increases the activity of Glucuronyl transferase which promotes conjugation of bilirubin.
  36. 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. 37. D. Hepatic Cell Injury Due to Infections -Results in the destruction of liver parenchyma thus reducing liver mass available for bilirubin excretion.
  38. 38. E. Substrate Deficiency (hypoglycemia)  Glucose is the precursor of glucuronic acid which is involved in bilirubin conjugation.
  39. 39. F. Mechanical Obstruction  Biliary Atresia - obstruction of the bile ducts  Idiopathic Neonatal Hepatitis - giant cell transformation, increased extramedullary hematopoiesis, and inflammation
  40. 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. 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. 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. 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. 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. 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
  46. 46.  Phototherapy - Primary treatment - infant is unclothed and is exposed to 20 watt daylight or blue fluorescent light at 30 inches.
  47. 47. 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
  48. 48. 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
  49. 49. Usually continued for 5 days, the time wherein physiologic jaundice subsides. - Baby’s eyes are shielded to avoid retinal degeneration
  50. 50. Complications of phototherapy  loose stools  erythematous macular rash  purpuric rash associated with transient porphyrinemia  overheating  dehydration (increased insensible water loss, diarrhea)  bronze baby syndrome
  51. 51. Management  Double volume exchange transfusion -160-180 ml/kg - the quickest way of clearing the bilirubin from circulation.
  52. 52.  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.
  53. 53. Thank You!
  54. 54. Go forth and get one forth! 1. True or False The incidence of hyperbilirubinemia is higher in term compared to preterm babies
  55. 55. 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
  56. 56. 3-4 Give at least 2 risk factors for neonatal hyperbilirubinemia Clue: J A U N D I C E
  57. 57. 5. What is the level of serum bilirubin in mg/dL that can usually cause kernicterus
  58. 58. 6. Primary treatment for hyperbilirubinemia
  59. 59. 7. What is the life span of RBCs in newborns?
  60. 60. 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
  61. 61. 10. What is the enzyme that catalyzes the hepatic conjugation of bilirubin to form bilirubin diglucoronide? Bilirubin + 2UDP-Diglucuronide enzyme? Bilirubin Diglucuronide + 2UDP

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