bsl hyperbil[1]
TRANSCRIPT
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Neonatal
HyperbilirubinemiaWILFREDO R. SANTOS, MD., FPPS., FPSNbM.Neonatal Medicine
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Bilirubin Biochemistry
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Bilirubin Biochemistry
Hemoglobin to heme by Heme oxygenase
Rate limiting step
Production of free iron and carbon dioxide
Oxidation of methene bridge of heme carbon
Biliverdin
Biliverdin reductase
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Bilirubin Biochemistry
Bilirubin isomer zz
Tertiary structural protein
Not water soluble and not readily excreted
Uridine Diphosphoglucuronate Glucuronosyltransferase(UGT)
Glucoronic acid
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Catabolismof Effete RBC
Ineffective Erythropoiesis- Bone marrow
Tissue Heme liverHeme Proteins
+Serum albumin
Ligandin
HemeOxygenase
BiliverdinReductase
SmoothEndoplasmicReticulum
Glucoronosyltransferase
Bilirubin glucuronide
Bilirubin
EnterohepaticCirculationbilirubin glucuronidase
Neonatal bilePigment metabolism
(Klaus & Fanaroff, 2001)
BILIRUBIN
Biliverdin
Fecal bilirubinUrobilinogen (minimal)
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Catabolism ofeffete RBC
Ineffectiveerythropoiesis(bone marrow)
Tissue heme &heme proteins
(liver)
Neonatal Bile Pigment Metabolis
m
75%heme 25%heme
Heme oxygenase
Heme
Biliverdin
Biliverdin reductase
Bilirubin
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Bilirubin UptakeFree Bilirubin
Albumin
hepatocyte
cell membrane
Albumin receptor
Y Y Y
Endoplasmic reticulum
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Bilirubin Conjugation
Bilirubin
Glucoronic Acid
Glucoronyl transferase
YY
Y+ Bilirubin
Bilirubin
monoglucoronide
+Glucoronic Acid
Glucoronyl transferase
Bilirubin
diglucoronide
Bile
Bile
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Neonatal Bile Pigment Metabolism
Bilirubin
+ Albumin
Ligandin
SmoothEndoplasmic
Reticulum
Glucoronosyl Transferase
Bilirubin glucoronide
glucoronidase
Fecal Bilirubin/ Urobilinogen
EnterohepaticCirculationBilirubin
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BILIRUBIN EXCRETION
-glucuronidase
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Bilirubin Production
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Bilirubin Production
RBC life span (70 to 90 days)
increased heme degradation from the very large
pool of hematopoietic tissue that ceases to functionshortly after birth, and possibly increased turnoverof cytochromes.
increased bilirubin is presented to the liver as aresult of enhanced absorption of unconjugatedbilirubin in the newborn by the intestinal mucosa
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Bilirubin Transport
Bilirubin bound to albumin in plasma
4 forms of bilirubin in plasma
Unconjugated bilirubin bound to albumin
Unconjugated bilirubin free (indirect reaction)
Conjugated bilirubin excretable (direct reaction)
Conjugated bilirubin bound to albumin
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Hepatic Uptake of Bilirubin
Carrier mediated diffusion (B-ligandin)
Reduced capacity of uptake implicated in
physiologic jaundice
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Conjugation of Bilirubin
2 step process
Endoplasmic reticulum houses UGT
uridine diphosphoglucose from free glucose
uridine diphosphoglucuronic acid
Bilirubin monoglucoronide
UDP-glucuronate glucuronosyltransferase(transglucuronidase) in bile canaliculi
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Enterohepatic Circulation
Unconjugated bilirubin
Doudenum and jejunum
-glucoronidase
Portal circulation
increased bilirubin production
exaggerated hydrolysis of bilirubin glucuronide
high concentrations of bilirubin found in meconium
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Enterohepatic Circulation
lack of bacterial flora to reduce bilirubin tourobilinogen further increases the intestinalbilirubin pool
increased hydrolysis of bilirubin conjugates in thenewborn is enhanced by high mucosal -glucuronidase activity and the excretion of
predominantly monoglucuronide conjugates
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Factors enhancingRBC breakdown1. RBC volume2. RBC diameter3. hemolytic causes
FACTORS CAUSING
INCREASE IN BILIRUBIN
HypoalbuminemiaHypothyroidism
HypoxiaAcidosis
Hypoglycemia
ObstructionProlonged NPO
Drugs1. ampicillin
2. sulfas3. ceftriaxone4. free fatty acid
Infection/ inflammation
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Physiologic Jaundice
Features Elevated unconjugated bilirubin
TSB generally peaks @ 5-6 mg/dL on day 3-4 and thendeclines to adult levels by day 10
Asian infants peak at higher values (10 mg/dL)
Exaggerated physiologic (up to 17 mg/dL)
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Ethnic differences
Exaggerated Hyperbilirubinemia (>12.8mg/dl)
4% African-Americans
6-10% Caucasian
25% Asian (>20mg% in 2%)
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Effect of Type of
Feeding
2/3 of breastfeeding infants (BF) will have chemicaljaundice for 2-3 weeks
TSB > 12mg% in 12% (BF) vs. 4% Formula Fed infants(FF)
TSB > 15mg% in 2% BF vs. 0.3% FF
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Mechanism of Physiologic Jaundice
Increased rbcs
Shortened rbc lifespan
Immature hepaticuptake &
conjugation
Increased enterohepaticCirculation
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Breast Milk Jaundice Elevated unconjugated
bilirubin
Prolongation ofphysiologic jaundice Slower decrease to adult
levels of bilirubin 66% of breastfed babies
jaundiced into 3rd
week of life May persist up to 3 months
May have second peak @ day10
Average max TSB = 10-12mg/dL
TSB may reach 22-24mg/dL
?Milk factor
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Breast feedingJaundice
Elevated unconjugated bilirubin
Benign or pathologic Elevated bilirubin in the 1st week of life tends to worsen
breast milk jaundice during later weeks
Equivalent to starvation jaundice in adults
Mandates improved/increased breastfeeding No water or dextrose supplementation
Formula OK
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Pathologic Jaundice
Features Jaundice in 1st 24 hrs
Rapidly rising TSB (> 5mg/dL per day)
TSB > 17 mg/dL
Categories
Increased bilirubin load
Decreased conjugation
Impaired bilirubin excretion
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Increased
Bilirubin Load
Hemolytic Disease
Features: elevated reticulocytes, decreased Hgb Coombs + Rh incompatibility, ABO incompatibility, minor
antigens
Coombs - G6PD, spherocytosis, pyrovate kinase deficiency
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Pathologic Jaundice
Non-hemolytic Disease
normal reticulocytes
Extravascular sources I.e. cephalohematoma Polycythemia
Exaggerated enterohepatic circulation I.e. CF, GIobstruction
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G6PD Deficiency
A cause of kernicterus in up to 35% of cases
Always suspect if severe hyperbilirubinemia orpoor response to phototherapy
Ethnic origin 11-13% of African Americans
Mediterranean, Middle East, Arabian peninsula, SEAsia, Africa
D d Bili bi
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Decreased BilirubinConjugation
Elevated unconjugated bilirubin
Genetic Disorders
Crigler-Najjar
2 types
Severe hyperbilirubinemia
Gilbert Syndrome
Mild hyperbilirubinemia
Hypothyroidism
I i d Bili bi E ti
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Impaired Bilirubin Excretion
Elevated unconjugated and conjugated bilirubin(> 2 mg/dL or > 20% of TSB)
Biliary Obstruction Structural defects I.e. biliary atresia
Genetic defects Rotors & Dubin-Johnson syndromes
Infection sepsis, TORCH
Metabolic Disorders I.e. alpha1antitrypsin
deficiency
Chromosomal Abnormalities Turners syndrome
Drugs I.e. ASA, sulfa, erythromycin
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Diagnosis & Evaluation
Physical Exam
Bilirubin > 5 mg/dL
Milder jaundice - face & upper thorax
Caudal progression generally signifies higher bilirubine levels
Should not rely on this system
Laboratory
Blood
Transcutaneous Generally within 2mg/dL of serum test
Most useful if serum bili < 15