bsl hyperbil[1]

7/31/2019 BSL hyperbil[1]

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Neonatal

HyperbilirubinemiaWILFREDO R. SANTOS, MD., FPPS., FPSNbM.Neonatal Medicine


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Bilirubin Biochemistry


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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 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

bsl hyperbil[1]

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