Hyperbilirubinemia- Its not easy being yellow

Hyperbilirubinemia: Update in
Newborn Care
David Mendez, M.D.
Kidz Medical Services
Miami Childrens Hospital

Hyperbilirubinemia: Update in Newborn Care

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All Yellow is Bad
 Prevent Yellow at all costs
 Watch out for 20
 Major inroad in Neonatal Care


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Bilirubin Physiology
Bilirubin Toxicity
Differential Diagnosis
Vigintiphobia
Work Up
Treatment
Breast Milk


GENERAL BILIRUBIN PHYSIOLOGY
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HEME CATABOLISM
BILIRUBIN TRANSPORT
HEPATIC UPTAKE
BILIRUBIN CONJUGATION


GENERAL BILIRUBIN PHYSIOLOGY
BILIRUBIN IS THE END PRODUCT OF HEME
DEGREDATION
MAJORITY DERIVED FROM ERYTHROCYTES
REMOVED AND DESTROYED BY RES


HEME CATABOLISM
HEME OXIDASE

HEME

BILIVERDIN
CO


NADPH DEPENDENT

BILIVERDIN

BILIRUBIN
BILIRUBIN REDUCTASE


HEME CATABOLISM
1 MOLE OF HEME = 1 MOLE OF CO
METALLOPORPHRYNS ACT AS A
COMPETITIVE INHIBITOR OF HEME OXIDASE


BILIRUBIN TRANSPORT
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Bilirubin formed in the RES or hepatic parenchymal cells and is
released into the circulation

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Bilirubin binds tightly, reversibly to albumin

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The free component of bilirubin is toxic


COMPOUNDS THAT BIND TO ALBUMIN
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SULFA MEDICATIONS
RADIOGRAPHIC CONTRAST MEDIA
ASPIRIN
BENZODIAZOPENES
DIURETICS
FUSIDIC ACID


HEPATIC UPTAKE
Uptake is rapid, transport carrier mediated
Cytosolic proteins

Ligandin (Y)
Fatty acid binding protein(Z)

* Not the area where bilirubin conjugation is delayed


UDP-GLUCOROSYL
TRANSFERASE

BILIRUBIN

BILIRUBIN
MONOGLUCORONIDE

-THIS IS THE ENZYME THAT IS RATE LIMITING


GIRLS HAVE LOWER SERUM BILIRUBIN LEVELS
THAN BOYS
ADULT BILIRUBIN IS IN THE DIGLUCOURONIDE
FORM


BILIRUBIN TOXICITY
RATE OF PRODUCTION
RATE OF ELIMINATION
UNCONJUGATED,UNBOUND


RATE OF PRODUCTION
DESTRUCTION OF FETAL HEMOGLOBIN
LIFE SPAN OF HgF ~ 90 DAYS vs HgA ~ 110 DAYS
DESTRUCTION BEGINS IN UTERO


RATE OF ELIMINATION
UPTAKE
INTRACELLULAR BINDING/STORAGE
CONJUGATION
EXCRETION
PLACENTA SERVES AS REMOVER OF UNCONJUGATED BILI

DISORDERS OF BILIRUBIN METABOLISM
UPTAKE DISORDERS
A FAMILY OF ORGANIC ANION TRANSPORT
PROTIENS (OATP) HAS BEEN IDENTIFIED.
THERE ROLE HAS NOT BEEN DIRECTLY
ESTABLISHED AND NO DISORDER HAS BEEN
ATTRIBUTED TO THIS PROCESS

BINDING AND STORAGE DISORDERS
WITHIN THE HEPATOCYTE, PROTEINS
DESIGNATED Y AND Z.
Y PROTEIN CALLED LIGANDIN , SMALL % OF
HEPACYTE COMPONENT
NO KNOWN DISORDER AS A RESULT OF ITS
ABSENCE

CONJUGATION DISORDERS
CRIGLER –NAJJAR SYNDROME TYPE I
ABSENT
UDP- GLUCOSYL TRANSFERASE ACTIVITY

CRIGLER –NAJJAR SYNDROME TYPE II
( aka Arias Syndrome)
REDUCED ACTIVITY
UDP- GLUCOSYL TRANSFERASE ACTIVITY
(makes mostly monglucoronide)

GILBERTS SYNDROME
(aka familial nonhemolytic jaundice)
Hepatic UDP transferase acitivty approx. 30%

EXCRETION DISORDERS
DUBIN-JOHNSON SYNDROME
“black liver disease”
Canalicular excretion is defective, affects
organic acid secretion from hepatocyte

HEPATIC STORAGE DISORDERS
ROTOR SYNDROME
Accumulation of Conj. Bili in plasma
Liver not pigmented


UNCONJUGATED,UNBOUND
BILIRUBIN
THAT BILIRUBIN THAT IS NOT BOUND TO ALBUMIN AND
HAD NOT BEEN CONJUGATED BY THE LIVER IS FREE TO
ENTER THE TISSUE


KERNICTERUS
DEF:

BILIRUBIN STAINING OF THE BASAL
GANGLIA AND CRANIAL NERVE
NUCLEI FOUND AT AUTOPSY


BILIRUBIN ENCEPHALOPATHY
EARLY SYMPTOMS (NEONATAL)
LETHARGY
POOR FEEDING
HIGH PITCHED CRY
VOMITING
HYPOTONIA


BILIRUBIN ENCEPHALOPATHY
LATE SYMPTOMS
IRRITABILITY
HYPERTONIA
OPISTHOTONOS
SEIZURES
CEREBRAL PALSY-ATHETOID, HEARING LOSS


BLOOD-BRAIN BARRIER
DEF:

A TIGHT-JUNCTIONED, DENSE PERICAPILLARY
SHEATH, COMPOSED OF GLIAL FOOT PROCESSES
AND A SERIES OF TRANSPORT SYSTEMS
* NORMALLY IMPERMEABLE TO ALBUMIN AND POLAR
WATER SOLUBLE BILIRUBIN COMPOUNDS


BLOOD-BRAIN BARRIER
WAYS TO PENETRATE
1. INCREASE THE VOLUME OF UNCONJUGATED
BILIRUBIN
2. INJURE THE BBB
3. DISPLACE BILIRUBIN FROM ALBUMIN


BLOOD-BRAIN BARRIER
1. INCREASE THE VOLUME OF UNCONJUGATED
BILIRUBIN
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HEMOLYSIS (ABO, RH BRUSING)
DECREASED ENZYME ACT. (GILBERT SYN)
ABSENT ENZYME ACT. (CRIGLER-NAJJAR)
LIVER DAMAGE (GALACTOSEMIA)


BLOOD-BRAIN BARRIER
2. INJURE THE BBB
MORE LIKELY IN:
TERM vs PRETERM
SICK NEONATES vs ASYMPTOMATIC
CONDITIONS: SEIZURES, SEPSIS,
MENNIGITIS,ACIDOSIS, HYPOTENSION,
DEHYDRATION, BRAIN BLEEDS


BLOOD-BRAIN BARRIER
3. DISPLACE BILIRUBIN FROM ALBUMIN
“LOW BILI KERNICTERUS IN 1960”S”
“SEDATION KERNICTERUS IN 1970’S”


DIFFERENTIAL DIAGNOSIS
INCREASED PRODUCTION
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BLOOD GROUP INCOMPATIBILITY
RED CELL MORPHOLOGY
HEMORRHAGE
POLYCYTHEMIA
INCREASED ENTEROHEPATIC CIRCULATION


DIFFERENTIAL DIAGNOSIS
DECREASED CLEARANCE
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INBORN ERRORS OF METABOLISM’
HYPOTHYROIDISM
BREAST MILK JAUNDICE
PREMATURITY


VIGINITIPHOBIA

“FEAR OF 20”


VIGINITIPHOBIA
1950’S STUDY FROM BOSTON AND LONDON
BABY’S WITH ERYTHROBLASTOSIS FETALIS
REPEATED EXCHANGE TRANSFUSIONS; KEEP BILI<20
LESS INCIDENCE OF KERNICTERUS
THEREFORE ANY BABY WITH BILI RISING TO 20……

EXCHANGE !!


RISK FACTORS
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JAUNDICE IN THE 1ST 24HRS
PREVIOUS SIBLING WITH JAUNDICE/PHOTORX
CEPHALOHEMATOMA OR BRUISING AT BIRTH
ABO INCOMPATIBILITY
PREDISCHARGE BILIRUBIN . 95TH % TILE


WORK UP
1. HISTORY
- UNDERLYING SIGNS OF ILLNESS
(LETHARGY, APNEA ,TACHYPNEA, TEMP.
INSTABILITY, BEHAVIOR CHANGES, VOMITING)
- 37 OR LESS WEEKS GESTATION


WORK UP
1. HISTORY
-MOTHER AND INFNAT ABO AND RH STATUS
-FAMILY HISTORY OF HEMOLYTIC DISEASE
-WHEN DID JAUNDICE PRESENT AND HOW LONG


WORK UP
-FEEDING ISSUES

-STOOL COLOR AND VOLUME, URINE VOLUME


WORK UP
2. LABS
- BILIRUBIN UC/C
- COOMBS (UNLESS BLOOD TYPE KNOWN)
- CBC
-RETIC
-SEPSIS SCREEN(BLOOD C/S, URINE,STOOL, CSF)


WORK UP
2. LABS
IF EVIDENCE OF HEMOLYSIS

G6PD SCREEN
SMEAR
HGB ELCTROPHORESIS


WORK UP
2. LABS
IF BABY IS SEVERELY JAUNDICED,
EARLY-ONSET, NON-HEMOLYTIC…..
THINK METABOLIC


DIAGNOSIS
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IT IS IMPORTANT TO INTERPRET BILIRUBIN
LEVELS IN TERMS OF THE BABY’S AGE IN
HOURS- NOT DAYS

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THAT BABY’S ARE ALLOWED TO GO HOME AS
SOON AS 36-72 HOURS AFTER BIRTH
COMPROMISES THAT INTERPRETATION


MAJOR RISK FACTORS
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PREDISCHARGE BILI IN HIGH-RISK ZONE(95%)
JAUNDICE 1ST 24 HRS
KNOWN BLOOD GROUP INCOMPATIBILITY
GESTATIONAL AGE < 36 WKS
CEPHALOHEMATOMA OR BRUISING
EXCLUSIVELY BREASTFEEDING
EAST ASIAN RACE


MINOR RISK FACTORS
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PREDISCHARGE BILI IN INTERMIEDIATE ZONE
GESTATIONAL AGE 37-38 WEEKS
JAUNDICED OBSERVED BEFORE DISCHARGE
PREVIOUS SIBLING WITH JAUNDICED
MACROSOMIC INFANT OF DIABETIC MOTHER
MATERNAL AGE > 25 YRS
MALE


DIAGNOSIS
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JAUNDICED IN 1ST 24 HRS
JAUNDICE APPEARS EXCESSIVE FOR AGE
LESS THAN 38 WEEKS
EXCLUSIVELY BREAST FED

“DON’T JUST LOOK….TEST”


PHOTOTHERAPY
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RESULTS IN A PHOTOISOMER OF BILIRUBIN WITH POLAR
PROPERTIES THAT ALLOWS FOR BILE EXCRETION

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DESCRIBED BY RJ CREMER IN ENGLAND(1958) WITH 1ST
PHOTOTHERAPY PAPER IN LANCET
BLUE LIGHT (450NM)
1ST U.S. PAPER BY LUCEY IN 1968.

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PHOTOTHERAPY
Can’t overdose on Phototherapy
Halogen lights effective but “hot”
Uncover the baby, “bathe in light”
Special Blue light (F20T12/BB)
(TL 52/20W phillips)
Irradiance level- 40-45


PHOTOTHERAPY
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INDICATIONS FOR BABIES > 35 WEEKS
- SICK OR HEALTHY
- HEMOLYTIC OR NOT
- MAJOR RISK FACTORS
- MINOR RISK FACTORS

Nomogram for designation of risk in 2840 well newborns at 36 or more weeks'
gestational age with birth weight of 2000 g or more or 35 or more weeks' gestational
age and birth weight of 2500 g or more based on the hour-specific serum bilirubin
values



Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation




EXCHANGE TRANSFUSION
A PROCEDURE WHERE THE TOTAL BLOOD
VOLUME IS ESTIMATED BASED ON NEONTAL
WEIGHT AND TRANSFUSED INTO THE INFANT
WHILE DRAWING OUT AN EQUAL AMOUNT OF
BLOOD


EXCHANGE TRANSFUSION
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INDICATIONS FOR BABIES > 35 WEEKS
-IMMEDIATELY IF S/SX OF ENCEPHALOPATHY
(HYPERTONIA, ARCHING, RETROCOLIS
OPISTHOTONOS, FEVER, HIGH PITCHED
CRY) OR IF TSB IS 5 MG/DL OVER LINE

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PRESENCE OF MAJOR RISK FACTORS+TSB

Guidelines for exchange transfusion in infants 35 or more weeks' gestation




COMPOUND IN BREAST MILK EITHER
INTERFERES WITH CONJUGATION OR
PROMOTES ENTEROHEPATIC CIRCULATION



IN A PROPERLY BREAST-FED, HEALTHY
WELL-HYRDATED NEWBORN, BILI LEVELS
NOTE A PHYSIOLOGIC DISTRIBUTION
AMONG A STUDY OF BABY’S WITH BMJ*
*ALONSO, GARTNER ET.AL


MOTHERS SHOULD NURSE THEIR INFANTS
8-12 TIMES/DAY
DO NOT SUPPLEMENT NON-DEHYDRATED
BREAST FED INFANTS WITH WATER OR
DETROSE WATER


ADEQUACY OF FEEDS
- BABY’S LOSE MAXIMUM WEIGHT LOSS DAY 3
- % LOSS ON AVERAGE 6.1% + 2.5% (SD)
- 4 TO 6 WET DIAPERS EVERY 24 HRS
- 3 TO 4 STOOLS PER DAY BY DAY 4
- MUSTARD YELLOW STOOLS BY DAY 3-4
IF WEIGHT LOSS >10%, EVALUATE INTAKE


FOLLOWING BILIS
FOR INFANTS ON INTENSIVE PHOTORX
-IF TSB > 25, REPEAT EVERY 2-3 HRS
-IF TSB 20-25 REPEAT EVERY 3-4 HRS
-IF TSB < 20 REPEAT EVERY 4-6 HRS
- IF TSB < 13-14 MAY DISCONTINUE PHOTO
MAY CHECK FOR REBOUND 24 HRS D/C PHOTO
WHENEVER POSSIBLE CONTINUE TO BREAST FEED

Relationship between average spectral irradiance and decrease in serum bilirubin
concentration




FOLLOW UP
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BABY D/C’D BEFORE 24 HRS
BABY D/C’D 24 TO 47.9 HRS
BABY D/C’D 48 TO 72 HRS

72 HR F/U
96 HR F/U
120 HR F/U


AAP JAUNDICE GUIDELINES
1.
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PROMOTE AND SUPPORT SUCCESSFUL BREAST
FEEDING
ESTABLISH NURSERY PROTOCOLS
GET TSB IF JAUNDICED IN 1ST 24 HOURS
DON’T RELY ON VISUAL ASSESSMENT
INTERPRET BILI LEVELS BASED ON INFANT AGE IN
HOURS


AAP JAUNDICE GUIDELINES
6.
7.
8.
9.
10.

INFANTS LESS THAN 38 WEEKS, PARTICLUARLY IF
BREAST FED ARE AT HIGHER RISK
PERFORM RISK ASSESSMENT PRIOR TO D/C
GIVE PARENTS WRITTEN AND ORAL INFORMATION
PROVIDE TIME-APPROPRIATE FOLLOW UP
TREAT NEWBORNS WHEN INDICATED WITH
PHOTOTHERAPY OR EXCHANGE TRANSFUSION

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