Hyperbilirubinemia- Its not easy being yellow

Hyperbilirubinemia: Update in Newborn CareHyperbilirubinemia: Update in Newborn Care

David Mendez, M.D.

Kidz Medical Services

Miami Childrens Hospital

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

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

GENERAL BILIRUBIN PHYSIOLOGY

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

NADPH DEPENDENT

BILIVERDINBILIRUBIN

BILIRUBIN REDUCTASE

HEME CATABOLISM

1 MOLE OF HEME = 1 MOLE OF CO

METALLOPORPHRYNS ACT AS A COMPETITIVE INHIBITOR OF HEME OXIDASE

BILIRUBIN TRANSPORT

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

Bilirubin binds tightly, reversibly to albumin

The free component of bilirubin is toxic

COMPOUNDS THAT BIND TO ALBUMIN

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

BILIRUBIN CONJUGATION

UDP-GLUCOROSYL

TRANSFERASE

BILIRUBIN BILIRUBIN

MONOGLUCORONIDE

-THIS IS THE ENZYME THAT IS RATE LIMITING

BILIRUBIN CONJUGATION

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 METABOLISMDISORDERS 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 BASALGANGLIA AND CRANIAL NERVENUCLEI FOUND AT AUTOPSY

BILIRUBIN ENCEPHALOPATHY

EARLY SYMPTOMS (NEONATAL)

LETHARGY

POOR FEEDINGHIGH PITCHED CRYVOMITINGHYPOTONIA

BILIRUBIN ENCEPHALOPATHY

LATE SYMPTOMS IRRITABILITYHYPERTONIAOPISTHOTONOSSEIZURESCEREBRAL 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 POLARWATER SOLUBLE BILIRUBIN COMPOUNDS

BLOOD-BRAIN BARRIERWAYS TO PENETRATE

1. INCREASE THE VOLUME OF UNCONJUGATED BILIRUBIN

2. INJURE THE BBB

3. DISPLACE BILIRUBIN FROM ALBUMIN

BLOOD-BRAIN BARRIER1. INCREASE THE VOLUME OF UNCONJUGATED

BILIRUBIN

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 PRETERMSICK 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 DIAGNOSISINCREASED PRODUCTION

BLOOD GROUP INCOMPATIBILITY RED CELL MORPHOLOGY HEMORRHAGE POLYCYTHEMIA INCREASED ENTEROHEPATIC CIRCULATION

DIFFERENTIAL DIAGNOSISDECREASED CLEARANCE

INBORN ERRORS OF METABOLISM’ HYPOTHYROIDISM BREAST MILK JAUNDICE PREMATURITY

VIGINITIPHOBIA

“FEAR OF 20”

VIGINITIPHOBIA

1950’S STUDY FROM BOSTON AND LONDONBABY’S WITH ERYTHROBLASTOSIS FETALISREPEATED EXCHANGE TRANSFUSIONS; KEEP BILI<20LESS INCIDENCE OF KERNICTERUS

THEREFORE ANY BABY WITH BILI RISING TO 20……

EXCHANGE !!

RISK FACTORS

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. LABSIF EVIDENCE OF HEMOLYSIS

G6PD SCREENSMEAR

HGB ELCTROPHORESIS

WORK UP

2. LABSIF BABY IS SEVERELY JAUNDICED, EARLY-ONSET, NON-HEMOLYTIC…..

THINK METABOLIC

DIAGNOSIS IT IS IMPORTANT TO INTERPRET BILIRUBIN

LEVELS IN TERMS OF THE BABY’S AGE IN HOURS- NOT DAYS

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

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

“DON’T JUST LOOK….TEST”

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316

Algorithm for the management of jaundice in the newborn nursery

PHOTOTHERAPY

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

DESCRIBED BY RJ CREMER IN ENGLAND(1958) WITH 1ST PHOTOTHERAPY PAPER IN LANCET

BLUE LIGHT (450NM) 1ST U.S. PAPER BY LUCEY IN 1968.

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 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 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

PRESENCE OF MAJOR RISK FACTORS+TSB

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

BREAST MILK JAUNDICE

COMPOUND IN BREAST MILK EITHER

INTERFERES WITH CONJUGATION OR

PROMOTES ENTEROHEPATIC CIRCULATION

IN A PROPERLY BREAST-FED, HEALTHY WELL-HYRDATED NEWBORN, BILI LEVELSNOTE 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

BREAST MILK JAUNDICEADEQUACY 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

BABY D/C’D BEFORE 24 HRS 72 HR F/U BABY D/C’D 24 TO 47.9 HRS 96 HR F/U BABY D/C’D 48 TO 72 HRS 120 HR F/U

AAP JAUNDICE GUIDELINES1. PROMOTE AND SUPPORT SUCCESSFUL BREAST

FEEDING

2. ESTABLISH NURSERY PROTOCOLS

3. GET TSB IF JAUNDICED IN 1ST 24 HOURS

4. DON’T RELY ON VISUAL ASSESSMENT

5. INTERPRET BILI LEVELS BASED ON INFANT AGE IN HOURS

AAP JAUNDICE GUIDELINES6. INFANTS LESS THAN 38 WEEKS, PARTICLUARLY IF

BREAST FED ARE AT HIGHER RISK

7. PERFORM RISK ASSESSMENT PRIOR TO D/C

8. GIVE PARENTS WRITTEN AND ORAL INFORMATION

9. PROVIDE TIME-APPROPRIATE FOLLOW UP

10. TREAT NEWBORNS WHEN INDICATED WITH PHOTOTHERAPY OR EXCHANGE TRANSFUSION

Hyperbilirubinemia- Its not easy being yellow

Health & Medicine

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