Division of Perinatology Department of Child Health

fDivision of PerinatologyDepartment of Child Health Medical School

University of Sumatera UtaraUniversity of Sumatera Utara

Bilirubin metabolism

HEME + GlobinHEME + Globin

BILIVERDIN

CO

BILIVERDIN

UCBLIVER

BILIRUBINAlb

UCB

Conjugated bilirubinFree unconjugatedbilirubin

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA

DEFENITION

Rate of bilirubin production exceeds the rate of bilirubin elimination↑ total serum bilirubin (TSB) concentration

hyperbilirubinemia (jaundice)


CLASSIFICATION

1. Physiologic jaundiceAlmost every newborn infantAlmost every newborn infantFirst week of life (2nd-3rd day)Resolves spontaneouslyResolves spontaneouslyIf develops in 1st 24 h of life considered pathologic until proven otherwisepathologic until proven otherwise


Physiologic jaundice……

CLASSIFICATION

Exclution criteria:

y g j

Exclution criteria:- Unconj bilirubin level >12.9 mg/dL in term - Unconj bilirubin level > 15 in pretermj p- Bilirubin level ↑ at rate >5 mg/dL/day- Jaundice in the 1st 24 h of life- Conj bilirubin level >2 mg/dL- Clinical jaundice persisting >1 week in fullterm or >2 weeks in preterm


A AT N

M h iPhysiologic jaundice……..

CLASSIFICATION

Mechanisms:- ↑ bil load because the larger RBC volume, the

h t lif f RBC ↑ t h tishorter life span of RBC, ↑ enterohepaticrecirc of bil in newborn.Defective uptake by the liver because- Defective uptake by the liver because↓concentration of bil binding protein (ligandin).Defective conjugation because ↓ glucoronyl- Defective conjugation because ↓ glucoronyltransferase activity.

- Impaired excretion into bile- Impaired excretion into bile.- Overall impairment/immaturity of liver function.


CLASSIFICATION

2. Hemolytic anemia- RBC defects: def G6PD, def piruvat kinase, , p ,halassemia. Etc

- Acquired hemolytic anemia: ABOAcquired hemolytic anemia: ABOincompatibility.

3. Polycitemia. The liver not have capacity to metabolize the ↑ bil load ↑ blood volmetabolize the ↑ bil load ↑ blood vol


4. Blood extravasationCLASSIFICATION

5. Defects of conjugationCongenital def of glucoronyl transferase

Cli l N jj d t I d f- Cligler-Najjar syndrome type I: severe def uridine diphosphate (UDP) glucoronyl transf.

U i t h b bit l thUnresposive to phenobarbital therapy.- Cligler-Najjar syndrome type II: moderate def

UPD glucoronyl transf responsive toUPD glucoronyl transf responsive tophenobarbital therapy.Gilbert syndrome: mild def UDP) glucoronyl- Gilbert syndrome: mild def UDP) glucoronyltransf responsive to pheno therapy


Defects of conjugation

CLASSIFICATION

Glucoronil transferase inhibition:

Defects of conjugation……

- Drugs (novobiocin)- Lucey-Driscoll syndrome: unspecifiedLucey Driscoll syndrome: unspecified

maternal gesation hormone in infantinterferes with the conj of bilinterferes with the conj of bil.


CLASSIFICATION6. Breast milk jaundice (late onset)

CLASSIFICATION

Prolongation of ↑enterohepatic circ of bil because of a factor in human milk that promote intestinal absorbtionintestinal absorbtion.Higher peak (10-30 mg/dL) by days 10-15.

7. Metabolic disorders: galactosemia, hypothyroidism, maternal diabetes, ect.yp y , ,

8. ↑ enteohepatic recirc: pyloric stenosis,↑ p pyduodenal atresia, ileus, ect.


MORBIDITY

Unconj bil cross blood brain barrier braincell neuronal dysfunction depress O2cell neuronal dysfunction depress O2consumption death.ENCEPHALOPATHYENCEPHALOPATHYKERNICTERUS

Post mortem diagnosisPost mortem diagnosis Risk if bi level >25 mg/dL


SIGNS AND SYMPTOMJoundice at face, especially at nose, d di t th t d l t iti

SIGNS AND SYMPTOM

descending to the torso and lower extremities.Areas of bleeding (cephalhematoma, ptechiae) indicates blood extravasationindicates blood extravasation.Hepatosplenomegaly (hemolytic disease, liver disease, or infection), )Sign of prematurity, IUGR, postmaturity.Plethora (polycitemia)(p y )Pallor (hemolytic disease) Neurologic signs: lethargy, poor feeding, vomiting, hypotonia.


DIAGNOSIS

1. Laboratory studiesTotal and direct bilirubinTotal and direct bilirubinComplete blood cell count and reticulocyte count.Blood type and Rh status in mother and infantBlood type and Rh status in mother and infantDirect Coomb’s testMeasurement of serum albuminMeasurement of serum albuminUrine test


2 Radiologis studies: intestinal

DIAGNOSIS2. Radiologis studies: intestinal

obstruction3 Transcutaneous bilirubimentry3. Transcutaneous bilirubimentry

(TcB)measures the degree ofmeasures the degree of

yellow color by selective wavelength reflection.

4. Expired carbon monoxide breath analyzer.


MANAGEMENT

1. Phototherapy TSB level 20 mg/dL ar 48 h of life maybeTSB level 20 mg/dL ar 48 h of life maybe treated initially with phototherapy.If TSB ↓ by 1-2 mg/dL within 4-6 h, exchange ↓ y g , gtransfusion maybe not necessary.Light source: blue fluorescent tubes.gDistance from the light to the infant: 12-16 inches


Eye should be covered with opaque

MANAGEMENT

Eye should be covered with opaque patchesTermination of phototherapy: bil level is e at o o p otot e apy b e e slow enough to eliminate the risk of kernicterus and the infants is old enough to handle the bil loadto handle the bil load.Complication: retinal degradation, increased insensible water loss ( ↑fluidincreased insensible water loss ( ↑fluid requirements by 25%), bronze baby syndrome (destruction of protoporphirin

i d ki b b )urine and skin become bronze)

Phototherapy


2. Exchange transfusion

MANAGEMENT2. Exchange transfusion

TSB 25-30 mg/dL (↑bil >0.5 mg/dL/h)Presence of hypoxia acidosis sepsis orPresence of hypoxia, acidosis, sepsis or hypoproteinemia.Albumin transfusions maybe useful if bil levelAlbumin transfusions maybe useful if bil level >20 mg/dL and serum albumin level <3 g/dL.Infusion of 1 g of albumin 1 h before exchange g gtransfusion may improve the yield of bil removal.

Exchange transfusion


3 Pharmacology

MANAGEMENT

3. PharmacologyPhenobarbital↑li di i li ↑ d ti f l l- ↑ligandin in liver, ↑ production of glucoronyltransferase, and enhancing bil excretion.T k 3 7 d t b ff ti l- Takes 3-7 day to become effective lesseffective in the newborn

- More useful to give pheno 1-2 week beforedelivery to pregnant woman whose fetusdocumented hemolytic disease.


MANAGEMENT

Metalloporphyrins- Inhibit heme oxygenase (HO) by acting asa competitive inhibitor.

Supportive management- breast feed

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA

DEFENITION

A sign of hepatobiliary dysfunctionAfter the first week of lifeAfter the first week of lifeDirect bil level > 2.0 mg/dL or is >20% of the TSBCaused by a defect or insufficiency in bile secretion, biliary flow, or both resulting in an y ginability to remove conj bil from the body.


CLASSIFICATION

1. Extrahepatic biliary diseaseBiliary atresiaBiliary atresiaCholedochal cysts dilatations of extrahepatic tree.pBiliary diseases: duct stenosis, cholelithiasis, and neoplasm.p


2. Intrahepatic biliary disease

CLASSIFICATION2. Intrahepatic biliary disease

Intrahepatic bile duct paucityProgressive intrahepatic cholestasisProgressive intrahepatic cholestasisInspissated bile

3. Hepatocellular diseaseMetabolic and genetic defects: cystic fibrosisMetabolic and genetic defects: cystic fibrosis, Dubin-Johnson and Rotor’s Syndrome, Galactosemia, etc.Galactosemia, etc.


Hepatocell lar diseaseCLASSIFICATION

Infection

Hepatocellular disease…..

Total parenteral nutrition (TPN) cholestasisIdiopathic neonatal hepatitisIdiopathic neonatal hepatitisMiscellaneous: shock or hyperperfusion


J di

CLINICAL PRESENTATIONJaundiceAcholic stoolsDark urineDark urineHepatomegalySplenomegalySplenomegalyPruritusFailure to thriveFailure to thriveDecrease feedingAscitesAscitesPortal hypertention


CLINICAL PRESENTATION

Alagille’ssyndrone: peripheral pulmonal stenosis, vertebral anomalies, peculiar facespZellweger’ssyndrome or cerebrohepatorenal syndrome: hypotonia, seizures, dysmorphic features.Congenital infection: microcephaly, intracranial calcifications, IUGR.


DIAGNOSIS1. Laboratory studies

Bilirubin levels (total and direct)Bilirubin levels (total and direct)Liver function testProthrombin time an partial trhomboplastinProthrombin time an partial trhomboplastin timeGamma-glutamil transpeptidase, 5-Gamma glutamil transpeptidase, 5nucleaotidase, serum bile aced: ↑ in cholestasis


DIAGNOSISLaboratory studies……

A complete blood cell count and reticulocyte countSerum cholesterol, triglycerides, and albumin levels: assessment of liver failureAmmonia levels: assessment of liver failureSerum glucose levelsgUrine testingTORCH


DIAGNOSISAlpha-fetoprotein (AFP)Other tests: hepatitis, sepsis, metabolic p pdisorders.

2. Radiologic studies: USG, hepatobiliary imaging.

3. Other studies: persutaneus liver biopsy, exploratory laparatomy.exploratory laparatomy.


MANAGEMENT

1. Medical managementPhenobarbitalPhenobarbitalCholestiramine: ↑fecal excretion of bile salts and ↑hepatic synthesis of bile salt from ↑ p ycholesterol.Actigall (ursodeoxycholic acid), sucsessfully g ( y ) yused in conjunction with phenobarbital and cholestyramine.


MANAGEMENT

2. Dietary managementMedium-chain triglycerida (MCT): can beMedium chain triglycerida (MCT): can be absorbed without the action of bile salt.Vitamin supplementation: A,D,E, and Kpp , , ,Dietary restriction: removal galactose, lactose,fructose, and sucrose may prevent y pcirrhosis.


3 Surgical management

MANAGEMENT

3. Surgical managementLaparatomy with biopsyKasai procedure: to establish biliary drainageKasai procedure: to establish biliary drainageLiver transplantation.

4. Other treatmentsInfectious diseases (hepatitis, bacterialInfectious diseases (hepatitis, bacterial infections)TPN-induced conjugated hyperbilirubinemia: will usually resolve once TPN is stopped.

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Division of Perinatology Department of Child Health