FATIMA C. DELA CRUZ

HYPERBILIRUBINEMIA

Jaundice

Yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration)

1st week of life 60% term and 80% preterm infants

Jaundice

Accumulation in skin of unconjugated, non-polar, lipidsoluble bilirubin pigment formed from Hgb by the action of heme oxygenase, biliverdin reductase, & non-enzymatic reducing agents in the reticuloendothelial cells

May also be due in part to deposition of the pigment after it has been converted in the liver cell microsome by the enzyme uridine diphosphoglucuronic acid (UDP)-glucuronyl transferase to the polar, water-soluble ester glucuronide of bilirubin (direct reacting)

Jaundice

Indirect Bilirubin (Unconjugated, B1)Non-polarReversibly, but tightly bound to albuminDoes not cross the BBBFree bilirubin: the form of indirect bilirubin

that crosses the BBB

Jaundice

Direct Bilirubin (Conjugated, B2)Always pathologicWater soluble, polarExcreted into the bile & into the small

intestine and filtered into the kidney

The serum bilirubin level required to cause jaundice

Face - 4 to 5 mg/dL (68 to 86 μmol/LUmbilicus - 15 mg/dL (258 μmol/L)Feet- 20 mg/dL (340 μmol/L)

Risk Factors for Hyperbilirubinemia in Newborns

Maternal factorsBlood type ABO or Rh incompatibilityBreastfeedingDrugs: diazepam (Valium), oxytocin (Pitocin)Ethnicity: Asian, Native AmericanMaternal illness: gestational diabetes

Risk Factors for Hyperbilirubinemia in Newborns

Neonatal factorsBirth trauma: cephalohematoma, cutaneous

bruising, instrumented deliveryDrugs: sulfisoxazole acetyl with erythromycin

ethylsuccinate (Pediazole), chloramphenicol (Chloromycetin)

Excessive weight loss after birthInfections: TORCInfrequent feedingsMale genderPolycythemiaPrematurityPrevious sibling with hyperbilirubinemia

Mechanisms of hyperbilirubinemia

Increased productionDecreased hepatic uptakeDecreased conjugationImpaired excretionImpaired bile flow (cholestasis)Increased enterohepatic circulation

Physiologic hyperbilirubinemia 

Shorter neonatal RBC life span increases bilirubin production

deficient conjugation due to the deficiency of UGT decreases clearance

low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation.

Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter

Breastfeeding jaundice

 develops in one sixth of breastfed infants in the first week of life.

Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake.

The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites.

Breast milk jaundice 

develops after the first 5 to 7 days of life peaks at about 2 weeks thought to be caused by an increased

concentration of β-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin.

Determine the cause of jaundice if:

Jaundice appears in the first 24-36 h of lifeTotal serum bilirubin (TSB) rises by > 5

mg/dL/daySerum bilirubin >12 mg/dL term and 10-14

mg/dL in preterm infantsJaundice persists after 10-14 days of lifeDirect-reacting bilirubin >2 mg/dL at any

time

Some of the most common pathologic causes

Immune and nonimmune hemolytic anemiaG6PD deficiencyHematoma resorptionSepsisHypothyroidism

Mechanism CausesIncreased enterohepatic circulation

Breast milk (breast milk jaundice)Breastfeeding failure (breastfeeding jaundice)Drug-induced paralytic ileus (Mg sulfate or morphine )Fasting or other cause for hypoperistalsisHirschsprung's diseaseIntestinal atresia or stenosis, including annular pancreasMeconium ileus or meconium plug syndromePyloric stenosis*Swallowed blood

Neonatal Hyperbilirubinemia

Mechanism causes

Overproduction Breakdown of extravascular blood (eg, hematomas; petechiae; pulmonary, cerebral, or occult hemorrhage)Polycythemia due to maternofetal or fetofetal transfusion or delayed umbilical cord clamping

Neonatal Hyperbilirubinemia

mechanis causes

Overproduction due to hemolytic anemia

Certain drugs and agents in neonates with G6PD deficiency (eg, acetaminophen ,alcohol,antimalarials, aspirin ,bupivacaine ,corticosteroids, diazepam,nitrofurantoin , oxytocin  penicillin, phenothiazine, sulfonamides)Maternofetal blood group incompatibility (eg, Rh, ABO)RBC enzyme deficiencies (eg, of G6PD or pyruvate kinase)SpherocytosisThalassemias (α, β–γ)

Neonatal Hyperbilirubinemia

mechanis causes

Undersecretion due to biliary obstructio

α1-Antitrypsin deficiency*Biliary atresia*Choledochal cyst*Cystic fibrosis* (inspissated bile)Dubin-Johnson syndrome and Rotor's syndrome* Parenteral nutritionTumor or band* (extrinsic obstruction)

Neonatal Hyperbilirubinemia

mechanis causes

Undersecretion due to metabolic-endocrine conditions

Crigler-Najjar syndrome (familial nonhemolytic jaundice types 1 andDrugs and hormonesGilbert syndromeHypermethioninemiaHypopituitarism and anencephalyHypothyroidismLucey-Driscoll syndromeMaternal diabetesPrematurityTyrosinosis

Neonatal Hyperbilirubinemia

mechanis causes

Mixed overproduction and undersecretion

AsphyxiaIntrauterine infectionsMaternal diabetesRespiratory distress syndromeSepsisSevere erythroblastosis fetalisSyphilisTORCH infections

Evaluation

HistoryHistory of present illness should note age

of onset and duration of jaundiceImportant associated symptoms include

lethargy and poor feeding (suggesting possible kernicterus), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia

Patterns of feeding can be suggestive of possible breastfeeding failure or underfeeding. 

Evaluation

Review of systems symptoms of causes, including respiratory

distress, fever, and irritability or lethargy (sepsis); hypotonia and poor feeding (hypothyroidism, metabolic disorder); and repeated episodes of vomiting (intestinal obstruction).

Evaluation

Past medical history  focus on maternal infections

(toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex [TORCH] infections)

disorders that can cause early hyperbilirubinemia (maternal diabetes)

maternal Rh factor and blood group (maternofetal blood group incompatibility)

history of a prolonged or difficult birth (hematoma or forceps trauma)

Evaluation

Physical examination Overall clinical appearance and vital signs

are reviewed.The skin is inspected for extent of jaundice. Gentle pressure on the skin can help reveal

the presence of jaundice. Also, ecchymoses or petechiae (suggestive of hemolytic anemia) are noted.

The physical examination should focus on signs of causative disorders

Evaluation

The general appearance is inspected for plethora (maternofetal transfusion) macrosomia (maternal diabetes) lethargy or extreme irritability (sepsis or

infection) and any dysmorphic features such as

macroglossia (hypothyroidism) flat nasal bridge or bilateral epicanthal

folds (Down syndrome)

Evaluation

Head and neck examinationany bruising and swelling of the scalp consistent

with a cephalohematoma are noted

Lungsare examined for rales, rhonchi, and decreased

breath sounds (pneumonia)

Abdomenis examined for distention, mass

(hepatosplenomegaly), or pain (intestinal obstruction)

Neurologic examination should focus on signs of hypotonia or weakness

(metabolic disorder, hypothyroidism, sepsis)

Treatment

Treatment is directed at the underlying disorder

Treatment

Breastfeeding jaundice increasing the frequency of feedingsIf the bilirubin level continues to

increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate

Treatment

Definitive treatment PhototherapyExchange transfusion

Treatment

Phototherapy standard of care, most commonly using fluorescent

white light. (Blue light is most effective for intensive phototherapy.)

Photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation

provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus

Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 25 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at > 72 h

Treatment

Exchange transfusion  This treatment can rapidly remove bilirubin

from circulation and is indicated for severe hyperbilirubinemia, which most often occurs with immune-mediated hemolysis

Small amounts of blood are withdrawn and replaced through an umbilical vein catheter to remove partially hemolyzed and antibody-coated RBCs as well as circulating Igs These then are replaced with uncoated donor RBCs.

Neonatal Hyperbilirubinemia

IV immunoglobulin can be effective adjunct to phototherapy in

immune hemolytic disease

Phenobarbital 5-8mg/kg/d (takes days to work)

Metalloporphyrins (experimental)

Sn-Mesoporphyrin (6umol/kg IM x 1), an inhibitor of bilirubin production, was

effective at reducing need for photo therapy, compared with "usual care"

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