Definition:
Elevation of indirect serum bilirubin level more than 10mg/dl in an infant is called indirect hyperbilirubinemia.The exact definition of a physiologic range and management is complex and based on many factors including gestational age,postnatal age,birth weight,disease state,risk factors,degree of hydration,nutritional status,and ethnicity

Bilirubin:
•Non-polar, water insoluble compound requiring conjugation with glucuronic acid to form a water soluble product that can be excreted through kidneys. Unconjugated Bilirubin can't be excreted through kidneys. Conjugation of bilirubin occurs in Liver.
It is reversely bound to albumin.

Bilirubin Physiology
•Increased production of bilirubin in neonate occurs due to larger red cell volume, which produces bilirubin as cells are broken down
•Heme is catabolized within the reticuloendothelial system by heme oxygenase to form biliverdin.
•Biliverdin is metabolized to bilirubin in the presence of biliverdin Reductase.
formation-of-bilirubin
Formation Of Bilirubin
formation-of-bilirubin
Formation and excretion of bilirubin from liver

Bilirubin conjugated in presence of UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides,

Entero-Hepatic Circulation
•Meconium contains 100-200mg of conjugated bilirubin at birth.
•Conjugated bilirubin is unstable and easily hydrolyzed to unconjugated bilirubin.
•This process occurs non-enzymatically in the duodenum and jejunum and also occurs in the presence of beta-glucuronidase, an enteric mucosal enzyme, which is found in high concentration in newborn infants and in human milk.
The Unconjugated bilirubin thus formed is absorbed into the blood and contribute to Unconjugated hyperbilirubinemia

Conjugation In Neonate
•Conjugated bilirubin crosses the placenta very little, and the process of conjugation is not active in the fetus because the level of UDPGT (enzyme necessary for conjugation) in fetus is about 1% of adult level at 30 - 40 weeks gestation
•After birth, the levels of UDPGT rise rapidly but do not reach adult levels until 4-6 weeks of age.
•Ligandins, which are necessary for intracellular transport of bilirubin, are also low at birth and reach adult levels by 3-5 days.
Therefore neonate lacks the ability to conjugate bilirubin and as unconjugated bilirubin can't excreted through kidneys the whole of the bilirubin in neonate is excreted through liver (in bile)

Statistics:
•50-70% of newborns have jaundice

•Moderate (>12 mg/dL) develops in 4% of bottlefed compared to 14% of breastfed

•Severe jaundice (>15 mg/dL) occurs in 0.3% bottlefed vs 2% of breastfed
The risk of jaundice is higher in breastfed neonates because of the presence of beta-glucuronidase in higher concentration in breast milk which is responsible for conversion of conjugated bilirubin which is present in muconium in to unconjugated bilirubin. 


Causes Of Unconjugated hyperbilirubinemia in Neonate
A: Increased destruction of RBC’s (Red Blood Cells)
§ Isoimmunization (blood group incompatibility: Rh, ABO and minor blood groups)
§ RBC enzyme defects (e.g., G6PD deficiency, pyruvate kinase deficiency)
§ RBC structural abnormalities (hereditary spherocytosis, elliptocytosis)
§ Infection (sepsis, urinary tract infections)
§ Sequestered blood (e.g., cephalohematoma, bruising, intracranial hemorrhage)
§ Polycythemia
§ Shortened life span of fetal RBCs (80 vs. 120 days)



B.Decrease in uptake and conjugation of Bilirubin.
The enzyme UDP-glucuronyl tranferase in term infant has 1% of adult concentration, preterm infants have 0.1%.  Other causes are:
•Gilbert Syndrome
•Crigler Najjar Syndrome (Non-hemolytic Unconjugated Hyperbilirubinemia):
•Inherited conjugation defect (very rare)
•Pyloric stenosis (mechanism is unknown)
•Hypothyroidism
•Infants of Diabetic Mothers
•Breast milk Jaundice (pregnanediol inhibits glucuronyl transferase activity)


C.Increased Enterohepatic Reabsorption: •Breast feeding jaundice (due to dehydration from inadequate milk supply and presence of enzyme already mentioned)
•Bowel obstruction No enteric feedings

Clinical Signs and Symptoms
•Clinical jaundice is visible when serum bilirubin level approaches 5- mg/dl.
•Jaundice Most often appears, 1st in face especially nose then descending to trunk and lower extremities as the degree of jaundice increases.

Examination Findings:
•Areas of bleeding such as cephalhematoma,petechiae or ecchymoses indicate blood extravasation.
•Hepatosplenomegaly may signify hemolytic disease,liver disease or infection.
•Plethora is seen with polycythemia.

Lab Investigations:1. Initial evaluation: Blood type and Rh (infant & mother)
Hematocrit •Direct Antiglobulin (Coombs) Test on infant
2. Later evaluation (as indicated):
••RBC smear, reticulocyte count (if evidence or suspicion of hemolytic disease)
••Blood culture, urinalysis, urine culture
••Thyroid function tests, G6PD assay, Hgb electrophoresis

Treatment:
•1.Phototherapy (click here)
•2.Exchange transfusion (click here)
•3.Pharmcologic therapy (click here)

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