Bilirubin Metabolism and Exchange Transfusion

Neonatal Jaundice (NNJ)

• Neonatal jaundice, also known as hyperbilirubinemia, is a condition characterized by yellowish discoloration of skin and other organs due to excessive bilirubin accumulation in the blood.
• Bilirubin metabolism is crucial for bilirubin clearance; it needs to be conjugated in the liver, excreted in bile, and eliminated through urine and stool.
• Unconjugated bilirubin, an insoluble form, is bound to albumin, while conjugated bilirubin, a water-soluble form, is excreted in the bile.
• In the intestine, conjugated bilirubin is reduced to urobilinogen, which gives stool its color.
• Most reduced bilirubin is excreted in feces; a small amount is eliminated in urine.
• Physiologic (developmental) factors, an association with breastfeeding, excess bilirubin production, and disturbed liver function can cause NNJ.
• Some disease states and genetic predispositions are also involved in a pathologic cause of NNJ.

Lecture Objectives

• Describe bilirubin metabolism
• Understand the clinical significance of hyperbilirubinemia
• Learn the diagnostic approach and further work-up
• Distinguish between indirect and direct hyperbilirubinemia
• Develop differential diagnoses for each type
• Understand management options for each type

Hyperbilirubinemia

• Represents an imbalance between bilirubin production and elimination.
• Bilirubin is a breakdown product of hemoglobin from red blood cell destruction.
• Heme is split into globin (protein) and heme (an insoluble substance bound to albumin).
• In the liver, bilirubin is conjugated with glucuronic acid, creating a highly soluble form.
• Conjugated bilirubin is then excreted into the bile.

Definition

• Hyperbilirubinemia refers to an excessive level of accumulated bilirubin in the blood, characterized by jaundice (icterus), a yellowish discoloration of skin and other organs.
• Most instances of hyperbilirubinemia in newborns are relatively benign.
• In extreme cases, it can indicate a pathologic state.

Pathophysiology

• Bilirubin is a byproduct of red blood cell breakdown.
• When red blood cells are destroyed, heme and globin are released.
• Globin is reused, while heme is broken down to unconjugated bilirubin (insoluble).
• Unconjugated bilirubin is transported bound to albumin to the liver.
• In the liver, bilirubin is detached from albumin and conjugated with glucuronic acid.
• Conjugated bilirubin is water-soluble and excreted into bile.
• In the intestine, bacteria convert conjugated bilirubin into urobilinogen, which gives stool its color.
• Most urobilinogen is excreted in feces.

Physiologic Jaundice

• Cause: Immature hepatic function, increased bilirubin load (RBC hemolysis), enterohepatic shunting.
• Onset: After 24 hours (prolonged in preterm), peak 2nd–5th day, duration 5th–7th day.
• Therapy: Increased feeding frequency; avoid supplements; evaluate stooling pattern; monitor TcB/TSB; risk assessment; phototherapy if needed.

Breastfeeding-Associated Jaundice (Early Onset)

• Cause: Decreased milk intake related to fewer calories consumed by the infant before adequately established milk supply, enterohepatic shunting, less frequent stooling.
• Onset: 3rd–4th day, peak 3rd–5th day, variable duration.
• Therapy: Breastfeed frequently; avoid supplements; evaluate stooling pattern; perform risk assessment; phototherapy may be required.

Breast Milk Jaundice (Late Onset)

• Cause: Possible factors in breast milk that prevent bilirubin conjugation, less frequent stooling.
• Onset: 4th day, peak 10th–15th day, may persist for 3–12 weeks.
• Therapy: Increase breastfeeding frequency, avoid supplements; perform risk assessment; temporary cessation of breastfeeding may be considered and subsequent TSB may be evaluated.

Hemolytic Disease

• Cause: Blood antigen incompatibility causing hemolysis of large numbers of red blood cells (RBCs), functional inability of liver to conjugate and excrete excess bilirubin from hemolysis.
• Onset: During the first 24 hours (levels increase ≥5 mg/dL/day).
• Peak: Variable.
• Duration: Depends on severity and treatment.
• Therapy: Monitor TCB/TSB levels; risk assessment; postnatal phototherapy, tin-mesoporphyrin, intravenous immunoglobulin; prenatal intrauterine transfusion; Rh immune globulin (RhIg) administration.

Complications

• Unconjugated bilirubin is extremely toxic to neurons.
• Bilirubin encephalopathy describes varying degrees of acute symptoms of bilirubin toxicity in the brain.
• Kernicterus is bilirubin-induced neurologic dysfunction; yellow staining of brain cells and brain cell necrosis result in chronic, permanent changes.

Diagnostic Evaluation

• TSB: Normal values for unconjugated bilirubin in newborns are 0.2 to 1.4 mg/dL; levels over 5 mg/dL imply jaundice.
• Risk Assessment: Factors associated with pathologic hyperbilirubinemia include jaundice appearing within 24 hours, elevated serum bilirubin levels in the high-risk zone, blood group incompatibility with positive Direct Coombs test, hereditary hemolytic disease (e.g., G6PD), gestational age 35 to 36 weeks, East Asian or Asian-American race, cephalhematoma or significant bruising, exclusive breastfeeding, and a history of a sibling with hyperbilirubinemia.
• Monitoring (Transcutaneous bilirubinometer, TcB): Accurate measurements within a 2-3 mg/dL range for serum bilirubin levels below 15 mg/dL are achievable.

Kramer's Index

• A method for grading the extent of jaundice based on visual inspection of the skin.
• Visual inspection is subjective and needs accurate measurements of serum bilirubin levels.
• The severity of jaundice is graded from 1 to 5, representing the extent of body areas affected (face, upper body, lower body, extremities, palms/soles).

Diagnostic Studies

• Include frequent assessment of blood type, Rh factor, direct and indirect Coombs test, complete blood count (CBC), reticulocyte count, blood smear, and albumin levels.
• Occasional imaging studies (liver/GB ultrasound, HIDA scan) may be warranted to rule out biliary atresia.

Treatment

• Goals: Prevent bilirubin encephalopathy and/or kernicterus, and, if applicable, reverse the hemolytic process.
• Methods: Phototherapy, exchange transfusion if phototherapy is ineffective, and appropriate feeding (encouraging frequent breastfeeding).
• Medications: Phenobarbital, possibly IVIG is effective for reducing bilirubin levels in infants with Rh- or ABO incompatibility.

Feeding Management

• Evaluate stooling frequency; increased feeding frequency is essential in some instances.
• Monitoring weight, voiding pattern, and stooling are also important aspects of management.

Nursing Care

• Routine physical assessment includes jaundice, skin color assessment using natural daylight and direct pressure on bony prominences.
• Use a transcutaneous bilirubinometer for non-invasive measurements.
• Obtain a careful history from parents regarding family history.
• Assess hydration status.

Hemolytic Disease of the Newborn (HDN)

• Characterized by hyperbilirubinemia in the first 24 hours due to rapid red blood cell destruction.
• Anemia from RBC destruction leads to accelerated erythropoiesis, resulting in immature red blood cells in the fetal circulation (erythroblastosis fetalis).
• Major causes are Rh and ABO incompatibilities.

ABO Incompatibility

• May result in hemolytic disease in newborns when the mother's blood type is different from the baby's.
• Antibodies in the mother's blood can cross the placenta, attach to the baby's red blood cells, and cause hemolysis.
• The reaction is typically less severe than Rh incompatibility.

Intrauterine Transfusion

• Infusion of blood into the umbilical vein of the fetus.
• Used for cases with significant fetal anemia, based on confirmed maternal-fetal blood incompatibility.

Exchange Transfusion

• A procedure to reduce elevated bilirubin levels in severely affected infants with hemolytic disease.
• Fresh, cross-matched blood is used to replace the infant's blood.
• Risks of exchange transfusions include cardiac and respiratory disturbances; shock; electrolyte imbalances (hyper/hypokalemia, hyper/hypoglycemia, hypocalcemia); infections; and complications due to clotting, air embolism and portal hypertension.
• Procedure involves insertion of a catheter into the umbilical vein and monitoring of vitals and complications.

Prevention of Rh Isoimmunization

• Rh immunoglobulin (RhIg) administration to Rh-negative mothers (within 72 hours of delivery, miscarriage, etc.; and at 26 to 28 weeks of gestation).
• RhIg is not effective against existing Rh-positive antibodies.
• RhIg is administered intramuscularly to the mother and not to the infant.