Lecture Notes: Bilirubin and Congenital Hyperbilirubinemia

Overview

• Topics Covered:
  • Bilirubin Physiology
  • Difference between Unconjugated and Conjugated Bilirubin
  • Congenital Hyperbilirubinemia Diseases:
    • Gilbert Syndrome
    • Crigler-Najjar Syndrome (Type 1 & 2)
    • Dubin-Johnson Syndrome
    • Rotor Syndrome

Bilirubin Physiology

• Initial Conversion:

  • Heme is converted to bilirubin through two enzymes:
    • Heme Oxygenase: Converts heme to biliverdin.
    • Biliverdin Reductase: Converts biliverdin to bilirubin.
  • Occurs in the Reticuloendothelial System.

• Unconjugated Bilirubin:

  • Circulates bound to albumin.
  • Physiologically moves to the liver for conjugation.

Conjugation Process

• UDP Glucuronosyltransferase (UGT):
  • Converts unconjugated bilirubin to conjugated form by adding glucuronic acid.
• Functionality:
  • Conjugated bilirubin enters the biliary system and then the intestine.
  • In the intestine:
    • Converted to urobilinogen by GI bacteria.
    • Urobilinogen pathways:
      • Reabsorbed into the cycle.
      • Converted to urobilin (yellow pigment in urine).
      • Converted to stercobilin (brown pigment in stool).

Congenital Hyperbilirubinemia

• Types:
  • Unconjugated
  • Conjugated

Unconjugated Hyperbilirubinemias

• Causes:

  • Overproduction of heme (hemolysis) or issues with UGT enzyme.

• Diseases:

  • Gilbert Syndrome:

    • Dysfunctional UGT1A1 gene.
    • Leads to increased unconjugated bilirubin.
    • Symptoms: Elevated indirect bilirubin.
    • Mnemonic: UGT (Unconjugated Gilbert).

  • Crigler-Najjar Syndrome:

    • Type 1: Complete UGT dysfunction.
      • High levels of unconjugated bilirubin.
      • Causes kernicterus (bilirubin neurotoxicity).
      • Does not respond to phenobarbital.
    • Type 2: Partial UGT deficiency.
      • Increases unconjugated bilirubin at lower levels than Type 1.
      • Responds to phenobarbital.
    • Mnemonic: Phenobarbi2 for Type 2 response.

Conjugated Hyperbilirubinemias

• Causes:

  • Issues with transporting conjugated bilirubin out of the liver.

• Diseases:

  • Dubin-Johnson Syndrome:

    • Dysfunctional MRP2 protein.
    • Causes black liver due to pigment accumulation.
    • Key point: Avoid oral contraceptives (estrogen/progesterone metabolism issues).
    • Mnemonic: Dwayne "The Rock" Johnson (part black) for black liver.

  • Rotor Syndrome:

    • Defective OATP1B1 and OATP1B3 polypeptides.
    • No black liver.
    • Conjugated bilirubin elevated.
    • Mnemonic: "Roater" for OATP polypeptides.

Summary

• Understand bilirubin pathways to comprehend associated diseases.
• Distinction between conjugated and unconjugated forms is crucial for diagnosing and understanding hyperbilirubinemia types.
• Memorize key mnemonics and enzyme roles for test preparation.