What are the substances formed during heme degradation and their respective roles in the body?

Substances Formed During Heme Degradation

The correct answers to the matching questions are: urobilinogen is produced in the intestine and recirculates to the liver (A), urobilinogen is converted to urobilin, unconjugated bilirubin is bound to albumin (C), conjugated bilirubin is produced in the liver (D), and stercobilinogen produces the brown color in feces (B).

Heme Degradation Pathway

Heme degradation is a critical physiological process that occurs primarily in the reticuloendothelial cells of the spleen, bone marrow, and liver. This process accounts for 80-90% of the 250-300 mg of bilirubin formed daily, with the remaining 10-20% coming from catabolism of other hemoproteins and destruction of maturing red blood cells in the bone marrow 1.

Step 1: Heme Breakdown to Bilirubin

• When senescent red blood cells are broken down, heme is released and degraded by heme oxygenase to form biliverdin
• Biliverdin is then reduced to unconjugated bilirubin by biliverdin reductase 1, 2
• This unconjugated bilirubin is lipophilic and cannot be excreted directly in urine

Step 2: Transport to the Liver

• Unconjugated bilirubin is tightly bound to albumin (C) in plasma due to its poor solubility in aqueous solutions 1
• This binding to albumin allows for transport in the bloodstream to the liver

Step 3: Liver Processing

• In the liver, unconjugated bilirubin dissociates from albumin and enters hepatocytes
• Inside hepatocytes, bilirubin is bound by cytoplasmic proteins Y (ligandin) and Z
• Bilirubin is then conjugated with glucuronic acid by the enzyme UDP-glucuronyl transferase to form conjugated bilirubin (D) 1
• This conjugation makes bilirubin water-soluble and allows for excretion

Step 4: Biliary Excretion and Intestinal Metabolism

• Conjugated bilirubin is excreted into bile and passes through the biliary system into the intestine
• In the intestinal tract, bacterial enzymes (specifically BilR) reduce bilirubin to urobilinogen (A) 3
• Urobilinogen has three fates:
  1. Most is further reduced to stercobilinogen (B) and stercobilin, which give feces its brown color
  2. Some is reabsorbed into the enterohepatic circulation, taken up by the liver, and re-excreted in bile
  3. A small amount enters the systemic circulation and is excreted by the kidneys as urobilin

Key Substances in Heme Degradation

1. Unconjugated Bilirubin:

   • Bound to albumin (C) in plasma
   • Lipophilic and potentially neurotoxic at high levels
   • Cannot be excreted in urine due to tight albumin binding

2. Conjugated Bilirubin:

   • Produced in the liver (D) through glucuronidation
   • Water-soluble
   • Excreted in bile

3. Urobilinogen:

   • Produced in the intestine by bacterial reduction of bilirubin
   • Partially reabsorbed and recirculates to the liver (A)
   • Colorless compound

4. Stercobilinogen/Stercobilin:

   • Formed by further bacterial reduction of urobilinogen in the intestine
   • Gives feces its brown color (B)
   • Not significantly reabsorbed

5. Urobilin:

   • Formed from urobilinogen
   • Contributes to urine color
   • The substance that urobilinogen is converted to

Clinical Significance

Understanding the heme degradation pathway is crucial for diagnosing various conditions:

• Elevated unconjugated bilirubin: Suggests hemolysis, Gilbert syndrome, or other conditions affecting bilirubin conjugation
• Elevated conjugated bilirubin: Indicates hepatocellular disease or biliary obstruction
• Absence of urobilinogen in urine: May indicate complete biliary obstruction
• Increased urobilinogen in urine: Suggests hemolysis or hepatocellular disease

This pathway represents an essential physiological process for eliminating the potentially toxic heme molecule while recycling the valuable iron component for future use.