Heme Metabolism and Jaundice
Heme Synthesis and Degradation
Learning Outcomes:
Explain the pathway of heme synthesis.
Explain the pathway of degradation of heme.
Discuss the basis of different types of jaundice.
Heme Metabolism (Heme Degradation)
Fate of Red Blood Cells (RBCs):
Lifespan of RBC: 120 days.
Senescent RBCs are lysed in the Reticuloendothelial system (macrophages of the spleen, bone marrow, liver) - extravascular hemolysis.
Breakdown Products:
Hemoglobin is broken down into globin and heme.
Globin is further broken down into amino acids, which enter the amino acid pool.
Heme is broken down into iron (Fe2+) and unconjugated bilirubin.
Heme Degradation Pathway:
Heme is converted to unconjugated bilirubin in macrophages.
This process requires Cytochrome P450 reductase for the activity of heme oxygenase (HO).
Carbon monoxide (CO) is a byproduct of this reaction.
Unconjugated bilirubin is transported in the blood bound to albumin as it is water-insoluble.
It is then transported to the liver for conjugation.
Bilirubin Conjugation
Location: Liver
Unconjugated bilirubin is conjugated in the liver to bilirubin diglucuronide.
The conjugated bilirubin is more water-soluble.
Secreted into the gall bladder and duodenum.
Normal Bilirubin Values
Total Bilirubin: mg/dl
Conjugated Bilirubin: mg/dl
Unconjugated Bilirubin: mg/dl
Heme Oxygenase (HO)
HO is the rate-limiting step in heme degradation.
Regulation: HO activity is increased by:
Smoking
Hypoxia
Heme
Oxidative stress (ROS, oxidized lipids)
Inflammation
Fate of Conjugated Bilirubin
Bilirubin diglucuronide is secreted into the intestine.
Enterohepatic Circulation: Some conjugated bilirubin is reabsorbed.
Bacterial Action: Bacterial enzymes in the intestine convert bilirubin to urobilinogen.
Excretion:
Most of the urobilinogen is converted to stercobilinogen, which is then oxidized to stercobilin, giving feces their brown color (100-200mg/day).
A small amount of urobilinogen is reabsorbed and excreted in the urine (4mg/day).
Bilirubin and Urine
Unconjugated bilirubin cannot appear in urine because it is water-insoluble and bound to albumin, preventing filtration by the kidney glomerulus.
Urobilinogen levels in urine increase during excessive bilirubin production, such as in hemolysis.
Jaundice
Jaundice occurs when bilirubin levels in the blood increase, typically above mg/dl.
This leads to the diffusion of bilirubin into tissues, causing yellow discoloration of the skin, conjunctiva, and mucous membranes.
Symptoms: Yellow itchy skin, dark urine.
Types of Jaundice
Pre-hepatic (Hemolytic):
Cause: Excessive bilirubin production due to hemolysis (e.g., sickle cell anemia).
Increased unconjugated bilirubin in blood as the liver's ability to conjugate is exceeded following hemolysis.
Hepatic:
Cause: Liver dysfunction (e.g., viral hepatitis, alcohol hepatitis, liver disease).
Mechanisms: Defective bilirubin uptake, defective conjugation, or regurgitation of conjugated bilirubin due to inflammation/cell swelling of hepatocytes.
Post-hepatic (Obstructive):
Cause: Obstruction of bile flow from the liver to the intestine (intra- or extra-hepatic obstruction).
Common causes: Gallbladder stones in the common bile duct, pancreatic tumors, biliary atresia.
Urine Bilirubin present.
Neonatal Jaundice (Physiologic)
Common in premature infants.
Transient, resolves in the first 10 days.
Cause: Increased hemolysis and an immature hepatic system, leading to glucuronosyl transferase deficiency.
High levels of unconjugated bilirubin (>25mg/dl) can cross the blood-brain barrier due to its hydrophobicity.
Kernicterus: Can cause mental retardation due to unconjugated bilirubin crossing the blood-brain barrier.
Hemolytic Disease of the Newborn (Erythroblastosis Fetalis): A blood disorder due to incompatibility between mother and baby blood types.
Phototherapy for Neonatal Jaundice
Uses blue light (wavelengths around nm) to transform bilirubin into water-soluble forms.
Allows excretion without requiring liver conjugation.