Heme Catabolism and Jaundice Flashcards
Where are the three locations that RBCs are phagocytized and degraded and what percentage is done in each?
- Spleen (70%)
- Bone marrow (30%)
- Tissues (30%)
What is the purpose of heme catabolism?
Alter the structure of heme to a non-toxic molecule, so it can be excreted from the body
What are the six steps of heme catabolism?
- Formation and transport of bilirubin to liver
- Uptake and conjugation of bilirubin in liver
- Secretion and catabolism of CB
- Auto-oxidation of urobilinogen to stercobilin
- Enterohepatic reabsorption of some urobilinogen from intestines (9%)
- Urinary excretion of reabsorbed urobilinogen (1%)
What is the first step of heme catabolism? Describe this step (2)
Step 1: Formation and transport of bilirubin to liver
- Heme is converted to bilirubin in macrophage
- Bilirubin is transported to the liver through circulation (bound to albumin)
What are the two enzymes used in the conversion of heme to bilirubin, and what is the starting substrate and end product for each?
- Heme > Biliverdin via Heme Oxygenase
- Biliverdin > Bilirubin via Biliverdin Reductase
What is bilirubin also called and what must it be bound to before entering circulation?
Bilirubin aka UCB is unconjugated bilirubin
- UCB is hydrophobic so it must bind to albumin before it can be carried through circulation
What is the second step of heme catabolism? Describe this step (2)
Step 2: Uptake and conjugation of bilirubin by the liver
- Trapping of bilirubin in liver cells
- Conjugation of bilirubin in liver cells
What are the three primary structures utilized in the uptake and conjugation of bilirubin by the liver? Describe the function of each. Which is the rate limiting step?
- OATP transporters: passive/facilitated transport of UCB into the hepatocyte
- UGT: converts UCB to CB
- MRP2: CB excreted from the hepatocyte into the bile duct - rate limiting step
What is bound to UCB before it is conjugated to CB to ensure it is trapped inside the cell?
GST
What is the third step of heme catabolism? Describe this step (2)
Step 3: Secretion and catabolism of conjugated bilirubin
- Secretion into bile and then into intestines
- Intestinal bacteria hydrolyze and reduce conjugated bilirubin to urobilinogen
What is the fourth step of heme catabolism? Describe this step (what percentage of urobilinogen is acted on in this step?)
Step 4: auto-oxidation of 90% of fecal urobilinogen to stercobilin
- Gives feces its brown color
What is the fifth step of heme catabolism? Describe this step
Step 5: Enterohepatic reabsorption of some urobilinogen from intestines
Of the 10% of urobilinogen reabsorbed into enterohepatic circulation what happens with 9% of it and what happens with the other 1%?
- 9%: Reabsorbed by liver and re-excreted into bile duct
- 1%: excreted in the urine via kidneys
What is the sixth step of heme catabolism? Describe this step
Step 6: Urinary excretion of reabsorbed urobilinogen (auto-oxidation of urinary urobilinogen to urobilin)
- Gives urine its yellow color
What is the traditional measurement method (test) for bilirubin levels?
Diazo reaction (purple color change)
What does the first step of the diazo reaction evaluate? What happens to CB and UCB during this step?
The first step of the diazo reaction evaluates DBIL (direct bilirubin)
Collect serum and directly add diazo dye to measure formation of purple color
- Fast color change: CB (unfolded and soluble)
- Slow color change: UCB (folded and insoluble)
What does the second step of the diazo reaction evaluate, and what is added to the tube? What happens to the UCB in this step?
The second step of the diazo reaction evaluated TBIL (total bilirubin)
Add methanol to the same tube
- UCB will be unfolded and solubilized by methanol so it can now react with diazo
How do you evaluate for Indirect Bilirubin (IBIL)? Is this a measurement or calculated value?
Indirect bilirubin is a calculation, NOT a measurement
IBIL = TBIL - DBIL
What causes Jaundice and what does it result in (blood)?
Jaundice (aka Icterus) is caused by the deposition of bilirubin
- Results in hyperbilirubinemia (high bilirubin in blood)
What are the four types of jaundice? What is each caused by?
- Neonatal: caused by low activity of liver enzymes at birth
- Pre-hepatic: caused by hemolytic anemia
- Hepatic: caused by viral infection/liver damage
- Post-hepatic: caused by bile duct obstruction
With neonatal jaundice, what does the immature liver of newborns result in (3)?
- Increased bilirubin load
- Decreased bilirubin conjugation
- Decreased bilirubin excretion
What is the primary treatment for neonatal jaundice? Describe how this works
Phototherapy (blue light therapy) treatment: blue light alters the conformation of UCB yielding photoisomers that are more soluble than UCB in its native form
What develops clinically in a patient with excess UCB levels? (hint: it is worse in infants) How does this present symptomatically?
Kernicterus: bilirubin encephalopathy
- Excess UCB in the blood can cross the blood brain barrier causing a buildup of UCB in the brain
- Can result in neurological damage (hearing issues to mental retardation) or even death
- Infants are more susceptible due to immature BBB
How does hemolytic anemia cause pre-hepatic jaundice?
Increased hemolysis of damaged/immature RBCs leads to increased heme metabolites and elevated levels of circulating UCB
