L25- Heme Catabolism and Jaundice (#7) Flashcards
Roughly ___% of heme destined for degradation by resident macrophages comes from SENESCENT RBCs , and ____% from the turnover of IMMATURE blast cells (in the bone marrow). Where do the rest come from?
70%
15%
Cytochromes (liver and many other cells)
What is free heme degraded by (although toxic and not recyclable)?
Heme oxygenase
What does heme oxygenase produce?
Biliverdin and releasing iron
What converts biliverdin into bilirubin?
Biliverdin reductase
What type of enzyme is heme oxygenase?
Cytochrome P450 enzyme, phase 1 drug metab
What is the unconjugated bilirubine (UCB) made from? (reaction) What do these two reactions require?
Heme oxygenase produces biliverdin
Biliverdin reductase converts biliverdin into bilirubin which is called UCB
NADPH
Why is UCB very hydrophobic? What binding does it form to serum albumin for its transport?
Due to internal H-bonding
UCB forms non-covalent binding to serum albumin for its transport
How is conjugated bilirubin formed during the step of uptake of UCB by the liver? What is this reaction catalyzed by?
Attachment of 2 glucornic acid residues
Catalyzed by liver UDP-glucuronyl transferase
UCB is taken up itno the liver via what carrier?
OATP
The addition of glucuronic acids to the bilirubin which forms CB during the uptake of UCB by liver does what?
Adding it makes CB hydrophilic so now it is amphipathic with both hydrophilic and hydrophobic characteristics
Clinical Note: Birds lack biliverdin reductase so in avian sepcies, biliverdin is the major pigment of ___
Bile
How is CB actively excreted into the bile?
Via an ATP-dependent carrier, MRP2
What happens to CB in healthy animals in relation to the blood? *
CB does NOT leak back into blood because presence of TIGHT JUNCTIONS*
Clinical Note: Dubin- Johnson Syndrome is caused by a deficiency in _____ resulting in ______________
caused by MRP2 resulting in conjugated hyperbilirubinemia
Clinical Note: Dubin-Johnson Syndrome is significant because there is no _______
Liver damage
During the step of formation of urobilinogen, the CB is metabolized by what?
Colonic bacteria
Urobilinogen during its formation goes through what type of oxidation? What does it produce?
Non-enzymatic Auto-oxidation
producing sterocobilin
The vast majority (>90%) of urobilinogen in the portal blood is ________________
Reabsorped by the liver and re-excreted into bile
The process of reabsorbing urobiliongen in blood and re-excreting it into the bile without and chemical alteration is termed what?
Enterohepatic (re)circulation
What happens to the small percentage of urobilinogen that is NOT taken up by the liver from the portal blood?
Enters systemic circulation and is filtered by the kidney
To produce urine, urobilinogen goes through the non-enzymatic auto-oxiation, yielding what?
Urobilin
Where is stercobilin found? Urobilin?
Stercobilin (found in the intestine)
Urobilin (found in the urine)
Unconjugated bilirubin is ____ and ______ filtered at the kidney
Hydrophobic and IS NOT filtered at the kidney
Conjugated bilirubin (if present) is _______ and ______ filtered at the kidney
Amphipathic and IS FILTERED at the kidney
What type of bilirubin would be present in a healthy organism? Unhealthy?
Healthy: Unconj bilirubin
Unhealthy: Conj bilirubin
Clinical note: Jaundice is not a disease but a ____?
Sign of a disease
Clinical note: It is detectable when serum bilirubin exceeds______ mg/dL
2.0-3.0 mg/dL (hyperbilirubineamia)
In pre-hepatic jaundice due to hemolysis, what would serum tests say about IBIL (indirect bilirubin) [UCB] and why?
Increased
RBC lysis –> UCB –> Exceed the transport and conjugation capacity
In pre-hepatic jaundice due to hemolysis, what would serum tests say about DBIL(direct bilirubin) [CB]?
Normal
Although more bilirubin is being conjugated, the CB is being secreted to bile rather than blood
In pre-hepatic jaundice due to hemolysis, what would serum tests say about urinary urobilinogen?
Increase
This increase is due to an increase of prod of CB which is the precursor for urobilinogen
In pre-hepatic jaundice due to hemolysis, what would serum tests say about urinary bilirubin?
Normal
This test measures CB- since level of CB in the serum is normal, it is not present in the urine.
When UCB accumulates and is highly elevated, it does not get filtered out in the urine because of what?
Too hydrophobic
In pre-hepatic jaundice due to hemolysis, what would serum tests say about fecal urobilinogen?
Increased
The increase in urobilinogen is due to an increase in prod of CB which is coverted into urobilinogen
In hepatic jaundice due to hemolysis, what would serum tests say about IBIL (indirect bilirubin) [UCB] and why?
Normal to increased
The increase is proportional to the extent of the liver cell dysfunction
(Note: not a reliable predicator of jaundice)
In hepatic jaundice due to hemolysis, what would serum tests say about DBIL?
Increased
A decrease transport of CB into the bile: depending on liver dysf severity, the transport of CB from hepatocyte may be reduced. The liver dmg results in leakage of CB in blood
(Note: DBIL increase is sign of liver dmg)
In hepatic jaundice due to hemolysis, what would serum tests say about urinary urobilinogen?
Increased
Liver is unable to reabsorb as much as urobilinogen as normal from the portal vein and more urobilinogen gets into the blood
- Serum urobilinogen is amphipathic and is filtered at kidney into urine
In hepatic jaundice due to hemolysis, what would serum tests say about fecal urobilinogen?
Normal to decreased
Liver damage results in a decrease in rpod of conjugated bilirubin
In hepatic jaundice due to hemolysis, what would serum tests say about urinary bilirubin?
Increased
Urinary bilirubin is increased, bc levels of the CB in blood is increased. CB is amphipathic and is readily filtered at the kidney
In post-hepatic jaundice due to hemolysis, what would serum tests say about IBIL (indirect bilirubin) [UCB] and why?
Normal to increased
If CB is increased, it is due to 2ndary liver damage- not a good indicator!
In oost-hepatic jaundice due to hemolysis, what would serum tests say about DBIL?
Increase
The increase in CB is ude to the backup of CB into the blood secondary to the bile blockage
In post-hepatic jaundice due to hemolysis, what would serum tests say about urinary urobilinogen?
Decreased
The decrease in urobilinogen is due to a decrease in synthesis because of the blockage of bile duct- thus, CB is not able to enter intestine and to be catabolized into urobilinogen
In post-hepatic jaundice due to hemolysis, what would serum tests say about urinary bilirubin?
Increased
Bc levle of CB in blood in increased- CB is amphipathic and ready to be filtered at kidney
In post-hepatic jaundice due to hemolysis, what would serum tests say about fecalurobilinogen?
Decreased
The decrease in urobilinogen is due to blockage of the bile duct which prevents CB from entering intestine
