heme degradation Flashcards
Review the steps in intravascular and extravascular hemoglobin degradation.
Extravascular:
—-characteristics——-
-aging RBCs
-causes: membrane abnormalities, physical abnormalities (sickle cell anemia, thalassemia, PK deficiency)
-their passage becomes difficult, they are sequestered by macrophages
-the shape is spherocyte
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Steps
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1. RBC is phagocytized by macrophages
2. RBC is degraded in lysosomes, releasing heme and globin
3. Globin is reduced into amino acids
4. Iron from heme is recycled and bilirubin is also produced from heme breakdown
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Intravascular:
—–characteristics————-
-RBCs lyse in circulation, hemoglobin is released to environment
-causes: trauma, Favism (hemolytic anemia due to consumption of broad bean)
-fragmented RBC is schistocytes
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Steps
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1. Hemoglobin is bound by Haptoglobin which is bound to receptor
or
free heme binds to Hemopexin, which is bound to receptor
2. Both are endocytosed and brought to lysosome, where heme is breaks down into carbon monoxide, bilirubin and iron is recycled.
What are the steps in the fate of bilirubin?
- Heme is broken down by heme oxygenase in the macrophage into biliverdin (only reaction that makes Carbon monoxide, thought to act as vasodilator) Biliverdin is an antioxidant and cytoprotective.
and then by Biliverdin reductase into Billirubin. - Bilirubin (as a very hydrophobic molecule) is bound to albumin as it moves through the blood stream to the liver.
- At the liver (GSTBeta) bincs bilirubin to prevent it from returning into circulation.
- In the liver there are two UDP-GlcA reactions. The end product (bilirubin-diglucuronide) is conjugated aka DIRECT.
- Conjugated bilirubin will be stored in the gallbladder. After a fatty meal it will be released into intestine.
- It will then be unconjugated back into bilirubin and then converted by bacterial enzymes into colorless urobilinogen.
- 10% Urobilinogen is absorbed into kidneys and brought back via portal circulation, some is excreted as urobilin (yellow), oxidized product.
- The urobilinogen which isn’t absorbed stays in small intestine, being turned by bacterial enzymes into stercobilin (red color of feces)
What are responsible molecules for these colors ?
- Yellow coloration of skin?
- Dark colored urine
- Its colorless
- It makes urine yellow
- It gives dark brown color to feces.
- Yellow coloration of skin: unconjugated bilirubin. It does not excrete because it is too large and therefore accumulates under skin.
- Conjugated bilirubin in urine - gives dark colored urine
- If patient has stool with no color: urobilinogen is not being secreted meaning the bile duct is clogged.
- Urobilin in urine and some feces (oxidized product or urobilinogen)
- Stercobilin in feces gives dark brown color (oxidized product of stercobilinogen)
Describe the bilirubin transporters in the liver.
- Bilirubin is bound to albumin. Bilirubin is taken up at the sinusoidal membrane via the OATP2beta1 (not as important)
- It is bound to GST-beta and undergoes conjugation via UDP-GT.
- Conjugated bilirubin mostly goes out MRP2 into the canalicular space for gallbladder storage
- Some go out of the hepatocyte via MRP3 as conjugated bilirubin which is a nono and that is caught by OATP 1B1/3. important clinically
What is Kernicterus
Although accumulation of bilirubin (jaundice) is hamrless in older children and adults, it is neurotoxic to newborns.
This is because UDP-GT is low in newborns and this conjugates the bilirubin.
In premature babies the consequences are even worse as serum bilirubin can be even higher.
Symptoms: extreme jaundice, absent startle reflex, poor feeding, extreme sleepiness, high pitched cry, arched back with neck hyperextended backwards, seizures, bulging fontanel
Later: muscle rigidity, intellectual problems, speech problems, high frequency hearing loss.
What is Criggler-Najjar Syndrome:
Type 1
Type 2
No activity of UDP-GT (because of no gene) = Kernicterus in newborns
Type II: mutation in UDP-GT, some activity and its benign.
What is Gilbert disease
What is Rotor disease
What is Dubin johnson
Gilbert: A rather common disease (2-10% of population).
“turn yellow when taking an exam”
*appears during or after adolescent years
-the problem is TRANSCRIPTION, a mutation in the promoter of UDP-GT leads to some activity but reduced transcription.
-With physiologic stress, you get jaundice.
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Rotor: appears shortly after birth
-biallelic inactivating mutations in OAT1B1 and OAT1B3
-no activity
-intermittent episodes of mild unconjugated and conjugated hyperbilirubinimia.
-presents EARLY
Dubin-Johnson: appears during adolescence or early adulthood.
-mutation in MRP2 (causing ** deposition of coarse granular dark brown pigments in hepatocytes.
-some activity, jaundice is only symptom.
Compare
- hemolytic jaundice -prehepatic
- neonatal jaundice - hepatic
- hepatocellular jaundice - hepatic
- Obstructive jaundice - post hepatic
- Hemolytic jaundice - there is huge lysis of RBCs in the blood stream which exceed the liver’s capacity to process it into direct bilirbuin.
- indirect bilirubin builds up in blood stream.
- urobilinogen in blood and urine are also increased. - Particularly in premature infants - low levels of hepatic UDP-GT and low GST-beta, no conjugation, indirect bilirubin returns to blood stream.
- Hepatocellular jaundice: damage to liver cells (hepatitis, cirrhosis) leads to decrease in normal function of hepatocytes. They cannot meet the normal loads
- there will be elevations of conjugated and unconjugated bilirubin.
- urobilinogen is elevated in blood and urine because the diseased liver loses ability to scavenge urobilinogen from portan circulation. - Obstructive jaundice- prevents draining of conjugated bilirubin into intestines. Feces will have pale clay color due to relative absence of stercobilin.
