Heme Degradation Flashcards
Pre-hepatic steps of heme degradation
- Heme oxygenase from reticuloendothelial cells in presence of O2 and NADPH add hydroxyl group to menthenyl btw 2 pyrrole rings in heme
- 2nd oxygenation by same enzyme system and another NADPH causes ferric and CO to release changing heme to biliverdin
- Biliverdin is reduced forming bilirubin
Color of biliverdin
Green
Color of bilirubin
Red-orange
What transports bilirubin in blood?
Albumin binds non-covalently
Effect of anionic drugs (sulfonamidea and salicylate) on bilirubin
Displaces from albumin
Bilirubin may enter CNS w/ potential neural damage
Protein bilirubin binds to in liver
Ligandin
Steps in hepatocyte in heme degradation
- Bilirubin becomes conjugated by adding 2 glucuronic acid molecules from UDP-glucuronic acid via glucuronate donor
- Bilirubin diglucuronide (conjugated) transported into bile canaliculi then into bile
Steps in heme degradation in small intestine
. Conjugated bilirubin hydrolyzed and reduced by bacteria in gut to form urobilinogen (colorless)
. Some urobilinogen reabsorbed into portal blood and transported to kidney
. Most urobilinogen oxidized by intestinal bacteria to stercobilin
Step in heme degradation in kidney
Urobilinogen that comes to kidney is converted to urobilin (yellow) and excreted in urine
Jaundice
. Also called icterus
. Yellow color of skin and sclera caused by bilirubin deposition from inc. bilirubin in blood
. Sign, not disease itself
Major forms of jaundice
Hemolytic/pre-hepatic, obstructive/post-hepatic, and hepatocellular
Hemolytic Jaundice
. Massive lysis of rbcs
. Greater than normal bilirubin so more unconjugated in blood
. Greater than normal amount is bilirubin is conjugated causing elevated levels of bilirubin excreted in bile through normal route
. Inc. urobilinogen enter circulation causing increased urobilin and urobilinogen in urine because not all can be converted
Obstructive jaundice (Post-hepatic)
. Obstruction in bile duct blocks passage of bilirubin to intestine
. Less bilirubin in intestine causes less urobiliogen and stercobilin
. Bile can back up into liver causing liver to regurgitate conjugated bilirubin in blood
. Conjugated bilirubin excreted into urine causing it to be dark red-orange
. Prolonged obstruction can cause liver damage and impair ability to conjugate (rise of unconjugated bilirubin in blood in this case)
Hepatocellular jaundice
. From damage to liver cells (cirrhosis, hepatitis)
. Elevation in serum AST, ALT, at early stages in response to hepatocyte necrosis
. Initial stages of damage release conjugated bilirubin into blood
. Urine dark (red-orange) due to conjugated bilirubin in blood
. Later liver disease stages (after necrosis ends) ability to take up and conjugate bilirubin impaired causing high serum unconjugated bilirubin
Jaundice in newborns
. Newborns accumulate bilirubin because activity of hepatic bilirubin glucuronyl transferase is low
. Adults levels achieved at 2 weeks old
. Inc. bilirubin in excess of albumin binding capacity can cause toxic encephalopathy
. Treated w/ blue fluorescent light that converts bilirubin into water-soluble form
How is bilirubin concentration determined?
Van den Berg reaction
Hemolytic jaundice TBIL, IBIL, and DBIL levels
Inc. TBIL, inc. IBIL, no DBIL
Obstructive jaundice TBIL, IBIL, DBIL levels
inc TBIL, normal to high IBIL, inc. DBIL
Hepatocellular jaundice TBIL, IBIL, DBIL
Inc. TBIL, normal to high IBIL, inc. DBIL
GIlbert Syndrome
. Benign hereditary disorder causing mild dec. of UDP-glucuronyltransferase causing inc. of IBIL
. 5% US population have it
. Usually incidental finding
. Junadice occurs in times of stress, fasting, or illness
. Transient, don’t require treatment
Crigler Najjar syndrome
Form of enzyme deficiency in heme degradation pathway Ew/ varying severity
