Bilirubin Metabolism Flashcards
(39 cards)
What is bilirubin? What are some consequences of defects in its metabolism?
Bilirubin is a product of heme breakdown. Defects in heme degradation or excretion of bilirubin through bile can result in Hyperbilirubinemia, juandice and other disturbances in metabolic pathways.
Briefly describe the process of heme degradation in 5 steps.
- Phagocytes eat up old RBCs to breakdown into globin, iron and heme.
- Heme is metabolized into bilirubin in phagocytes.
- Albumin binds to bilirubin to transport it to hepacytes by circulation.
- Hepatocytes free bilirubin and combine it with glucuronic acid to make conjugated bilirubin.
- Conjugated bilirubin is excreted into bile to head out into intestines.
Up to ___% of daily production of bilirubin comes from breakdown of ___. The remainder of other heme-like proteins is turned over in the ____ ____.
85% of daily bilirubin from metabolism of old RBCs.
Remainder of hemoproteins is converted in bone marrow.
The lifespan of a RBC is from __ to __ days. Old RBCs are either filtered in the ____ to be swallowed up by macrophages of the ______ system. This process represents ___% of degradation.
Life of RBC = 60-120 days
90% of old RBCs are filtered in spleen to be phagocytosed as part of the reticuloendothelial system (RES).
About ___% of RBCs undergo intravascular ______. This is the ____ of RBCs within circulation.
~10% of old RBCs undergo hemolysis where they rupture in circulation.
Abnormalities in the RBC membrane restricts ______. This leads to RBC _____ and _____ by macrophages in the splenic cords.
Extravascular hemolysis pathologies restrict RBC “deformability”. Leads to RBC sequestration and phagocytosis by splenic macrophages.
Pathologies in intravascular hemolysis include (but are not limited to)… This results in fragmented RBCs called ____.
Intravascular hemolysis pathologies include G6PD deficiency, mechanical trauma and Favism (toxic damage). This results in Schistocytes.
What RBC membrane abnormalities can result in an upregulation of extravascular hemolysis?
Sickle cell anemia, thalassemia and Pyruvate Kinase Deficiency.
What are the 2 ways that heme can be taken into the macrophages of the liver in intravascular hemolysis?
- Extracellular heme is incorporated into hemopexin-heme that enter macrophage.
- Hb binds haptoglobin to undergo receptor-mediated endocytosis in liver macrophages.
What enzyme is involved with the 1st step in degradation of heme? What are the requirements and side-products?
Heme Oxygenase converts Heme into (green) Biiverdin. This step requires NADPH and O2 but releases Iron, NADP and Carbon monoxide (vasodilator). This is the only reaction in the body that produces CO
What enzyme is involved in the 2nd step of heme degradation? What are the requirements and product?
Biliverdin Reductase converts Biliverdin into (yellow) Bilirubin. This step requires NADPH to make the hydrophobic bilirubin that has a high affinity for albumin if unconjugated.
In the blood, bilirubin is bound to _____;whereas, in the liver cell, it is bound to _____.
Albumin;
Ligandin (cytoplasmic transport protein in hepatocytes)
What is the function of ligandin as it relates to bilirubin metabolism?
Ligandin, which is an intra-cellular transport protein in the liver cell, has a higher affinity for bilirubin than albumin does. It transports bilirubin to the liver cell’s SER to be processed.
What happens to bilirubin within the SER of Hepatocytes? What are the effects?
Bilirubin becomes more SOLUBLE from the addition of glucoronic acid moieties by UDP-glucoronyl transferase (UDP-GT) enzyme. Conjugated bilirubin (BDG 85% and BMG 15%) is more POLAR and thus more soluble.
What is the enzyme responsible for conjugating Bilirubin?
UDP-GT or UGT1A1 in the smooth ER of hepatocytes adds glucoronic acid (sugar) moeities to bilirubin. This makes it more soluble in blood.
Bilirubin is converted into pigments that color the wastes that leave the body. Feces are brown because most urobilinogen is converted to ______. Meanwhile, urine is yellow because the remaining urobilinogen is turned into ______.
90% of urobilinogen is converted to red-brown “Stercobilin” by microbial enzymes. 10% of reabsorbed urobilinogen is turned into yellow “Urobilin” in the kidney.
Unlike bile salts/acids, most of the bilirubin is ______, so it does not circulate ______.
Most bilirubin is EXCRETED in the feces, so it does not circulate enterohepatically.
Oral administration of _______ antibiotics greatly reduces the formation of ________.
Broad-spectrum antibiotics reduces the formation of Urobilinogen. This is due to the changes in gut microbiota that impacts its formation.
Heme degradation produces the insoluble bilirubin by-product. How does the body manage the low solubility in a healthy individual?
Acidic derivative of glucose are covalently attached to bilirubin prior to its export in the bile.
Bilirubin _______ is made in the liver and sent into bile. Bilirubin that is ______ is bound to albumin in the blood stream.
Bilirubin Diglucuronide;
Unconjugated Bilirubin
Explain the purpose of bilirubin “Hepatocyte Hopping”. What are the transporters involved in this process?
A fraction of conjugated bilirubin is off-loaded to downstream hepatocytes to prevent the saturation of biliary transport in upsteam hepatocytes. MRP2 normally shuttles the product into canalicular space, but MRP3 on the sinusoidal side reroutes some to the blood for downstream liver cells to pick up.
What deficiency results in Rotor Syndrome? What are the effects?
Deficiency in the transporters that take in unconjugated bilirubin from blood into liver cells (OATP1B1/3). This can present as juandice since too much bilirubin would be in circulation.
What deficiency results in Dubin-Johnson Syndrome? What are some possible effects?
Deficiency in MRCP2 transporters from mutations in ABCC2 gene can result in less conjugated bilirubin being taken into the canalicular space.
Only the ____ bilirubin can be measured DIRECTLY. Concentrations of ______ bilirubin can be calculated indirectly.
Conjugated measured directly; unconjugated measured indirectly. “Un is In-direct!”
Indirect unconjugates = Total bilirubin - direct conjugates