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31 Cards in this Set
- Front
- Back
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What are the functions of heme?
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It's a prosthetic group used for transport and storage of oxygen, electron transpot, and oxidation reduction reactions.
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Where are the major sites of heme synthesis?
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In the bone marrow for hemoglobin, in the liver for cytochrome enzyme synthesis, and in all cells to a varying degree that use the ETC.
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What are porphyrias?
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Inherited or acquired disorders of heme biosynthesis.
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What is the major product of heme degradation?
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bilirubin
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What are some consequences of hyperbilirubinemia?
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Jaundice and icterus
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How are the steps of heme synthesis compartmentalized?
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The first step starts in the inner mitochondrial membrane, the next few steps occur in the cytosol, and the last few steps occur in the intermembrane space.
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What is the first step in heme synthesis?
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5-aminolevulinate synthase (ALAS) catalyzed synthesis of delta-aminolevulinate (ALA)from succinyl CoA and glycine. (Localized to inner mitochondrial membrane and utilizes B6 as a cofactor.)
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How is heme synthesis differentially regulated in the liver and erythroid cells?
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ALAS is the committed step in heme synthesis. ALAS1 is the enzyme expressed hepatically and ALAS2 is the erythroid enzyme.
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How is ALAS1 regulated?
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regulatory heme inhibition, phenobarbitol upregulation
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What disease results in iron accumulation in erythroblast mitochondria?
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X-linked sideroblastic anemia (an ALAS2 disorder)
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What two aspects of heme synthesis can be affected by lead poisioning?
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Lead can inhibit ALA dehydratase (ALAD) from condensing two molecules of ALA to make porphobilinogen (PBG), and lead can inhibit ferrochelatase from inserting iron into the portoporphyrin IX complex at the end of heme synthesis.
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What are porphyrias and how can they be broadly separated?
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Porphyrias are inherited or acquired disorders in porphyrin synthesis that are classified as hepatic or erythroid. They can be phontosensitive if the disorder occurs after the ring structure has closed (i.e. after the PBGD step where UROS closes the ring--or the ring closes spontaneously).
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Did you review the summary of clinical disorders of heme synthesis?
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Do it for the boards! (lead poisoning, hereditary copropporphyria, porphyria cutanea tarda, acute intermitted porphyria, congenita erythropoietic prophyria)
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Where is heme catabolized?
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Primarily in senescent erythrocytes engulfed by macrophages. About 20% also occurs in immature RBCs and in cytochromes of nonerythroid tissues. Erythrocyte degradation occurs in the reticuloendothelia system of liver and spleen.
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How is the wastr product of heme processed?
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Bilirubin binds to serum albumin and is transported to liver where it is excreted into bile for further processing and elimination.
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What is a unique feature of the first few steps of heme catabolism involving the opening of the heme ring structure?
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Catabolism of heme by microsomal heme oxygenase in the macrophage actually releases CO as a by-product of metabolism.
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Why is biliverdin converted to bilirubin during heme catabolism?
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Bilirubin is less polar and can more readily cross the cell membrane.
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How is bilirubin processed in the liver?
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After uptake, bilirubin is temporarily stored through interactions with ligandins in hepatocytes. Excreation across the bile canliculis occurs after bilirubin is converted to polar conjugates.
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***Describe the bilirubin conjugation process.***
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Bilirubin is conjugated with one or two glucuronic acid moieties by uridine diphosphoglucuronate glucuronyltransferase (UDPGT) to form bilirubin monoglucuronide or diglucuronide (BMG) and (BDG).
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Describe the bilirubine excretion process.
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BMG or BDG are extreted across the hepatocyte canalicular membrane via the action of an ATP-dependent pump known as MRP2 (multi-drug resistance pump 2).
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What happens to bilirubin conjugates in the urine and feces?
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(Bilirubin is degraded by intestinal bacteria into yellow urblinin and brown stercobilin.)
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What does the van den bergh assay measure?
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Water soluble (conjugated) bilirubin--or direct bilirubin.
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How is a total bilirubin assay performed?
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Using a van den bergh assay in methanol.
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How can one measure unconjugated (indirect) bilirubin?
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By measuring total bilirubin and conjugated (direct) bilirubin and determining the difference.
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Why does neonatal jaundice occur?
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50% of newborns have neonatal jaundice which is due to delayed maturation of the liver and is treated by phototherapy.
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What is a complication of neonatal jaundice if untreated?
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Yellow discoloration of basal ganglia (kernicterus).
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What are three symptoms associated with defects in bilirubin conjugation?
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Gilbert syndrome, Crigler-Najjar type II, and Crigler-Najjar type I disease are all associated with disorder in UDPGT expression via the UGT1A1 gene. Severity of disorder increases from former to latter.
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Why must persons with Gilbert's syndrome be carefully assessed when administering certain medications?
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Although Gilbert's syndrome is largely a benign cause of hyperbilirubinemia, these individual are predisposed to experiencing toxicity forom drugs such as protease inhibitors (atazanavir and indinavir) and anti-cancer drugs (irinotecan) due to lowered UGT1A1 activity.
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What are some inherited disorders that should be considered in the differential diagnosis of conjugated hyperbilirubinemia?
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Dubin-Johnson syndrome and Rotor syndrome are two rare disorders associated with conjugated hyperbilirubinemia that can be differentiated by urinary coproporhyrin excretion. RS has elevated total coprophorphyrin levels wherease DJS does not. DJS is caused by an inherited deficiency in the MRP2 transporter.
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What are two common causes of jaundice associated with increased indirect bilirubin (unrelated to UDPGT)?
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Anemias--hemolytic jaundice & impaired liver conjugation capacity--hepatocellular jaundice
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What is a common cause of increased direct bilirubin?
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Blockage of bile ducts--obstructive jaundice
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