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51 Cards in this Set
- Front
- Back
Structure of Heme |
Protoporphyrin 9 ring that can bind FE2+ reduced iron or Fe3+ oxidized iron -Fe2+ is desirable in the human body |
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Heme is prosthetic group for... |
Hemoglobin, myoglobin, cytochromes, cyclooxygenases, catalase, and CYP450 enzymes |
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Regulatory step of heme biosynthesis |
Succinyl CoA+Glycine (delta ALA synthase) -Negative feedback occurs via heme production |
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delta ALA function |
Allows ALA to leave the mitochondria |
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Cytosolic delta ALA |
converted to 4 things 1. Porphobilinogen 2. Hydroxymethylbilane 3. Uroporphyrinogen III 4. Coproporphyrinogen III --- Number 4 reenters the mitochondria |
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Mitochondrial Coproporphyrinogen III |
Converted to; 1. Protoporphyrinogen IX 2. Protoporphyrin IX 3. Adds Iron 2+= heme |
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Where is heme made? |
All cells de novo, but mainly in reticuloendothelial system (liver, bone marrow) |
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ALA synthase is committed step, and it requires... |
Pyridoxal 5' phosphate (PLP) as coenzyme |
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Isoform ALAS1 |
ALAS1- in non erythroid cells. Heme synthesized in hepatocytes is incorporated into CYP450 enzymes. Expression of ALAS1 increases in response to toxins/drugs |
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Isoform ALAS2 |
ALAS2 is present in erythroid cells. - Heme that is made in erythroid cells is committed to hemoglobin synthesis. HYPOXIA and ERYTHROPOIETIN increase heme synthesis via ALAS2. ALAS2 mRNA contains Fe-Responsive element and responds to intracellular availability of iron. Coordinated w/ globin chain synthesis. |
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Protoporphyrin IX-->Heme |
Fe2+ is incorporated into Heme via insertion through Ferrochetalase. This reaction also requires ascorbic acid and cysteine as reducing agents |
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Acquired v. Congenital Disorders of Heme synthesis |
Acquired: iron deficiency and lead poisoning Congenital: Porphyrias- enzymes are deficient and most likely genetic based |
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Iron Deficient Anemia v. Lead Poisoning Anemia |
--IDA- No heme. Microcytic hypochromic anemia occurs, and higher levels of ZnPP will occur --LPA- Where lead is a competitive inhibitor of iron, iron cannot go in. Again will see microcytic hypochromic anemia, but iron levels will be normal, as well as free PP9 |
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Lead poisoning affects on Heme biosynthesis |
ALA Dehydratase and ferrochetalase enzymes are inactivated by Pb and other heavy metals (no porphobilinogen). Increases urinary excretion of del ALA is a leading indicator of heavy metal poisoning |
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Symptoms of note of Lead toxicity in Newborns, Children, and Adults |
N: Learning difficulties, stunted growth C: Developmental delay, GI problems, Weight loss, malaise, hearing loss, irratibility A: Hypertensive, joint/muscle pain, memory loss/cognitive or mental regression, Reproductive issues, headache, parasthesia |
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Treatment of Lead Toxicity |
Chelation with EDTA |
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Porphyrias |
Congenital enzyme deficiencies that result in the accumulation of any intermediate in heme biosynthesis pathway. Can be primarily hepatic or erythroid. Most have neurotoxic component d/t build up. Photosensitivity (porphyrin+O2=Orad) due to porphyrinogens in the skin |
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Acute Intermittent Porphyria |
Enzyme: Porphobilinogen deaminase Accumulating intermediate: Porphobilinogen 10% show manifestation- GI, MS, and CV problems. Mental derangement, agitation and seizures are also common d/t ALA and PBilinogen accumulation in blood and CSF |
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Barbituates and AIP |
Acute AIP attacks can be precipitated w/ barbituates, phenytoin, or any drug that induces synthesis of CYP450. P450 takes heme and ALA synthase is jacked because heme will not inhibit via negative feedback. |
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Hematin |
stable derivative of heme in which heme iron is in ferric form |
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Tx of AIP |
Withdrawal of any offending drugs and hematin infusion. Hematin represses synthesis of ALA synthase. Carbohydrate-rich prescribed for long term mgmt because it represses ALA synthase synthesis- though dieting can cause attack |
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Porphyria Cutanea Tarda |
Most common porphyria. Seen in older men during summer months. Cases caused by uroporphyrinogen decarboxylase defect and alcholism/liver damage. No neuro or GI problems, but cutaneous photosensitivity is hallmark. |
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Tx for PCT |
Avoidance of sunlight, alcohol abstinence, and phlebotomy |
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Heme degradation/Bilirubin excretion |
RBCs last 120 days and are degraded by liver and spleen. 85% heme from RBCs and rest from turnover of other heme containing proteins Hemoglobin breaks down into Heme and Globins. Globins to AA pool and Heme breaks to bilirubin and Fe2+. Bilirubin usually excreted fecally. |
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Heme catabolism and bilirubin excretion |
1. Porphyrin ring cleaved via heme oxygenase and produces biliverdin and CO. Fe released same time. 2. Biliverdin reductase reduces biliverdin central CH bridge producing bilirubin 3. Bilirubin is transferred to liver via albumin and liver UDP glucuronyl transferase makes water soluble conjugates |
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How to make bilirubin more water soluble |
Bilirubin (UDP glucuronyl transferase) conjugates bilirubin w/ diglucuronide and is excreted in urine or bile |
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Bilirubin in intestine |
Converted to urobilinogen via intestinal bacteria, and most goes on to stercobilin. Accumulation=Jaundice. |
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Hyperbilirubinemia |
AKA- Jaundice. Increased plasma concentrations of bilirubin occurring from imbalance b/t production and excretion |
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4 categories of jaundice |
1. Prehepatic 2. Intraepatic 3. Posthepatic 4. Neonatal |
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Prehepatic Jaundice |
AKA Hemolytic - Liver can handle 3000mg bilirubin a day, and we only make on average 300 mg. -Hemolytic anemia causes MASSIVE increase in bilirubin and liver cannot keep up to conjugate it --Increased bilirubin excreted into bile --Urobilinogen increased in blood --Unconjugated increase=jaundice |
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Genetic causes of hemolytic anemia |
- SCA -Thalassemia -Hereditary spherocytosis |
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Inborn errors of metabolism in hemolytic anemia |
Insufficient activities of pyruvate kinase or G6PD -No G6PD, no glutathione reduction |
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Hemolytic anemia via environmental factors |
-Infections, certain drugs, autoimmune reactions, and poisons |
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Diagnosis of Hemolytic Jaundice |
-Low plasma levels of haptoglobin --Excess hemoglobin binds to a2 of haptoglobin and removes it from circulation. |
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Intrahepatic Jaundice |
AKA Hepatocellular jaundice -Impaired liver function is major cause (Hep) -Bilirubin cannot be conjugated and unconjugated bilirubin increased in blood -Lower secretion of direct conjugated bilirubin into bile also compromised, so urobilinogen decreased in urine |
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Diagnosis Intrahepatic Jaundice |
-Pale or clay color stool -ALT, AST, and bilirubin all increased -Kernicterus can occur where bilirubin hurts BBB. |
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Posthepatic Jaundice |
AKA Obstructive Jaundice -Obstruction of bile duct d/t bile stones or tumor -Back up of conjugated bilirubin in liver results in abnormal spillage of conjugated into blood and excretion in urine (dark color) |
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Diagnosis Posthepatic Jaundice |
GI pain and nausea, Pale and clay colored stool d/t absence fecal bilirubin, dark urine d/t increased conjugated. EVENTUALLY can lead to liver damage and increased unconjugated if backs up before this process. |
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COMPARISONS OF NORMAL, HEMOLYTIC, HEPATIC, AND OBSTRUCTIVE JAUNDICE |
N- .1-.4 mg/dL direct serum bilirubin, .2-.7 mg/dL indirect serum bilirubin. 0-4mg/24hr Urine Urobilinogen. No urine bilirubin. 40-280 mg/24hr Fecal urobilinogen -Hem- +Indirect, +Urine Uro, No Urine Bili, +FU -Hep- +Indirect/direct, - urine uro if microobstruction, + urine bili if microobst, -FU -Obs- +Direct, No UUro, PresentUroB, No FU |
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Neonatal Jaundice |
Newborns often accumulate d/t combination of: 1. Late onset of expression of bilirubin glucouronyl transferase -There is a breakdown of Fetal Hb as it is replaced by adult Hb. Premature infants develop more sever jaundice due to hepatic immaturity (Enz mature at 4 weeks) 2. Hemolytic diseases associated w/ mother child blood incompatibility. Indirect bili toxic to newborn- MR because hydrophobic indirect can cross BBB |
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Tx of incompatible hemolytic anemia |
Blue fluorescent light changes structure to make more water soluble by making more polar and can be secreted sans conjugation |
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Gilbert's Syndrome |
-Benign, inherited liver disorder -Ability of liver to conjugate bilirubin is decreased due to decreased UDP glucuronyl transferase activity -Onset in teens, 20s, and 30s -Tx: Small doses of phenobarbital to stimulate UGT activity |
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Dietary sources of Iron |
10-15 mg/day recommended In meat, heme, readily absorbed In plants, non-heme, not as easily absorbed d/t other compounds precipitate iron |
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Absorption of Iron |
Iron is absorbed in ferrous state (2) and oxidized by ferroxidase (ceruloplasmin) to ferric for transport |
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Transport of Iron |
-Apotransferrin binds Ferric w/ transferrin and carries ferric iron to cells -Transferrin=iron transport protein -Cells take up transferrin through transferrin receptors -Iron is stored as ferritin in cells, and excess is stored as hemosiderin -Ferritin also present in small amounts in plasma, proportional to intracellular stores |
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Iron Homeostasis |
Regulated by controlling the uptake of dietary iron and release of iron from liver -Fe stored as ferritin -0 in many children and menstruating women -Older men, +1mg -Hemosiderin- storage form excess iron, and excess is hemosiderosis |
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When iron stores are low... |
Liver cells translate transferrin receptors but not ferritin. This makes sure iron can be absorbed from intestine and taken up from blood for heme biosynthesis. apo-IRP binds to IRE in 3' UTR and TR mRNA not degraded. in 5' UTR of ferritin mRNA inhibits mRNA initiation |
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When intracellular iron is high |
IRP binds IRON making it inactive -2 regulatory processes act to inhibit iron uptake via; 1. down regulating transferrin receptor 2. Increasing ferritin |
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Iron deficiency can result from... |
Inadequate intake or loss of iron/blood -Chronic blood loss (peptic ulcer, hemorrhoids, blood-sucking intestinal parasites, tumors) -Growth -Pregnancy and lactation --250-300mg of iron is transferred to fetus --80-400 lost placenta, umbilical cord, and blood loss at birth --100-180 mg lost during lactation |
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Test for iron levels |
1. Serum Fe- Fe in your blood. Can be normal even if total amount is low. Why we do others 2. Serum Ferritin- Iron storage protein, How much of your stored has been used 3. Transferrin level (TIBC)- IDA free transferrin high 4. Transferrin Sat- SFe/TIBCx100 |
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Hereditary Hemochromatosis |
-Accumulation of excess iron in cells -Clinical hallmarks- cirrhosis, diabetes, cardiac failure, skin bronzing -Mutation in HFE gene ---HFE protein usually binds to transferrin receptor and reduces affinity of receptor for transferrin- LOF mutation leading to increase absorption of Fe by liver and uptake by intestine into blood -HEMOSIDERIN DEPOSITS- liver, pancreas, skin, joints TX- Bloodletting |