Iron deficiency anemia


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  • Iron deficiency anemia

    2. 2. Iron deficiency in the United States National Health and Nutrition Examination Survey (NHANES)MMWR 51(40); 897-9 Survey of sample US households: ferritin, % saturation, FEP
    3. 3. CAUSES OF IRON DEFICIENCYOVERT BLOOD LOSS Hematemesis, melena Severe menorrhagia Hemoptysis, hematuria, traumatic hemorrhageOCCULT BLOOD LOSS Small bowel, vascular, inflammatory Voluntary blood donations, post-op, iatrogenic Menses OBS: delivery, direct iron loss to fetus, iron loss to the neonate during lactation
    4. 4. CAUSES OF IRON DEFICIENCYUNCOMMON• Reduced GI absorption of iron: Celiac Disease, Atrophic Gastritis, H Pylori• Gastric Bypass for obesity ; Billroth II• Diet deficient in iron (phytates)• Intravascular hemolysis — PNH, malfunctioning heart valve prostheses, Intravascular Hemolysis (Cold Agglutinin)• Pulmonary Hemosiderosis• ( IRIDA ) Iron-refractory iron deficiency anemia-- TMPRSS6,DMT1EMERGING Response to erythropoietin — Mobilization of iron stores
    5. 5. Unexplained iron deficiency: “Gastrointestinal sideropenia”• Consider in patients with relapsed/refractory iron deficiency: – Celiac disease – Atrophic body gastritis – H. pylori infection – Gastric bypass surgery
    6. 6. Body Iron Distribution and Storage Duodenum Dietary iron (average, 1 - 2 mg Utilization Utilization per day) Plasma transferrin (3 mg) Bone Muscle marrow (myoglobin) Circulating (300 mg) (300 mg) erythrocytes Storage iron (hemoglobin) (1,800 mg) Sloughed mucosal cells Desquamation/Menstruation Other blood loss (average, 1 - 2 mg per day) Reticuloendothelial Liver (1,000 mg) macrophages Iron loss (600 mg)
    7. 7. Iron Cycling Erythrocytes RBC 2500 mg Production Monocyte- Macrophage System Bone Marrow RBC Destruction Fe-Transferrin 20 mg 20 mg Daily Fe-Transferrin Fe-Transferrin Daily Plasma Loss 4 mg 1-2 mg Body Stores 500-1000 mg Daily 5 mg Daily Fe-Transferrin Absorption Myoglobin 1-2 mg and Respiratory Enzymes Daily 300 mgHudson JQ, Comstock TJ. Clin Ther. 2001;23:1637-1671.Eschbach JW et al. Kidney Int. 1992;42:407-416.
    8. 8. Major Iron CompartmentsMetabolic Hemoglobin 1800-2500 mg Myoglobin 300-500 mgStorage Iron storage 0-1000 mgTransit Serum iron 3 mgTotal 3000-4000 mg
    9. 9. Iron Intake • Mean iron intake 10-14 mg/d Contribution iron intake 1992-3 to the of food groups • Historically, main source of to the iron intake 1992-3 iron intake has been meat Other Bread Other Bread 11% • Iron intake has stabilized 16% 16% 11% over the past 25 years Vegetables Vegetables 16% • Not a marker of iron status 16% Cereals Cereals • Not a marker of overall Meat 39% 39% Meat Eggs nutrition 15% Eggs 15% 3% 3%Fairweather-Tait S.; Proc Nutrition Society (2004) 63:519-528
    10. 10. Effectors of Iron Absorption • Inhibiting Iron Absorption – Coffee, tea, milk, cereals, dietary fiber, carbonated beverages – Dietary supplements with Ca, Zn, Mn, Cu – Antacids, H2 blockers, and PPI’s • Facilitating Iron Absorption – Vitamin C – Acidic foodsAlleyne, M. Am J Med. (2008) 121:943-948
    11. 11. Proteins Regulating Iron Absorption Lumen Hepcidin CirculationAndrews N Engl J Med 353:2508
    12. 12. Laboratory diagnosis of iron deficiency: Serum iron and transferrin (TIBC) Parameter Sensitivity (%) Specificity (%) Accuracy (%) Serum Iron 82 30 53 TIBC 60 63 54
    13. 13. Ferritin µg/l Bone marrow iron stores
    14. 14. Laboratory Diagnosis of Iron Deficiency Soluble Transferrin Receptor (sTfR)• Transferrin receptor located on surface of erythroid precursors in bone marrow• Small amount of transferrin released into circulation (sTfR)• Iron deficiency anemia associated with increased sTfR
    15. 15. sTfR: Distinguish Iron Deficiency from Other Hypoproliferative Anemias Overall results of sTfR Sensitivity ~100% Specificity 69% Accuracy 88%
    16. 16. Neurologic syndromes associated with iron deficiency• Pica • Restless leg syndrome – Definition: Compulsive − Common neurologic ingestion of a non- disorder food substance − Criteria for diagnosis: – Pagophagia Ice eating 1. An urge to move the legs usually accompanied by – Occurs in women more uncomfortable sensations commonly then men 2. Sensation begins or – Occurs in all causes of worsens during periods of iron deficiency anemia rest 3. Sensations relieved by (~25%) movement 4. Worse in the evening/night − Occurs in ~10% of cases of iron deficiency anemia
    17. 17. Treatment With Iron: Principles• Ferrous salts are absorbed better than ferric salts• All ferrous salts are absorbed to the same extent• Ascorbic acid increases absorption and toxicity• Iron is absorbed best on an empty stomach; not given with antacids• Prescription iron generally better tolerated than iron salts• Reticulocytosis occurs <7days; Increase in Hgb 2-3 weeks• Maximum iron dose ~200 mg/day
    18. 18. Available Oral Iron Supplements Approx. cost Oral iron Typical Elemental to give 5000 preparations dose (mg) iron (mg) mg Ferrous sulfate 325 mg tid 65 $10.00Ferrous gluconate 300 mg tid 36 $7-8.00Ferrous fumarate 100 mg tid 33 $8.00-9.50 Iron 150 mg polysaccharide 150 $11.00 bid complex Carbonyl iron 50 mg tid 50 $18.00
    19. 19. Inadequate Response to Oral Iron  Intolerance/Noncompliance (~30% discontinue)  Persistent blood loss  Decreased iron absorption  Chronic inflammation or bone marrow damage  Chronic kidney disease
    20. 20. Investigati Investigati onal agent onal agent Intravenous Iron Preparations (not FDA (not FDA approved) approved)Generic name High Molecular Low Ferric Iron Ferumoxtyol Iron Ferric Wt Iron Dextran Molecular Wt Gluconate Sucrose Isomalto- Carboxy- Iron Dextran side maltoseTrade name DEXFERRUM INFeD Ferrlecit Venofer FERAHEME Monofer6 Injectafer American Regent Watson Watson American AMAG Pharmacosmo AmericanManufacturer Pharmaceuticals Pharmaceuticals Regent Pharmaceuticals s A/S RegentCarbohydrate High-molecular- Low-molecular- Gluconate Sucrose Polyglucose Isomaltoside Carboxymalt weight iron dextran weight iron sorbitol ose dextran carboxymethyl etherMolecular weight 265,000 165,000 289,000-440,000 34,000- 750,000 150,000 150,000measured by 60,000manufacturer(Da)Total-dose or Yes Yes No No No Yes Yes>500-mginfusionPremedication TDI only TDI only No No No No NoTest dose Yes Yes No No No No NorequiredIron 50 50 12.5 20 30 100 30concentration(mg/mL)Black box Yes Yes No No Np NA NAwarning
    21. 21. IV Iron Agents are Spheroid Particles with an Iron Core and Carbohydrate Shell iron carbohydrate oxyhydroxide shell coreSource of core sizes: Kudasheva and Cowman, J Biol Chem
    22. 22. IV Iron Agents Differ by Core Size and Shell Chemistry Iron Sucrose Ferric Gluconate bound bound sucrose gluconate & weakly associated sucrose coreKudascheva, J Inorg Biochem. 2004 Nov; 98(11):1757-69
    23. 23. Plasma Kinetics of IV Iron Agents:Ionic Fe+3>SFGC > iron sucrose >> iron dextran 100 % Initial Value Dexferrum® 50 Plasma IronDisappearance INFeD® Iron sucrose 10 SFGC Fe+3 0 20 40 60 80 Hours
    24. 24. Use of IV Iron Products 18 16 14 Venofer 12 Millions of Ferrlecit Units 10 Dexferrum 8 INFeD 6 Total IV 4 Iron 2 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008Notes: Ferric gluconate approved February 1999, iron sucrose approved November 2000Source: IMS Health National Sales Perspectives 1999-2008
    25. 25. Iron-Restricted Erythropoiesis Hematocrit, % 45 Anephric 1000 mg IV Iron Dextran 35 200 mL 25 RBCs 15 6.0 Reticulocytes Corrected, % 4.0 2.0 0 -12 -8 -4 0 +4 +8 +12 +16 +20 +24 Weeks rHuEPO 50 U/kg 3 /wk % Saturation 52 13 26 Ferritin 885 578 1036Eschbach JW et al. N Engl J Med. 1987;316:73-78.
    26. 26. Percent Hypochromic Red Cells (%HYPO)• Flow cytometry with 2 detectors – High angle for Hb content – Low angle for cell size – Allows construction of a histogram for Hb content Depleted Iron Stores Intense Erythropoietic Stimulus, eg ESA
    27. 27. Recommended Dosing of IV Iron Iron Ferric Iron Ferumoxytol Sucrose Gluconate Dextran 100 mg/ 2 min Observe patient for 510 mg/ 17 sec at least one hour Observe patient for at after test dose for 100 mg over 2-5 min 125 mg over signs and symptoms least 30 minutes after administration for signs Push (HDD-CKD) 200 mg over 2-5 min 10 min of anaphylaxis (Documented iron & symptoms of (HDD-CKD) (NDD-CKD) deficiency in whom oral hypersensitivity adminstration is (CKD) unsatisfactory or impossible) 100 mg/100 ml over 15 min (HDD-CKD) 125 mg/100 1000 mg at 6Infusion 300 mg/250 ml over 1.5hr ml over 1 hr mg/min Not(0.9% NaCl) (PDD-CKD) (HDD-CKD) (Not FDA-approved) recommended 400 mg/250 ml over 2.5hr (PDD-CKD)
    28. 28. Classification ofAdverse Iron Reactions
    29. 29. Serious IV Iron Reactions: Three syndromes• Anaphylaxis or anaphylactoid reaction – Sensitivity reaction, marked by allergic manifestations ♦ Hypotension with dyspnea, chest pain, angioedema, or urticaria – Immediate, sudden, severe, usually with test dose or 1st dose• Labile iron reaction – Non-allergic, commonly dose-related• Intolerance reaction – Presumed sensitivity reaction of any kind, may not be anaphylactic, preclude further treatment – Incidence of adverse reactions increases with underlying autoimmune disease or infection
    30. 30. Iron Dextran: Boxed Warning due to the Risk of Anaphylaxis IMPORTANT SAFETY INFORMATION Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection.• Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during iron dextran administration.• Administer a test dose prior to the first therapeutic dose.• During all iron dextran administrations, observe for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran injection and in situations where the test dose was tolerated.• Use iron dextran only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.
    31. 31. Incidence of Life-threatening Adverse Events (Anaphylaxis) Incidence of Adverse event Product (per 106 infusions) Comment Iron dextran 3.3-11.3 HMW dextran>LMW dextran Ferric gluconate 0.9 Iron sucrose 0.6Chertow GM et al Nephrol Dial Transplant 2006;21:378-382
    32. 32. Labile iron reactions• Incidence, severity varies by – Total dose administered – Rate of administration – Iron agent chemical class• Findings include: – Cramping, flank pain, chest pain – Hypotension without allergic manifestations – Lowering dose or slowing administration prevents recurrence (not a sensitivity reaction)
    33. 33. Intolerance reactions: Common,Mild IV Iron Reactions• Taste disturbance – “Minty” or “metallic” taste• Flushing – Without hypotension• Like labile iron reaction: – Transient – Abate after slowing infusion rate
    34. 34. Tolerability of IV iron products• Hemodialysis patients intolerant to iron dextran were shown to tolerate ferric gluconate• Hemodialysis patients intolerant to iron dextran or ferric gluconate were able to tolerate iron sucrose