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Running the Ironman Brad Lewis SFGH

Running the Ironman Brad Lewis SFGH. Blood alone moves the wheels of history. Benito Mussolini Blood will tell, but often it tells too much. Don Marquis. An Approach to Anemia. Anemia. ?. An Approach to Anemia. Anemia. ?. Smear LDH Bilirubin Iron Studies B12 Coombs.

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Running the Ironman Brad Lewis SFGH

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  1. Running the IronmanBrad LewisSFGH Blood alone moves the wheels of history. Benito Mussolini Blood will tell, but often it tells too much. Don Marquis

  2. An Approach to Anemia Anemia ?

  3. An Approach to Anemia Anemia ? Smear LDH Bilirubin Iron Studies B12 Coombs

  4. Evaluating HemolysisThe Bucket with The Hole

  5. Evaluating HemolysisThe Bucket with The Hole Retic Hemoglobin Level Loss or Hemolysis

  6. Reticulocytes Retic #=1/mm Retic %= 20% Corr Retic = Retic x hgb/nl hgb Retic # = 1/mm Retic % = 30% RPI = corrected retic. count/Maturation time (Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for 25%, and 2.5 for 15%.)

  7. An Approach to Anemia Anemia Retic Hi Retic Low

  8. An Approach to Anemia Anemia Retic Hi Retic Low MCV Lo MCV Nl MCV Hi

  9. An Approach to Anemia Anemia Retic Hi Retic Low Loss Destruction MCV Lo MCV Nl MCV Hi Tissue On Floor Occult Intrinsic Extrinsic Splenic Mechanical Recovery Iron (Lead) Thal Frags Chronic Disease Renal Mixed Mild/Treated Early Transfused Endocrine Intrinsic BM Dilution B12 Folate Liver ETOH Thyroid Toxic MDS

  10. Anemia Retic Hi Retic Low Loss Destruction MCV Lo MCV Nl MCV Hi Iron (Lead) Thalassemia Fragmentation Sideroblastic Anemia acquired congenital

  11. Diagnostic TestsLow Retic Microcytic Iron/TIBC vs. Ferritin Hemoglobin Electropheresis GENETIC SCREENING OF FAMILY The “Normal” Electropheresis Smear? Value of MCV and RDW Lead?

  12. 23 yo Chinese Woman 13 wks Pregnant Hgb 11, MCV 72 What Tests?

  13. 23 yo Chinese Woman 13 wks Pregnant Hgb 11, MCV 72 What Tests? Iron Studies first may mask beta-Thal by decreasing Hgb A2 What if Hemoglobin Electropheresis is normal? If iron nl, then not beta-thal BUT alpha-thal carrier state has normal HPLC

  14. Diagnostic TestsLow Retic Microcytic Iron/TIBC vs. Ferritin Hemoglobin Electropheresis GENETIC SCREENING OF FAMILY The “Normal” Electropheresis Smear? Value of MCV and RDW Lead?

  15. Dietary iron Duodenum (average, 1-2 mg Utilization Utilization per day) Plasma transferrin (3 mg) Muscle Bone marrow (myoglobin; (300 mg) 300 mg) Circulating erythrocytes Storage (hemoglobin; iron 1800 mg) Sloughed mucosal cells Desquamation/menstruation Other blood loss Reticuloendothelial (average, 1-2 mg per day) Liver macrophages (1000 mg) (600 mg) Iron loss Body Iron Distribution and Storage Andrews NC. N Engl J Med. 1999;341:1986–1995.

  16. Iron Metabolism Spleen Liver RBC Plasma Fe-Tf Bone Marrow Duodenum Tomas Ganz ASH 2006

  17. Iron Metabolism 20 mg/d Spleen RBC Plasma Fe-Tf Bone Marrow Duodenum Tomas Ganz ASH 2006

  18. Iron Metabolism Spleen RBC Plasma Fe-Tf Bone Marrow Duodenum Tomas Ganz ASH 2006

  19. Hepcidin • Small molecule which blocks iron movement • Evolutionary conservation • Problems with assays • Regulation • Increased by dietary iron <1day • Congenital absence>>juvenile hemochromatosis • Decreased by anemia, hypoxia

  20. Hepcidin Regulation Adequate Iron Intake Increased Inflammation IL-6 Hypoxia Hepcidin Anemia? Decreased RBC turnover Hemochromatosis

  21. 20 mg/d Spleen RBC Plasma Fe-Tf 3 mg Hepcidin and Inflammation • Suppressed in hours by IL-6 (?others) • Not in IL-6 deficient mice • Plasma Iron turnover q3hrs • 30% drop in 1 hour if recycling blocked • “Anemia of Acute Disease” • ??Role in host defense Bone Marrow Tomas Ganz ASH 2006

  22. Infectious Risk of Iron Overload • Bacterial • Hepcidin, lactoferrin, transferrin bacteriostatic in vitro • Listeria, Yersenia, Aeromonus • Cunninghamella bertholletiae • Fungal • Increased growth in vitro • Case reports of increased Mucor in MDS pts • ? Increased risk with chelation with streptomyces pilosis

  23. Hepcidin and Iron Transport Low Hepcidin High Hepcidin Iron Iron DMT1 ferritin ferritin lysosome Fpn Enterocytes Macrophages Fpn Hepcidin Iron release into Plasma

  24. Hepcidin Hepcidin Iron Metabolism Iron Signal Spleen Hepcidin RBC Plasma Fe-Tf Hepcidin Bone Marrow Duodenum Erythropoiesis Signal Tomas Ganz ASH 2006

  25. Hepcidin Hepcidin Iron Metabolism Iron Signal Spleen Hepcidin RBC Plasma Fe-Tf Hepcidin Bone Marrow Duodenum Erythropoiesis Signal Tomas Ganz ASH 2006

  26. Evaluating IronStores vs. Response • Ferritin • Sensitive/specific • Except increased in inflammation, liver disease, malignancy • Fe/TIBC (Transferrin) and Saturation • Decreased in inflammation, malignancy • THEREFORE: • Iron Trial • Serum (soluble) Transferrin Receptor • Mediates iron transfer into cell • Increased in Fe-def, rapid cell production • CHR-Retic Hemoglobin Concentration? • Follow-up GI Eval • 10 -15% with malignancy • ?Only if ferritin <100?

  27. Colon CA in Iron Deficiency Am J Gastroenterol. 2007;102(1):82-88.

  28. Evaluating Iron in Inflammation • Bone Marrow Iron Stores?? • Saturation (Fe/Transferrin) <8-10% • Iron Trial • ?IV repletion, check 1 month • % Hypochromic RBC’s • Nl. <2.5%, Fe-deficient >10% correlates with Fe response • Reticulocyte Hgb Concentration? • Sensitive, specific for diagnosis in dialysis pts • Responds to iron in 48 hours • Serum (soluble) Transferrin Receptor • Increased in Fe deficiency or increased RBC turnover

  29. Treatment of Iron Deficiency • Oral always preferred • ?low dose equally effective (325 mg FeSO4) • ?role for Vitamin C • When to use IV iron • Recent decreased risk of anaphylaxis • Poor compliance • Side-effects, etc • Poor Absorption • Jejeunal/duodenal disease • Sprue • “Chronic Disease” • Anemia of Malignancy

  30. Iron Overload Iron overload Serum transferrin iron binding capacity exceeded NTBI circulates in the plasma Insoluble iron complexes are deposited in body tissues Excess iron promotes free radical formation Cardiac Liver Pancreas Reproductive Endocrine NTBI = non-transferrin bound iron Adapted from: Olivieri NF, et al. Blood. 1997;89:739-761; Olivieri NF. N Engl J Med. 1999;341:99-109.

  31. Basic Causes of Iron Overload • Acquired iron overload1 • Transfusional • Ineffective erythropoiesis • Toxic ingestion (very rare in adults) • Hereditary • HFE hemochromatosis • Homozygous C282Y mutation in HFE gene2 • Defective regulatory receptor in intestine results in increased absorption of iron • Other genetic mutations 1. Porter JB. Br J Haematol. 2001;115:239–252. 2. Feder JN, et al. Nat Genet. 1996;13:399–408.

  32. Diseases With High Risk of Iron Overload • Diseases requiring frequent or repeatedtransfusions • -Thalassemia (major and intermedia) • Sickle cell anemia • Myelodysplastic syndromes (MDS) • Aplastic anemia • Rare chronic anemias • Blackfan-Diamond anemia (red cell aplasia) • Fanconi anemia (hypoplastic anemia) • Others

  33. Iron Loading From Blood Transfusions • 1 unit of blood contains 200 mg of iron1 • Chronic transfusion-dependent patients have an iron excess of ~0.4 to 0.5 mg/kg/day2 • There is no physiologic mechanism to remove excess iron • Therefore, iron accumulates with repeated blood transfusions • Signs of iron overload can be seen anywhere between 10 and 20 transfusions1 • Iron overload can result in iron-related dysfunction of key organs1,2 1. Porter JB. Br J Haematol. 2001;115:239–252. 2. Kushner JP, et al. Hematology. 2001;47–61.

  34. Iron Metabolism Iron Signal Spleen Hepcidin Hepcidin RBC Hepcidin Plasma Fe-Tf Bone Marrow Duodenum Erythropoiesis Signal Tomas Ganz ASH 2006

  35. Hereditary Hemochromatosis • Autosomal recessive • HFE gene in 90% (hepcidin deficiency) • Rare Transferrin Receptor 2 defect • Variable penetrance, caucasions only • Severe Disease • Hemojuvelin • HAMP (hepcidin) • Autosomal dominant • Rare, ferroportin defect • Severe, early onset, Hepatocytes only • Other rare defects • DMT1(microcytosis), atransferrenemia, ceruloplasmin

  36. Hemochromatosis Diagnosis • Consider in : • Chronic fatigue • Arthropathy • Impotence • Hyperpigmentation • Cirrhosis • DM • Cardiomyopathy • Screening elevated Fe sat or Ferritin

  37. Hemochromatosis Diagnosis • Fe/TIBC >60% • Decreased in early, family-hx diagnosis • Decreased with inflammation • HFE testing (C282Y) • Compound hetero C282Y/H63D • Rarely a problem, unless ETOH • Ferritin to quantify iron overload • IF confusing, consider MRI

  38. Hemochromatosis Management • Ferritin >1000 associated with sx • Fe/TIBC saturation >75% • Unstable/labile iron with increased risk of oxidant damage • Urgent phlebotomy • IF sx or end organ damage • Weekly to <1000 ferritin as tolerated • Target ferritin <50 • ? Role of deferasirox (Exjade) • Rarely in hemochromatosis • intolerance

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