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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 Anemia An Approach to Anemia ?

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

4 Evaluating Hemolysis The Bucket with The Hole

5 Retic Hemoglobin Level Loss or Hemolysis

6 Reticulocytes Retic #=1/mm Retic %= 20% Retic # = 1/mm Retic % = 30% Corr Retic = Retic x hgb/nl hgb 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 Retic Hi Retic Low Anemia An Approach to Anemia

8 Retic Hi Retic Low Anemia MCV HiMCV NlMCV Lo An Approach to Anemia

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

10 Retic Hi Retic Low Anemia DestructionLossMCV HiMCV NlMCV Lo Iron (Lead) Thalassemia Fragmentation Sideroblastic Anemia acquired congenital

11 Diagnostic Tests Low 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 A 2 What if Hemoglobin Electropheresis is normal? If iron nl, then not beta-thal BUT alpha-thal carrier state has normal HPLC

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

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

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

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

18 Iron Metabolism Plasma Fe-Tf RBC Bone Marrow Duodenum Spleen 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 Hepcidin Adequate Iron Intake Inflammation IL-6 RBC turnover Hypoxia Hemochromatosis Increased Decreased Anemia?

21 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 Plasma Fe-Tf 3 mg RBC Spleen 20 mg/d

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 Fpn Low HepcidinHigh Hepcidin Iron ferritin Hepcidin Iron release into Plasma lysosome Enterocytes Macrophages DMT1

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

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

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

29 Treatment of Iron Deficiency Oral always preferred ?low dose equally effective (325 mg FeSO 4 ) ?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 NTBI circulates in the plasma Liver Insoluble iron complexes are deposited in body tissues Pancreas Endocrine Serum transferrin iron binding capacity exceeded Iron overload Cardiac Reproductive NTBI = non-transferrin bound iron Adapted from: Olivieri NF, et al. Blood. 1997;89: ; Olivieri NF. N Engl J Med. 1999;341: Excess iron promotes free radical formation

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

32 Diseases With High Risk of Iron Overload Diseases requiring frequent or repeated transfusions  -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 iron 1 Chronic transfusion-dependent patients have an iron excess of ~0.4 to 0.5 mg/kg/day 2 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 transfusions 1 Iron overload can result in iron-related dysfunction of key organs 1,2 1. Porter JB. Br J Haematol. 2001;115:239– Kushner JP, et al. Hematology. 2001;47–61.

34 Iron Metabolism Plasma Fe-Tf Hepcidin Iron Signal Erythropoiesis Signal RBC Bone Marrow Duodenum Spleen 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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