8 An Approach to AnemiaAnemiaRetic HiRetic LowMCV LoMCV NlMCV Hi
9 An Approach to Anemia Anemia Retic Hi Retic Low Loss Destruction MCV LoMCV NlMCV HiTissueOn FloorOccultIntrinsicExtrinsicSplenicMechanicalRecoveryIron(Lead)ThalFragsChronic DiseaseRenalMixedMild/TreatedEarlyTransfusedEndocrineIntrinsic BMDilutionB12FolateLiverETOHThyroidToxicMDS
10 Anemia Retic Hi Retic Low Loss Destruction MCV Lo MCV Nl MCV Hi Iron (Lead)ThalassemiaFragmentationSideroblastic Anemiaacquiredcongenital
11 Diagnostic Tests Low Retic Microcytic Iron/TIBC vs. FerritinHemoglobin ElectropheresisGENETIC SCREENING OF FAMILYThe “Normal” ElectropheresisSmear?Value of MCV and RDWLead?
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 firstmay mask beta-Thal by decreasing Hgb A2What if Hemoglobin Electropheresis is normal?If iron nl, then not beta-thalBUT alpha-thal carrier state has normal HPLC
14 Diagnostic Tests Low Retic Microcytic Iron/TIBC vs. FerritinHemoglobin ElectropheresisGENETIC SCREENING OF FAMILYThe “Normal” ElectropheresisSmear?Value of MCV and RDWLead?
15 Body Iron Distribution and Storage Dietary ironUtilizationDuodenum(average, 1-2 mgper day)Muscle(myoglobin;300 mg)Liver(1000 mg)Bonemarrow(300 mg)Circulatingerythrocytes(hemoglobin;1800 mg)Reticuloendothelialmacrophages(600 mg)Sloughed mucosal cellsDesquamation/menstruationOther blood loss(average, 1-2 mg per day)StorageironPlasmaIron losstransferrin(3 mg)Andrews NC. N Engl J Med. 1999;341:1986–1995.
16 Iron Metabolism Spleen Liver RBC Plasma Fe-Tf Bone Marrow Duodenum Increased Hepcidin in inflammation blocks the marked iron movementsBone MarrowDuodenumTomas Ganz ASH 2006
17 Iron Metabolism 20 mg/d Spleen RBC Plasma Fe-Tf Bone Marrow Duodenum Increased Hepcidin in inflammation blocks the marked iron movementsBone MarrowDuodenumTomas Ganz ASH 2006
18 Iron Metabolism Spleen RBC Plasma Fe-Tf Bone Marrow Duodenum Increased Hepcidin in inflammation blocks the marked iron movementsBone MarrowDuodenumTomas Ganz ASH 2006
19 Hepcidin Small molecule which blocks iron movement Evolutionary conservationProblems with assaysRegulationIncreased by dietary iron <1dayCongenital absence>>juvenile hemochromatosisDecreased by anemia, hypoxia
20 Hepcidin Regulation Hepcidin Adequate Iron Intake Inflammation Hypoxia IncreasedInflammationIL-6HypoxiaHepcidinAnemia?In irradiated mice, anemia does not decrease hepcidien, it is the rbc turnover (phenylhydraxine hemolysis in mice)DecreasedRBC turnoverHemochromatosis
21 Hepcidin and Inflammation Suppressed in hours by IL-6 (?others)Not in IL-6 deficient micePlasma Iron turnover q3hrs30% drop in 1 hour if recycling blocked“Anemia of Acute Disease”??Role in host defensePlasmaFe-Tf3 mgRBCSpleen20 mg/dBone MarrowTomas Ganz ASH 2006
22 Infectious Risk of Iron Overload BacterialHepcidin, lactoferrin, transferrin bacteriostatic in vitroListeria, Yersenia, AeromonusCunninghamella bertholletiaeFungalIncreased growth in vitroCase reports of increased Mucor in MDS pts? Increased risk with chelation with streptomyces pilosisBoth transferrin and the structurally related protein, lactoferrin, are bacteriostatic in vitro for a number of bacteria. Lactoferrin is a prominent component of the granules of polymorphonuclear leukocytes. The protein is released at high concentrations by the cells in areas of infection. There is also evidence that iron overload per se compromises the ability of phagocytes to kill microorganisms. A combination of problems likely contribute to the increase in susceptibility to infection in these patients. Therefore, iron overload does not produce the susceptibility to infection seen with defects in more central systems (e.g., chronic granulomatous disease). Nonetheless, a number of infections, often with unusual organisms, have been reported in patients with iron overload (Bullen, Spaulding et al. 1991); (Abbott, Galloway et al. 1986); (Christopher 1985).•Abbott, M., A. Galloway, et al. (1986). Haemochromatosis presenting with a double Yersinia infection. Journal of Infection 13: •Boelaert, J., G. van Roost, et al. (1988). The role of desferrioxamine in dialysis-associated mucormycosis: report of three cases and review of the literature. Clinical Nephrology 29: •Bullen, J. J., P. B. Spaulding, et al. (1991). Hemochromatosis, iron and septicemia caused by Vibrio vulnificus. Archives of Internal Medicine 151: •Christopher, G. (1985). Escherichia coli bacteremia, meningitis, and hemochromatosis. Archives of Internal Medicine 145: 1908.•Daly, A., L. Velzquez, et al. (1989). Mucormycosis: association with deferoxamine therapy. American Journal of Medicine 87: •Robins-Browne, R. and J. Prpic (1985). Effects of iron and desferrioxamine on infections with Yersinia enterocolitica. Infection and Immunity 47: •Windus, D., T. Stokes, et al. (1987). Fatal Rhizopus infections in hemodialysis patients receiving deferoxamine. Annals of Internal Medicine 107:
23 Hepcidin and Iron Transport Low HepcidinHigh HepcidinIronIronDMT1ferritinferritinlysosomeFpnThis works well in the enterocytes, which are then sloughed q2-3 days, but leads to BM iron stores artefactually elevated.FpnEnterocytesMacrophagesHepcidinIron release into Plasma
24 Erythropoiesis Signal Iron MetabolismIron SignalSpleenHepcidinHepcidinRBCPlasmaFe-TfHepcidinIncreased Hepcidin in inflammation blocks the marked iron movementsHepcidinBone MarrowDuodenumErythropoiesis SignalTomas Ganz ASH 2006
25 Erythropoiesis Signal Iron MetabolismIron SignalSpleenHepcidinHepcidinRBCPlasmaFe-TfHepcidinIncreased Hepcidin in inflammation blocks the marked iron movementsHepcidinBone MarrowDuodenumErythropoiesis SignalTomas Ganz ASH 2006
26 Evaluating Iron Stores vs. Response FerritinSensitive/specificExcept increased in inflammation, liver disease, malignancyFe/TIBC (Transferrin) and SaturationDecreased in inflammation, malignancyTHEREFORE:Iron TrialSerum (soluble) Transferrin ReceptorMediates iron transfer into cellIncreased in Fe-def, rapid cell productionCHR-Retic Hemoglobin Concentration?Follow-up GI Eval10 -15% with malignancy?Only if ferritin <100?Anemia of chronic disease and iron deficiency anemia, the most common forms of anemia, are differentiated primarily by estimates of iron status. Standard measures of iron status, such as ferritin, total iron-binding capacity, and serum iron are directly affected by chronic disease. In contrast, soluble transferrin receptor (sTfR) is elevated in iron deficiency but is not appreciably affected by chronic disease. sTfR is elevated in subjects with hyperplastic erythropoiesis (eg, hemolytic anemia, beta-thalassemia, polycythemia, etc) and depressed in subjects with hypoplastic erythropoiesis (eg, chronic renal failure, aplastic anemia, or post-transplant anemia). Transferrin receptor (TfR) is the major mediator of iron uptake by cells. TfR is a transmembrane, disulfide-linked dimer of two identical subunits that binds and internalizes diferric transferrin, thereby delivering iron to the cell cytosol. When a cell needs iron, TfR expression is increased to facilitate iron uptake. Since the major use of iron is for hemoglobin synthesis, about 80% of total TfR is on erythroid progenitor cells. Soluble transferrin receptor arises from proteolysis of the intact protein on the cell surface, leading to monomers that can be measured in plasma and serum. Thus, the concentration of sTfR in plasma or serum is an indirect measure of total TfR. The serum level of sTfR reflects either the cellular need for iron or the rate of erythropoiesis. The concentration of sTfR in plasma or serum is elevated in iron deficiency. The concentration of sTfR in plasma or serum is correlated with erythron transferrin uptake, a ferrokinetic measure of erythropoietic activity.Postgraduate Medical Journal 2004;80: risk of colon CA with iron deficiency
27 Colon CA in Iron Deficiency Am J Gastroenterol ;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’sNl. <2.5%, Fe-deficient >10% correlates with Fe responseReticulocyte Hgb Concentration?Sensitive, specific for diagnosis in dialysis ptsResponds to iron in 48 hoursSerum (soluble) Transferrin ReceptorIncreased 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 CWhen to use IV ironRecent decreased risk of anaphylaxisPoor complianceSide-effects, etcPoor AbsorptionJejeunal/duodenal diseaseSprue“Chronic Disease”Anemia of MalignancyIron replacement at low doses: Am J Med Volume 118, Issue 10, Pages (October 2005)
30 Iron Overload Iron overload Serum transferrin iron binding capacity exceededNTBI circulates in the plasmaInsoluble iron complexes are deposited in body tissuesExcess iron promotes free radical formationCardiacLiverPancreasReproductiveEndocrineNTBI = non-transferrin bound ironAdapted from: Olivieri NF, et al. Blood. 1997;89: ; Olivieri NF. N Engl J Med. 1999;341:
31 Basic Causes of Iron Overload Acquired iron overload1TransfusionalIneffective erythropoiesisToxic ingestion (very rare in adults)HereditaryHFE hemochromatosisHomozygous C282Y mutation in HFE gene2Defective regulatory receptor in intestine results in increased absorption of ironOther genetic mutations1. 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 repeated transfusions-Thalassemia (major and intermedia)Sickle cell anemiaMyelodysplastic syndromes (MDS)Aplastic anemiaRare chronic anemiasBlackfan-Diamond anemia (red cell aplasia)Fanconi anemia (hypoplastic anemia)Others
33 Iron Loading From Blood Transfusions 1 unit of blood contains 200 mg of iron1Chronic transfusion-dependent patients have an iron excess of ~0.4 to 0.5 mg/kg/day2There is no physiologic mechanism to remove excess ironTherefore, iron accumulates with repeated blood transfusionsSigns of iron overload can be seen anywhere between 10 and 20 transfusions1Iron overload can result in iron-related dysfunction of key organs1,21. Porter JB. Br J Haematol. 2001;115:239–252.2. Kushner JP, et al. Hematology. 2001;47–61.
34 Erythropoiesis Signal Iron MetabolismIron SignalSpleenHepcidinHepcidinRBCHepcidinPlasmaFe-TfIncreased Hepcidin in inflammation blocks the marked iron movementsBone MarrowDuodenumErythropoiesis SignalTomas Ganz ASH 2006
36 Hemochromatosis Diagnosis Consider in :Chronic fatigueArthropathyImpotenceHyperpigmentationCirrhosisDMCardiomyopathyScreening elevated Fe sat or Ferritin
37 Hemochromatosis Diagnosis Fe/TIBC >60%Decreased in early, family-hx diagnosisDecreased with inflammationHFE testing (C282Y)Compound hetero C282Y/H63DRarely a problem, unless ETOHFerritin to quantify iron overloadIF confusing, consider MRI
38 Hemochromatosis Management Ferritin >1000 associated with sxFe/TIBC saturation >75%Unstable/labile iron with increased risk of oxidant damageUrgent phlebotomyIF sx or end organ damageWeekly to <1000 ferritin as toleratedTarget ferritin <50? Role of deferasirox (Exjade)Rarely in hemochromatosisintolerance