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Iron Metabolism in Anaemia of Chronic Disease

Iron Metabolism in Anaemia of Chronic Disease. Guenter Weiss, MD Professor of Medicine Department of Internal Medicine, Clinical Immunology, and Infectious Diseases Medical University of Innsbruck Innsbruck, Austria. Anaemia of Chronic Disease (ACD).

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Iron Metabolism in Anaemia of Chronic Disease

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  1. Iron Metabolism in Anaemia of Chronic Disease Guenter Weiss, MD Professor of Medicine Department of Internal Medicine, Clinical Immunology, and Infectious Diseases Medical University of Innsbruck Innsbruck, Austria

  2. Anaemia of Chronic Disease (ACD) Most frequent anaemia among hospitalised patients Mild to moderate, normo-/normochromic Develops in patients with cellular immune activation Degree of anaemia correlated to immune activation

  3. Inflammatory Diseases Associated with the Development of ACD I. Infections (acute and chronic) Viral infections including HIV Bacterial Parasitic Fungal Helminth II. Malignancies Haematologic Solid tumor III. Autoimmune Rheumatoid arthritis Systemic lupus erythematosus and connective tissue diseases Vasculitis Inflammatory bowel disease IV. Chronic kidney disease and inflammation

  4. Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Impairment of erythrocyte progenitor formation • Inadequate formation and function of erythropoietin

  5. DcytB Fe2+ Fe2+ Fe2+ DMT1 Baso-lateral Luminal Intestinal Iron AbsorptionEnterocyte Fe3+ Tf Fe3+ Hephaestin - Ferroportin Heme Heme-oxygenase Fe2+ Hepcidin Fe + HCP-1 Slide courtesy of G. Weiss, MD Hentze MW, et al. Cell. 2010;142:24-28.

  6. Hepcidin Master Regulator of Iron Homeostasis • 20-,22-,25- AA peptide with antimicrobial potential • Expression induced by iron in the liver • Stimulated also by LPS and IL-6 by an iron independent pathway—acute phase protein (blocked by TNF-a) • Hepcidin over-expression leads to iron-deficient anaemia and hepcidin knock-out to iron overload • Hepcidin inhibits duodenal iron absorption and macrophage iron release • Mechanism of action:interferes with ferroportin, thereby leading to ferroportin degradation and blockage of iron export

  7. Control of Body Iron Homeostasis by Hepcidin Luminal Baso-lateral Macrophage Enterocyte Tf Fe3+ Fe3+ DcytB HO-1 Heph Fe2+ Fe2+ Fpn1 Fe2+ Fe2+ - DMT1 Heme Fe2+ - + HO-1 Heph Fe Fpn1 HCP-1? Hepcidin Tf-Fe+3 Fe2+ Tf Fe3+ - + Hepcidin Inflammation (IL-6, LPS) + Tf-Fe+3 Liver Slide courtesy of Dr. G. Weiss. Hentze MW, et al. Cell. 2010;142:24-28

  8. Pathophysiology—Cornerstones Iron retention within the reticulo-endothelial system Inadequate formation and function of erythropoietin Impairment of erythrocyte progenitor formation

  9. Pathways for Iron Retention in ACD A collaborative work of acute phase proteins (Hepcidin) and cytokines Hepcidin Hepcidin Duodenum Fe+2 + - Liver Fe+2 b ACD is an immunity driven disease IL-6 LPS IL-1 Monocyte TNF-α IL-10 CD3+ IFN-γ a Hepcidin + Fe+2 DMT1 + + Tf/TfR Fe+2 Ferritin Macrophage FP-1 - - + Fe+2 c Slide courtesy of Dr. G. Weiss. Weiss G. Biochim Biophys Acta. 2009;1790:682-693.

  10. Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Impairment of erythrocyte progenitor formation • Inadequate formation and function of erythropoietin

  11. Cytokine Effects on Epo Production IL-6 • Putative molecular mechanisms: • TNF-α/IL-1 induce NF-kB/GATA-2 with suppression of Epo gene promotor • Cytokine mediated radical formation negatively affects Epo-producing cells in the kidney • Interaction with Epo/EpoR signal transduction (JAK2/STAT5/MAPK/PKC) • Reduction of EpoR expression on CFU-e • Impaired Epo function because of reduced iron availabiltiy • Impaired Epo function due to impaired erythroid progenitor proliferation LPS IL-1 Monocyte TNF-α IL-10 CD3+ IFN-γ - - ? Epo - Kidneys Bone marrow Fe+2 Slide courtesy of Dr. G. Weiss. Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.

  12. Pathophysiology—Cornerstones Iron retention within the reticulo-endothelial system Inadequate formation and function of erythropoietin Impairment of erythrocyte progenitor formation

  13. Cytokine Effects on Erythroid Progenitor Cell Proliferation IL-6 LPS • Putative molecular mechanisms: • TNF-α -inhibitory effect via stroma cells • IL-1 acts primarily via IFN-g induction • IFN-γ induces apotposis of CFU-e • IFN-γ: caspase mediated apoptosis involving ceramide • IFN-γ induces NO; inhibits heme synthesis • Cytokines (IFN-γ) inhibit Epo and SCF formation and functionality • Iron restriction due to cytokines/hepcidin IL-1 Monocyte TNF-a IL-10 CD3+ IFN-abg - Epo - - Kidneys Bone marrow Fe+2 Slide courtesy of Dr. G. Weiss. Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.

  14. Hepcidin ACD Is an Immunity-Driven Disease Hepcidin Duodenum + Fe+2 - Liver Spleen Fe+2 IL-6 LPS IL-1 + Monocyte Fe+2 TNF-α IL-10 DMT1 CD4+ IFN-γ + Fe+2 + Ferritin Tf/TfR - - Macrophage - Epo FP-1 - - - Bone marrow Fe+2 Fe+2 Hepcidin Slide courtesy of Dr. G. Weiss.

  15. Positive Effects of ACD? Withholding iron from infectious pathogens in order to limit their growth1 Iron acquisition linked to pathogenicity in microbes, fungi? Reducing the supply of oxygen to rapid proliferating tissues Strengthening of immune response Weinberg ED. Biochim Biophys Acta. 2009;1790:600-605.

  16. Fe Fe MEF Iron Loading of Macrophages Impairs Their Ability to Kill Intracellular Pathogens by IFN- Mediated Pathways IFN- IFN- MEF, macrophage effector function - + MEF Macrophage Macrophage Slide courtesy of Dr. G. Weiss.Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023. Nairz M, et al. Cell Microbiol. 2009;11:1365-1381. Wessling-Resnick M. Annu Rev Nutr. 2010;30:105-122.

  17. Iron, Immunity, and Infection Iron affects cell-mediated immune function and thus host responses towards pathogens Microbes need iron for proliferation and pathogenicity Cytokines and acute-phase proteins regulate iron metabolism genes under inflammatory conditions, leading to Development of anaemia of chronic disease Iron limitation for pathogens Thus, ACD may result from the endeavour of the body to limit the availability of iron for invading pathogens and to strengthen antimicrobial immune effector pathways

  18. ACD Diagnosis Parameter ACD IDA Serum iron concentrationReduced to normal Reduced Transferrin levelsReduced to normal Increased Transferrin saturationReduced to normal Reduced Ferritin Normal to increased Reduced Serum transferrin receptorNormal Increased sTfR/log ferritin Low (<1) High (>2) Zinc protoporphyrin IXHigh High Percentage hypochromic RBC N/A High Cytokines (TNF, IL-1, IL-6)Increased Normal Cytokine levels are inversely correlated with the degree of anaemia Sole iron determination in serum is clinically not useful Slide courtesy of Dr. G. Weiss.

  19. Several Patients Suffer from a Combination of ACD and Iron Deficiency (ACD/IDA) as a Consequence of Inflammatory Anaemia and Blood Loss (Mostly on the Basis of Gastrointestinal or Urogenital Bleeding)

  20. Why Is the Differential Diagnosis Between ACD and ACD + IDA Important? Because these patients need contrasting therapies!

  21. Differential Diagnosis Between ACD and ACD Plus IDA Anaemia Biochemical or clinical evidence of inflammation Transferrin saturation <16% Rule out other causes of anaemia Ferritin <30 mg/L Ferritin 30–100 mg/L Ferritin >100 mg/L sTfR determination sTfR/log ferritin >2 sTfR/log ferritin <1 ACD/IDA ACD/IDA ACD With permission from Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.

  22. Diagnostic Window with sTfR/log Ferritin How suitable are other haematologic parameters (MCH, MCV, hepcidin) for the differential diagnosis of ACD vs ACD/IDA? With permission from Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023. Anaemia Biochemical or clinical evidence of inflammation Transferrin saturation <16% Ferritin <30 mg/L Ferritin >100 mg/L Ferritin 30–100 mg/L sTfR determination sTfR/log ferritin >2 sTfR/log ferritin <1 >1 to <2? ACD/IDA ACD/IDA ACD

  23. Valuable Diagnostic Tools for the Differential Diagnosis Between ACD and ACD/IDA (Separated by the sTfR/log Ferritin Ratio) sTfR and CHr are also used in combination for the Thomas blot to estimate iron availability for erythropoiesis in patients with inflammation

  24. Assessment of Iron Status in the Setting of Inflammation and Anaemia Hepcidin expression is more affected by the needs of iron for erythropoiesis than by inflammation Hepcidin levels closely correlate to sTfR/ log ferritin ratio in patients with inflammation, thus both parameters (hepcidin currently not widely available) can differentiate between absolute vs functional iron deficiency Haematologic indices (eg, MCH, CHr, and combinations with sTfR) may add additional information on true iron availability for erythropoiesis in patients with ACD and/or sTfR/ log ferritin between 1 and 2

  25. ACD Best Therapy Treatment or Cure of the Underlying Disease!

  26. Current Therapeutic Options in ACD Blood transfusions Recombinant human erythropoietin Iron Therapeutic measures are aimed to increase haemoglobin levels in ACD patients However, the impact of such interventions on iron overload on the reticulo-endothelial system, immunity, radical formation, and most importantly the underlying disease, are largely unknown

  27. ACD TherapyBlood Transfusions Can be readily used for rapid correction of severe anaemia Immediate increase of haemoglobin 1 unit contains ~200 mg of iron Uncertainties Negative effects on immune effector function Risk of infections In some studies, associated with increased risk of cancer (Possible bias – more need for transfusions may reflect more advanced disease) Negative effects seen with transfusions older than 3 weeks? Effects also seen with leukocyte-depleted products?

  28. ACD TherapyIron NO, if infections or cancer underlie ACD; ferritin >100 ng/mL May favor proliferation of pathogens By countering iron-withholding strategy By impairing immune function May not reach erythroid cells due to diversion into reticulo-endothelial system May cause tissue damage via formation of toxic radicals by the Fenton reaction (triggered by TNF-a) However, in autoimmune diseases, iron may inhibit pro-inflammatory immune effector pathways, thus reducing disease activity Kaltwasser JP, et al. J Rheumatol 2001; 28:2430-2436. Weiss G, et al. Kidney Int. 2003;64:572-578.

  29. ACD TherapyIron What to do in ACD with true iron deficiency (ACD and IDA)? Iron is needed for basic metabolic functions and cannot be mobilized How to substitute iron? Iron is very poorly absorbed in ACD (down-regulation of ferroportin in the duodenum by hepcidin)1 1. Theurl I, et al. Blood. 2009;113:5277-5286.

  30. ACD TherapyIron What to do in ACD with true iron deficiency (ACD and bleeding)? Iron is needed for basic metabolic functions and cannot be mobilized How to substitute iron? Iron is very poorly absorbed in ACD (down-regulation of ferroportin in the duodenum by hepcidin)1 IV iron administration is very effective in inflammatory bowel disease and ACD but also increases haemoglobin in cancer patients2 Caveat No prospective studies on such intervention on the course of underlying malignant diseases Retrospective analyses: iron supplementation may negatively impact disease progression in cancer 1. Theurl I, et al. Blood. 2009;113:5277-5286. 2. Auerbach M, et al. J Clin Oncol. 2004;22:1301-1307.

  31. Iron Therapy in Dialysis Patients Prospective study investigating the incidence of infectious complications in ESRD patients receiving IV iron therapy Group 1: ferritin <100 ng/mL and TfS <20% Group 2: ferritin >100 ng/mL and TfS >20% Observation period: 1 year Frequency of septicaemia in Group 2 was 2.5-fold higher than in Group 1 Too much iron may be harmful in ACD! Plotkin SA. Clin Infect Dis. 2004;38:1030-1039.

  32. Why Is the Differential Diagnosis Between ACD and ACD + IDA Important? Because these patients need contrasting therapies!!! No iron in ACD Iron needed in ACD/IDA

  33. Therapy—Erythropoietin-Stimulating Agents (ESA) Effective in increasing haemoglobin levels in ACD: patients with cancer, infections, and autoimmune disorders Response rate to treatment depends on underlying disease, stage, immune activation, and iron availability Increase of haemoglobin with ESA treatment is associated with a gain in QOL and a decreased need for blood transfusions Uncertainties based on recent studies indicating increased mortality in certain patient groups in association with ESA therapy; biologic role of EpoR on tumor cells undefined

  34. Therapeutic End Points Optimal haemoglobin related to the course of the disease underlying ACD, minimization of cardiovascular risk, best QOL? The maximum incremental gain in QOL in patients with anaemia and cancer occurs (upon anaemia treatment with ESA) when the haemoglobin is between 11 and 13 g/dL1 However, a normal target haemoglobin may not be optimal! 1. Crawford J, et al. Cancer. 2002;95:888-895.

  35. Therapeutic End Points Normalization of haemoglobin levels in end stage renal disease patients was associated with a significant increase of cardiovascular mortality as compared with patients with haemoglobin levels below the normal range1 Dialysis patients: risk of death was highest with haematocrit levels between 33% and 36%2 Avoid over-correction of anaemia (Hgb >12 g/dL) Currently recommended therapeutic end point: Hgb 11–12 g/dL (some guidelines cite up to13 g/dL for men) 1. Besarab A, et al. N Engl J Med. 1998;339:584-590. 2. Locatelli F, et al. Nephrol Dial Transplant. 2004;19:121-132.

  36. Anaemia of Chronic Disease Unanswered Questions—THERAPY Effects of anaemia correction by different treatments (iron, transfusion, ESA) on the underlying disease Evaluation of the positive effects(radio/chemosensitizer, cardiac performance, QOL) vs the putative negative effects (feeding of pathogens, immunodepression) of various treatments

  37. Anemia of Chronic Disease Unanswered Questions—THERAPY Urgent need for randomized, prospective trials Definition of therapeutic end points, which are associated with Good QOL Best outcome concerning the underlying disease Cardiovascular endpoints Emerging therapies (Anti)-cytokine therapies Iron chelation Hepcidin/ferroportin agonists/antagonists Combination therapy (Epo + iron) Epo R modulation

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