Iron metabolism - Fortbildung USZ
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Iron metabolism and disorders Georg Stüssi DIM Fortbildung 8.12.2008 Iron metabolism Iron deficiency anemia Anemia of chronic disorders Iron overload Distribution of iron in adults • Adult men 35‐45mg iron/kg BW • Each RBC contains 109 atoms of iron • 2x1020 iron atoms are incorporated into RBC/day • 1 g/L Ferritin corresponds to storage of 8‐10mg iron. N. Andrews, NEJM, 1999 Enteral resorption • Proximal jejunum/duodenum • Resorption: 10% of nutritional iron supply • Increased resorption: 40% • DMT1 (Divalent metal ion transporter 1) • Ferric reductase Fe3+ => Fe2+ • Ferroportin: • Basolateral transporters Heme and non‐heme iron Iron uptake HFE • • • • • • Chromosome 6 (6p21.3) Atypical HLA molecule Aggregates with 2‐microglobulin No peptide binding Membrane protein Inhibits the cellular iron uptake by interacting with the transferrin receptor 1. Hepcidin – Key player in iron homeostasis R. Fleming, NEJM, 2005 Hepcidin First description Nemeth et al., Science 2001 Synthesis in the liver Deficiency: Iron overload Overexpression: Hypochromic microcytic anemia • Increased synthesis upon stimulation with IL‐6 (inflammation) • • • • Summary • Enteral resorption – DMT1 – HCP1 – Ferric reductase • Serum transport – Transferrin • Cellular uptake – TFR1/2 • Basolateral membrane – Ferroportin – Hephaestin • Regulation – HFE (direct) – Hepcidin (indirect) Overview iron metabolism Iron metabolism Iron deficiency anemia Anemia of chronic disorders Iron overload Anemia diagnostics Iron deficiency anemia Laboratory evaluation • • • • Serum iron Ferritin Transferrin Total iron binding capacity (TIBC) – Transferrin saturation • Soluble transferrin receptor (sTfR) Serum iron Serum Eisen • Non‐bound iron in the serum • Large diurnal variability – Concentration evening = ½ morning • No test for iron deficiency Ferritin Ferritin and iron deficiency Low ferritin = Iron deficiency Transferrin/TIBC Transferrin • Produced in the liver • One molecule binds to iron • Total iron binding capacity (TIBC) • • • • Iron 18 mol/l TIBC 56 mol/l Saturation: 32% Iron deficiency < 16% Soluble transferrin receptor (sTfR) • • • Shedded form of TfR > 80% of the TfR is expressed in the erythroid bone marrow sTfR Erythroid activity in the bone marrow Increased sTfR Increased erythropoiesis – Hemolysis, Bleeding – MDS (ineffective Erythropoiesis) TfR increased/erythroblast – Iron deficiency Iron deficiency vs chronic inflammation Iron Normal Iron deficiency Inflammation TIBC sTfR Ferritin Time course of IDA Normal Iron Ferritin Hb normal normal Iron deficiency normal Anemia Microcytic anemia normal MCV normal normal DD Iron deficiency Iron supplementation Venofer • Calculation of iron supplementation – BW (kg) x [Target‐Hb – actual Hb (g/l)] x 2.4 + 500mg – Simple: 200mg iron / 1g/dl Hemoglobin • No more than 500mg/week • No more than 300 (200) mg/infusion • Test dosage Iron carboxymaltose (Ferinject®) • 15mg/kg BW • Maximum 1000mg/week 1000mg 297.00 SFR 1000mg 336.90 SFR bei Verwendung von Ampullen à 500mg 363.10 SFR bei Verwendung von Ampullen à 100mg Response after iron supplementation Reticulocyte Hb (CHr) Reticulocytes Nails/hair Hemoglobin RBC indices Ferritin steady state 4 days 5‐10 days 1‐2 weeks 1‐2 months 3 months 3 months Iron metabolism Iron deficiency anemia Anemia of chronic disorders Iron overload Anemia of chronic disorder G Weiss, NEJM, 2005 Iron deficiency vs ACD vs both Treatment of ACD Iron metabolism Iron deficiency anemia Anemia of chronic disorders Iron overload Iron overload Hemochromatosis Hemochromatosis Anemia and iron overload • With iron overload => anemias with ineffective erythropoiesis – Thalassemia syndromes – Congenital dyserythropoitic anemias – Sideroblastic anemias • Without iron overload => anemias with peripheral destruction – Autoimmune hemolytic anemias – Sickle cell anemia – Paroxysmal nocturnal hemoglobinuria 200–250 mg Iron Deferoxamin (Desferal®) Kontinuierliche s.c.‐Applikation erforderlich. Medikamenten‐Preis bei 2g pro Tag: 50Fr/Tag, 1‘500Fr/Monat Deferiprone (Ferriprox®) Bei kurzer Halbwertszeit Verteilung über den ganzen Tag (bis 10 Tabletten). Medikamenten‐Preis bei 10x500mg pro Tag: 45Fr/Tag, 1‘350Fr/Monat Deferasirox (Exjade®) Einmal tägliche Einnahme. Auf nüchternen Magen, ≥ 30 min. vor einer Mahlzeit. Die Tabletten werden in Wasser oder Orangensaft aufgelöst. Medikamenten‐Preis bei 3x500mg pro Tag: 125Fr/Tag, 3‘750Fr/Monat Vielen Dank für Ihre Aufmerksamkeit !