Iron metabolism

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 !