Iron Metabolism

1. Blood-Hematopoiesis-Lymphatics IronMetabolism William F. Kern, M.D. Department of Pathology william-kern@ouhsc.edu

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3. Iron • Essential component of heme ring: • Hemoglobin, myoglobin, some enzymes • Iron also required for some other enzymes • Mediates electron exchange; also O2 carrier • Abundant in nature: • Mostly ferric (Fe3+) form – insoluble at neutral pH • Potentially toxic: • Generation of reactive oxygen species

4. Regulation of Iron Stores • Iron stores regulated by absorption • Iron absorption can be increased – to some extent - in states of iron deficiency • Iron absorption decreases in states of iron sufficiency or overload • No physiologic way to significantly increase iron excretion • Obligate iron loss: ~1 mg/day (~2 mg/day for menstruating woman)

5. Control of Iron Absorption

6. Control of Iron Absorption • “Stores regulator”: Dependent on iron stores: • Absorption inversely proportional to body iron stores • “Erythropoiesis regulator”: Driven by erythropoiesis in marrow: • Increased erythropoiesis – effective or ineffective – increases iron absorption • Can override “stores regulator” • Chronic increase in erythropoiesis (effective or ineffective) can result in iron overload

7. Iron Metabolism & Storage:Key Players • Transferrin: Iron transport molecule in blood • Transferrin receptor (TfR): Cell surface receptor required for iron uptake • Ferritin: Primary iron storage molecule: • Predominantly present in cells; small amount present in blood • Hepcidin: Primary iron regulatory molecule

8. Iron Absorption • Iron absorption occurs predominantly in duodenum • Iron in the diet comes in two forms: hemeiron and non-heme iron • Non-heme iron is predominantly in ferric form (Fe3+): Must be converted to ferrous (Fe2+) form to be absorbed • Heme iron is readily absorbed into enterocyte

9. Iron Absorption

10. Decreased gastric acidity Phytates in grains Tannates in tea Phosphates Some vegetable proteins Cow’s milk proteins Ascorbic acid Human breast milk Factors that Influence Iron Absorption Decrease: Increase:

11. Iron Absorption • Normal ~1-2 milligrams/day: Balance iron loss • Maximum iron absorption on normal diet ~4 mg/day

12. Regulation of Iron Transport & Storage Molecules • Synthesis of key molecules (transferrin, ferritin, etc.) regulated by intracellular iron level • Intracellular iron binds to iron regulatory proteins (IRPs) • IRPs bind to iron responsive elements (IREs) on mRNA • IRPs can result in increased or decreased protein synthesis

13. Regulation of Iron-Related Molecules Downloaded from: Hoffman Hematology: Basic Principles & Practice

14. Regulation of Iron-Related Molecules 5’: Iron allows transcription 3’: Iron blocks transcription Downloaded from: Hoffman Hematology: Basic Principles & Practice

15. Body Iron Stores Data from: Schrier, SL: Scientific American Medicine, Scientific American, 1995

16. The Iron Cycle Downloaded from: Hoffman Hematology: Basic Principles & Practice

17. Hepcidin • Key regulatory molecule of iron metabolism • Produced by HAMP gene in liver

18. Hepcidin: Effects • Blocks iron export from cells: • Binds to and degrades ferroportin • Blocks iron absorption from enterocytes in duodenum • Blocks iron release from macrophages • Decreases serum iron • Blocks iron transfer to RBC precursors in marrow

19. Control of Hepcidin Synthesis • Hepcidin synthesis decreased by iron deficiency, hypoxia, increased erythropoiesis: • States of possible increased iron need • Hepcidin synthesis increased by inflammatory cytokines, iron overload

20. Control of Hepcidin Synthesis • Control mechanisms complex • Multiple proteins involved: • HFE • Hemojuvelin • Transferrin receptor 2 (TfR2) • Deficiency of some of these results in hemochromatosis due to deficient hepcidin synthesis For reference only.

21. Markers of Iron Status • Serum iron level • Transferrin level: • Sometimes reported as total iron binding capacity (TIBC) • Transferrin saturation (%): • Often reported as [iron ÷ TIBC] x 100 • Serum ferritin You need to know these, and how to interpret them.

22. Markers of Iron Status • Iron level: Decreases with iron deficiency and also inflammation • Transferrin: Increases in iron deficiency; decreases with inflammation • Transferrin saturation: Typically decreases in iron deficiency and inflammation • Ferritin: Decreases in iron deficiency; increases in inflammation You need to know this.

23. Iron Indices Serum Iron: Transferrin (TIBC): Sat: Ferritin Iron Deficiency: Inflammation: ? ? Combined*: * Patient with iron deficiency and inflammatory condition Saturation (%)= Iron ÷ TIBC x 100 TIBC = measure of transferrin concentration in plasma