IRON IN HEALTH AND DISEASE

1. IRON IN HEALTH AND DISEASE Dilys Rapson

3. PERCEPTIONS OF IRON UK Ironman Triathlon, Llanberis 8th September 2002 One of the toughest Ironman courses ever devised “From Stettin in the Baltic to Trieste in the Adriatic anironcurtain has descended across the Continent.” Pumping Iron

4. 1. IRON METABOLISM INTRODUCTORY BACKGROUND • Essential element in all living cells • Transports and stores oxygen • Integral part of many enzymes • Usually bound to other molecules • Quantity of body iron carefully controlled

5. Clinical Relevance • Iron deficiency affects the whole body • Excess free iron can lead to serious organ damage

6. 2. BODY IRON DISTRIBUTION • Metabolically Active Iron: • Haemoglobin • “Serum” iron bound to a protein transferrin in blood • Tissue Iron: in cytochromes and enzymes • Myoglobin: oxygen reserve in muscles

7. APPROXIMATE DISTRIBUTION OF BODY IRON IN A MAN Hemoglobin 2000mg Storage Iron 1000mg Myoglobin iron 130mg Labile Pool 80mg Other tissue Iron 8mg Transport Iron 3mg

8. HAEM MOIETY : HAEMOGLOBIN

9. 2. BODY IRON DISTRIBUTION B.Storage Iron: • Ferritin: found in blood, tissue fluids, and cells • Haemosiderin: found in macrophages and assessed by staining bone marrow with Prussian Blue stain

10. BONE MARROW FILM STAINED FOR HAEMOSIDERIN

11. Clinical Relevance:Body Iron status can be measured • Serum Iron level ( Transferrin bound iron) • Total iron binding capacity (TIBC): measurement of transferrin • % transferrin saturation = (Serum iron/TIBC x 100) • Serum ferritin : Level correlates with body stores • Haemosiderin assessment in bone marrow

12. 3. DIETARY SOURCES OF IRON Organic iron eg beef Inorganic Iron eg lentils DAILY IRON REQUIREMENT 10-15mg/day (5-10% absorbed)

13. 4. IRON ABSORPTION • Iron kept soluble and in ferrous state by gastric acid • Absorbed mainly in duodenum • Quantity absorbed regulated by enterocyte • Multiple proteins involved in control of iron transport • Haem iron enters the enterocyte through different process than inorganic iron

14. ABSORPTION OF IRON Enterocyte Gut Fe+++ Ferritin Fe++ Tf-Fe+++ Fe++ Fe++ Haem Tf

15. 4. IRON ABSORPTION (cont) • Transferrin bound iron in plasma delivered to body cells according to cellular iron requirements Note: Only 20% of plasma bound iron derived from gut. Most plasma iron is derived from breakdown of senescent red cells.

16. BODY IRON CYCLING

17. 5. PROTEINS INVOLVED IN IRON METABOLISM Upstream regulators eg. HFE HEPCIDIN Synthesized in liver. Present in blood Infections and inflammatory stimuli degrades X Transferrin receptors FERROPORTIN Apoferritin No cellular egress of iron

18. Clinical Relevance • Iron balance physiologically regulated by control of iron absorption at enterocyte. • Mutations in the gene HFE associated with most common form of hereditary iron overload (HFE- haemochromatosis) • Humans unable to excrete excess iron. Interventions which circumnavigate the enterocyte can result in iron loading • Conditions such as infection and inflammation have an effect on iron metabolism

19. CHRONIC TRANSFUSION OVERWHELMS IRON BALANCE PRBC is the red cells in a single donation or “unit” of blood

20. WHAT YOU NEED TO KNOW • Daily requirements and dietary sources of iron • Where iron is absorbed in the gut • Control of iron balance at level of enterocyte • How body stores of iron are assessed • Proteins involved in regulation of iron

21. IRON DEFICIENCY • Commonest cause of anaemia worldwide • Cause of chronic ill health • May indicate the presence of important underlying disease eg. blood loss from tumour

22. 1.EVOLUTION OF IRON DEFICIENCY ANAEMIA • Earliest stage : depletion of body iron stores only • “Biochemical” iron deficiency without anaemia • Iron deficiency anaemia

23. 2. CLINICAL FEATURES IRON DEFICIENCY • Symptoms eg. fatigue, dizziness, headache • Signs eg. pallor, glossitis, angular cheilosis, koilonychia, Plummer Vinson syndrome Koilonychia Glossitis

24. CLINICAL FEATURES OF IRON DEFICIENCY Plummer Vinson Syndrome : Oesophageal Web Angular Cheilosis or Stomatitis

25. 3. LABORATORY DIAGNOSIS: IRON DEFICIENCY • Microcytic hypochromic anaemia • Often pencil cells and target cells on blood film • Decreased serum ferritin • Decreased serum iron, increased TIBC, decreased % transferrin saturation • Absent bone marrow haemosiderin : (rarely required for diagnosis )

26. Hypochromic microcytic red cells

27. Pencil Cell

28. ABSENT IRON STORES IN BONE MARROW IN IRON DEFICIENCY Normal control Iron deficiency

29. Things you need to know about Laboratory Testing for Iron Status • Serum ferritin most useful test • Low serum ferritin certain proof patient iron deficient • Normal serum ferritin does not always rule out iron deficiency • Certain conditions raise ferritin for reasons unrelated to iron status

30. 4.DIFFERENTIAL DIAGNOSIS: IRON DEFICIENCY ANAEMIA

31. 5. PRINCIPLES OF TREATMENT • Use oral iron ( not enteric coated tablets ) • Replace iron deficit in total : • Restore haemoglobin and MCV to normal • Replenish iron stores • Establish and treat the cause

32. LOOK FOR THE CAUSE OF IRON DEFICIENCY

33. 6. CAUSES OF IRON DEFICIENCY • Increased physiologic demand eg. pregnancy, lactation, rapid growth • Blood loss from GI tract, uterus, haemoglobinuria • Malabsorption • Diet colon cancer

34. WHAT YOU NEED TO KNOW • Symptoms and signs of iron deficiency • Laboratory diagnosis of iron deficiency • Differential diagnosis of a microcytic hypochromic anaemia • Importance of finding a cause for iron deficiency • Principles of treatment

35. IRON OVERLOAD

36. Iron overload Capacity of serum transferrin to bind iron is exceeded Non-transferrin-bound iron (NTBI) circulates in the plasma EFFECTS OF IRON OVERLOAD O2- + H2O2 O2 + OH- + HO Excess iron promotes the generation of free hydroxyl radicals, propagators of oxygen-related tissue damage Insoluble iron complexes are deposited in body tissues and end-organ toxicity occurs (Fenton Reaction) Liver cirrhosis/ fibrosis/cancer HSC senescence Diabetes mellitus Cardiac failure Growth failure Infertility

37. WHEN DOES IRON BECOME A PROBLEM? • Normally 2.5 – 3.5g of iron in the body. • Tissue damage when total body iron is 7 – 15 g

38. LABORATORY DIAGNOSIS • Elevated % transferrin saturation • Increased serum ferritin • Genetic testing for mutations of HFE gene • Evidence parenchymal iron overload on liver biopsy • Amount of iron removed by venesection

39. TREATMENT AND PREVENTION • Phlebotomy until ferritin <50µg/ml • Maintenance venesection • Screen family members • Prevention Cirrhosis of liver

40. CAUSES OF IRON OVERLOAD • Hereditary haemochromatosis • Multiple transfusions • Liver disease • Prolonged use medicinal iron • Ineffective erythropoiesis • African Iron Overload

41. HEREDITARY HAEMOCHROMATOSIS • Most common cause of iron overload in North America • Most cases due to mutations of the HFE gene • Results in increased inappropriate iron absorption from gut

42. CLINICAL DIAGNOSIS • Commonly made on basis of biochemical changes : increased serum ferritin or % transferrin saturation • May have non-specific symptoms/signs such as fatigue or arthropathy • Discovered as part of family screening • Rarely fullblown picture : cirrhosis, diabetes, cardiomyopathy, skin pigmentation, gonadal dysfunction

43. WHAT YOU NEED TO KNOW • Association of mutations of the HFE gene with the most common inherited iron overload disorder : HFE- hemochromatosis • Hereditary haemochromatosis common in North America • “Early” symptoms/signs non-specific. Have to think of it • Severe morbidities avoidable if early diagnosis • Genetic testing available for patient and family