1. 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

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

3. 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

4. 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

5. BONE MARROW FILM STAINED FOR HAEMOSIDERIN

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

7. 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

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

9. 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.

10. BODY IRON CYCLING

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

12. 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

13. 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

14. 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

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

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

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

18. 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 )

19. ABSENT IRON STORES IN BONE MARROW IN IRON DEFICIENCY Iron deficiencyNormal control

20. 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

21. 4.DIFFERENTIAL DIAGNOSIS: IRON DEFICIENCY ANAE 4.DIFFERENTIAL DIAGNOSIS: IRON DEFICIENCY ANAEMIA

22. LOOK FOR THE CAUSE OF IRON DEFICIENCY

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

24. 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

25. IRON OVERLOAD

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

27. 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

28. 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

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

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

31. 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

32. 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

33. 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