CSIM2.25 IRON METABOLISM & STORAGE BACKGROUND It is important for 1) O2 transportation (Hb) and storage (Mb) molecules, 2) energy production molecules Krebs cycle enzyme & oxidative phosphorylation, 3) liver detoxification molecule (CY P450), 4) host defence molecule (NADPH oxidase). Iron Distribution 1. Hematologists have been especially interested in the system of iron metabolism because iron is essential for red blood cells, where most of the human body's iron is contained; in rbc as Hb 50%, Stored as ferritin, In muscles as myoglobin. In other haem proteins, eg. Cytochromes. Free in serum 0.1%. 2. Understanding this system is also important for understanding disease of iron overload, like HAEMOCHROMATOSIS and iron deficiency like IRON DEFICIEINCY ANAEMIA. What are haems? A haem is a prosthetic group consisting of an iron atom contained in the centre of a large organic (porphyrin) ring. Haems are most commonly recognized as components of haemoglobin, the red pigment in blood. Haem = >half of iron in western diet but much less in other diets. Split from globin in intestine & absorbed by enterocytes. process not well understoodIron Storage 1. Ferritin is a protein with a capacity of about 4500 iron (III) ions per protein molecule. This is the major form of iron storage. Outer shell: apoferritin. 2. If the capacity for storage of iron in ferritin is exceeded, a complex of iron with phosphate and hydroxide forms. This is called hemosiderin; it is physiologically available. (Bila ferritin penuh, pakai hemosiderin) 3. As the body burden of iron increases beyond normal levels, excess hemosiderin is deposited in the liver and heart. This can reach the point that the function of these organs is impaired, and death ensues. 4. Ferritin always indicates Fe deficiency, but normal Ferritin cannot always exclude it, due to acute phase effect, etcIron regulation Hepcidin The Master Regulator Antimicrobial activity; Hepatic bacteriocidal protein Hepcidin is a key regulator of the entry of iron into the circulation in mammals. It has been found to have anti-inflammatory properties. This is a negative feedback: it reduces the inflammation which caused the elevated hepcidin level In states in which the hepcidin level is abnormally high such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red cells. When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to excessive ferroportin mediated iron influx. Blocks Fe release from enterocytes and RES macrophages by degrading the Fe exporter Ferroportin.

Regulatory mechanism

Iron balance Intestinal iron absorption

Iron Transport 1. Red cells As haemoglobin Cannot be exchanged 2. Plasma Bound to transferrin Carries iron between body locations. Eg: between gut, liver, bone marrow, macrophages. Fe taken up into cells by transferrin receptors. Production in iron overload. Production in iron deficiencyserum Iron Test The serum contain about 0.1% of iron. Whereas, >95% serum iron is bound to transferrin. It measure all serum iron (not in red cells) Of limited use on its own in the interpretation of iron status. Commonly combined with serum transferrin to express transferrin saturation (%). Transferrin Saturation Test % of transferrin iron-binding sites that are filled with iron Combines two lab tests (Fe & transferrin) to sensitivity Iron overload: iron + transferrin saturation (50100%) = Best serum marker of increased body iron. Used as biochemical screen for iron overload.Disrupted Iron Homeostasis 1. Hepcidin Deficiency:a. Hereditary Haemochromatosis:i. Absorb excessive iron relative to body stores implying the set-point for the stores regulator is altered.b. Ineffective erythropoiesis:i. Destruction of erythroid precursors (eg. thalassemia), but this is coupled to increased iron absorption.2. Hepcidin Excess:a. Anaemia of Chronic disease:i. Infection/inflammation induces iron sequestration in macrophages and decreases intestinal absorption.Genetic Haemochromatosis >95% defect in HFE gene typically homozygous C282Y mutation nearly 10% of Northern Europeans carry 1 allele Founder effect ~4-5,000 y.a. (spread by Vikings?) HFE hepcidin overactivity of ferroportin duodenal iron absorption Also hepcidin-independent mechanisms DMT1 and DcytB activity (= iron transporters) Limited penetrance: Other genetic & environmental factors likely to be involved. Biochemical penetrance = 36-76%. clinical disease penetrance = 2-38% (men); 1-10% (women) Lower penetrance in younger women due to menstrual loss.Cells and Tissues that might be affected by Iron Overload from GHaemo1. Beta cells in endocrine pancreas Diabetes mellitus.2. Hepatocytes liver disease fibrosis cirrhosis -USS/biopsy.3. Articular surfaces arthritis.4. Heart muscle restrictive cardiomyopathy -Echo.5. Pituitary gonadotrophs hypogonadotropic hypogonadisma. LH+FSH deficiency causing 20 low testosterone -MRIManagement for Iron Excess 1. VENESECTION 2. Global (specific & general) & tissue-specific measures:a. Depletion of iron stores by regular venesection. (takes years to achieve maximum benefit)b. Avoid EtOH & lose weight (hepatotoxic & insulin-resistance).c. Diet, drugs and/or Insulin for Diabetes (interim or lifelong).d. Testosterone replacement (may be interim or lifelong).i. Testosterone for hypogonadism will energy levels, muscle function, bone health/density, erythropoiesis & sexual function.ii. Fertility (& testis volume) can be restored with a prolonged course of LH (hCG) & FSH injections.