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Fe metabolism


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Fe metabolism

  1. 1. Iron Metabolism Prof. Aparna Misra Department of Biochemistry
  2. 2. Learning Objectives: Functions of Iron Dietary sources and daily requirement Metabolism of Iron: Absorption, storage and excretion Disorders of Iron metabolism: Iron deficiency, Iron excess
  3. 3. Micronutrients: minerals required in minute quantities, and are known as trace elements or micronutrients eg. Fe, I, Cu, Zn, Co, Mn , Mo, Cr, Se and F Macronutrients: Some of these are required in relatively large quantities, and are known as principal elements or macronutrients. eg. Ca, P, Mg,Na, K, Cl and S
  4. 4. • Iron  Total amount of iron in an adult human being is 3-5 gm  Blood and blood-forming organs are the largest reservoirs of iron in our body  But small amounts of iron are present in nearly every tissue
  5. 5. Important iron-containing compounds are:  • Haemoglobin  • Myoglobin  • Ferritin  • Haemosiderin  • Transferrin  • Cytochromes  • Iron-containing enzymes
  6. 6. TYPES OF THE IRON PRESENT IN THE BODY 1.Essential ( or functional) iron a.Hemeproteins b.Cytochromes c. Iron requiring enzymes 2. Storage iron a.Ferritin b.Haemosiderin
  7. 7.  About 70% of the body iron is present in haemoglobin and 5% in myoglobin, Ferritin and haemosiderin, which are storage forms of iron, contain about 20% of the body iron  Transferrin, an iron carrier protein present in plasma, contains 0.1% of the body iron  The remaining iron is present in cytochromes and enzymes
  8. 8. • Ferritin • Ferritin is present in liver, spleen, bone marrow, brain, kidneys, intestine, placenta etc • It is one of the storage forms of iron • The protein portion is known as apoferritin • Apoferritin combines with iron to form ferritin • The first step in the synthesis of ferritin is the formation of apoferritin induced by the entry of ferrous iron in the cell
  9. 9. • This is followed by oxidation of ferrous iron to the ferric form • Ferric iron forms ferric hydrophosphate micelles, which enter the protein shell to form ferritin • Apoferritin is made up of 24 identical subunits, each having a molecular weight of 22,000 to 24,000 • The subunits are arranged at the vertices of a pentagonal dodecahedron with a hollow space in the centre
  10. 10. • Ferric hydrophosphate micelles are present in this space • When fully saturated, a molecule of ferritin contains 5,000 atoms of iron, and has a molecular weight of 900,000
  11. 11. • Haemosiderin • Haemosiderin is a granular iron-rich protein • It is insoluble in water unlike ferritin • The exact structure of haemosiderin is not known • It has been shown that iron is first stored in the body in the form of ferritin
  12. 12. • As the iron stores increase, the older ferritin molecules are aggregated to form haemosiderin • Some of the protein is degraded in this process • Therefore, the percentage of iron in haemosiderin is higher as compared to that in ferritin • Normally, about two thirds of the stored iron is in the form of ferritin and one third in the form of haemosiderin
  13. 13. • Transferrin • Transferrin is a carrier protein which transports iron in circulation • Free iron is toxic, and has a tendency to precipitate • These problems are overcome by combining iron with transferrin • Transferrin is a β1-globulin with a molecular weight of about 90,000 • It is made up of two non-identical subunits • One molecule of transferrin can transport two ferric atoms
  14. 14. • Transferrin carries iron to and from various tissues through circulation • There are specific receptors for transferrin on the cell membranes of the cells requiring iron e.g. red cell precursors • Transferrin-iron complex attaches to these receptors • This attachment produces a conformational change in the transferrin molecule as a result of which the iron is released • The free transferrin molecules are then displaced from the cell membrane by molecules carrying iron
  15. 15. • The concentration of transferrin in plasma is 200-400 mg/dl • This amount of transferrin is capable of carrying 250-400 mg of iron per dl of plasma • This is known as the total iron binding capacity of plasma
  16. 16. • Normal plasma iron level is 50-175 μg/dl which means that the iron binding capacity of plasma is only about 30% saturated in healthy subjects
  17. 17. • Functions • • Transport of oxygen • • Oxidative reactions • • Tissue respiration
  18. 18. Flavoproteins Hemeproteins Fe-sulfur Nzms Other Fe Nzms Other Fe Proteins Fe-Containing Proteins Transferrin & Others Ferritin & Hemosiderin Other NzmsHeme Flavoproteins Hemoglobin Other Nzms Iron Activated Nzms 2Fe-2S 4Fe-4S Nzms Myoglobin Cytochromes Other Nzms Function
  19. 19. Functions • Oxygen Transport & Storage – Hemoglobin – Myoglobin • Electron Transport & Energy Metabolism – Cytochromes – Fe-S proteins • Substrate Oxidation & Reduction – Iron dependent enzyme- – Ribonucleotide reductase – Amino acid oxidases – Fatty acid desaturases – Nitric oxide synthetase – Peroxidases • Regulation of intracellular iron
  20. 20. FUNCTIONS  Iron mainly exerts its function through the compound in which it is present.  Hemoglobin and myoglobin are required for the transport of O2 and CO2.  Cytochromes and certain non heme proteins are necessary for electron transport chain and oxidative phosphorylation.  Iron is associated with effective immunocompetence of the body.
  21. 21. • Transport of oxygen • The most important function of iron is to transport oxygen in the body in the form of haemoglobin • A similar function is performed in muscles by myoglobin
  22. 22. • Oxidative reactions • As a component of the various oxidoreductase enzymes mentioned earlier, iron plays a role in a number of oxidative reactions
  23. 23. • Tissue respiration • As a component of cytochromes in the respiratory chain, iron is involved in tissue respiration • It is the iron component of the cytochromes that accepts and donates electrons
  24. 24. • Iron Balance • Iron status depends upon the relative rates of iron absorption and iron excretion • Iron absorption is the major mechanism for maintaining normal iron balance
  25. 25. • Iron metabolism is said to occur within a closed system in the body i.e. there is hardly any exchange of iron between man and his environment • The iron present in the body is continuously reutilised • Only a minute amount of iron is lost everyday from the body in the form of exfoliated cells
  26. 26. • The faecal iron loss in 0.4-0.5 mg a day • The urinary iron loss is about 0.1 mg a day • About 0.2-0.3 mg of iron is lost daily from the skin along with the exfoliated cells • Thus, the total iron loss is just under one mg a day
  27. 27. • In premenopausal women, there are two additional routes of iron loss • About 20-25 mg of iron is lost with menstrual blood in each cycle • This is equivalent to a daily loss of 0.7-0.8 mg of iron
  28. 28. • During pregnancy, there is no menstrual loss but the expectant mother has to provide iron to the foetus • This amounts to about 0.6 mg a day in the first trimester, about 2.8 mg a day in the second trimester, and about 4 mg a day in the third trimester of pregnancy
  29. 29. • The iron losses are balanced by intestinal absorption of iron • The intestinal absorption is affected by body iron stores, erythropoietic activity, degree of saturation of plasma transferrin, the amount of dietary iron, valency of ingested iron (Fe++ or Fe+++) and presence of other substances in the food
  30. 30. • Absorption is more when body iron stores are low, erythropoietic activity is increased, saturation of plasma transferrin is low and iron is ingested in ferrous form • Presence of ascorbic acid, succinic acid, histidine and cysteine in the food increases iron absorption • Phytates and phosphates retard iron absorption
  31. 31. • Iron can be absorbed from all segments of the Small intestine but presence and normal functioning of stomach are also essential • Patients with achlorhydria and those who have undergone gastrectomy absorb less iron as compared to normal persons • Gastric enzymes and hydrochloric acid release iron from iron-containing com-pounds and reduce ferric iron to the ferrous form
  32. 32. • It is believed that ferritin content of mucosal cells of the intestine regulates the absorption of iron • These cells are formed in the crypts of Leiberkuhn • They gradually reach the tip of the villi and are shed off into the intestinal lumen • Their average life-span is three days
  33. 33. • The function of ferritin in these cells is to blockthe absorption of iron • Those cells which are formed during a period of iron overload are rich in ferritin • These cells will absorb little iron during their lifespan • Moreover, when these are shed off, their iron content will also be lost in faeces
  34. 34. • Conversely, the cells formed during a period of iron deficiency are poor in ferritin • These cells absorb more iron and transfer it into the plasma
  35. 35. • Requirement • Though the actual requirement of iron is very small, much larger amounts have to be provided in diet because only a small proportion of the dietary iron is normally absorbed
  36. 36. • The daily requirement in different age groups is follows: • Infants : 6-10 mg/day • Children : 10 mg/day • Adolescents : 12 mg/day • Adult men and postmenopausal women : 10 mg/day • Menstruating women: 20 mg/day • Pregnant and lactating women : 40 mg/day
  37. 37. SOURCES • Rich Sources: Organ meats (Liver, heart, kidney) • Good Sources: Leafy Vegetables, pulses, cereals, fish, apple, dried fruits. • Poor Sources: Milk, wheat, polished rice
  38. 38. • A much greater proportion of iron can be absorbed from animal foods than from vegetable foods • On a mixed diet, healthy subjects absorb 5-10% of the dietary iron
  39. 39. • Iron deficiency • Iron deficiency is widespread both in poor and in affluent countries • Iron deficiency is the commonest cause of anaemia throughout the world
  40. 40. Deficiency Signs Koilonychia “Spoon Nails” Glossitis Angular Stomatitis
  41. 41. • Deficiency can be caused by inadequate intake of iron especially when the requirement is high e.g. in infancy, adolescence and pregnancy • Malabsorption resulting from steatorrhoea, coeliac disease, gastrectomy etc can also cause iron deficiency • Persistent blood loss, e.g. from genital tract,gastrointestinal tract, hookworm infestation etc, can also result in iron deficiency
  42. 42. • When iron deficiency develops, the earliest change is a depletion of body iron stores • Other changes follow progressively • Plasma transferrin saturation is decreased • Plasma iron is decreased
  43. 43. • A microcytic, hypochromic anaemia develops • Poikilocytosis becomes evident • Hemoglobin level falls • Severe and prolonged deficiency leads to tissue changes e.g. koilonychia, angular stomatitis, glossitis, pharyngeal and oesophageal webs, atrophic gastritis, partial villus atrophy etc
  44. 44. • Iron overload • Iron overload is much less common than iron deficiency • Two types of iron overload syndromes are known: • When excessive iron is deposited in reticuloendothelial cells without tissue damage, it is known as haemosiderosis
  45. 45. • This occurs when excessive amounts of iron enter the body through the parenteral route • Repeated blood transfusions given to patients with thalassaemia and sideroblastic anaemia may lead to deposition of iron in reticuloendothelial cells
  46. 46. • When excess iron enters the body through the alimentary route, it gets deposited in parenchymal cells and causes tissue damage • This condition is known as haemo-chromatosis • It may be primary or secondary • Primary (genetic) haemochromatosis is far more common
  47. 47. • The gene responsible for this and the protein encoded by it have not been identified • The genetic defect leads to excessive intestinal absorption of iron • Excess iron is deposited in liver, heart, pancreas and other endocrine glands, skin etc
  48. 48. • Hepatomegaly, cardiomegaly, congestive heart failure, hypogonadism, diabetes mellitus and bronze-coloured pigmentation of skin are the usual clinical abnormalities • The condition is also known as bronzed diabetes
  49. 49. • Serum iron, ferritin and per cent saturation of iron- binding capacity are increased in haemo- chromatosis • Phlebotomy and iron-chelating agents e.g. desferrioxamine are used to remove excess iron
  50. 50. • Secondary haemochromatosis may occur in alcoholic liver disease in which iron deposition is usually confined to hepatic tissue • South African Bantus are known to develop haemochromatosis due to excessive ingestion of iron present in an alcoholic beverage brewed in iron vessels
  51. 51. EVENTS IN INTESTINAl MUCOSAL CELL • In the mucosal cell cytoplasm, there is a carrier called intracellular iron carrier (I.I.C.). • Fe++ iron is oxidized again in mucosal cell to Fe+++ form by ceruloplasmin. • IIC delivers a fixed amount of iron to mitochondria. • It also transfers certain amount of iron Fe+++ to apoferritin, which synthesized by mucosal cell.
  52. 52. IRON ABSORPTION • Mainly, stomach & duodenum • In normal people, about 10 % of dietary iron is usually absorbed. • Iron is mostly found in the foods in ferric form. • Iron in the ferrous form is soluble and readily absorbed. • Garnick proposed a “Mucosal block theory” for iron absorption.
  53. 53. IRON ABSORPTION & TRANSPORT Mucosal Cell of GIT Apoferritin Ferritin (Fe+++) Fe+++ Fred Fe++ Ferroxidase Fe++ Plasma Apotransferritin Transferritin (Fe+++) Fe+++ Ceruloplasmin Fe++ Tissues Liver Ferritin Hemosiderin Bone marrow (Hb) Muscle (Mb) Other tissues (Cyts & NHI) Lumen of GIT Food Fe Hcl Fe+++ Vit C Fe++
  54. 54. FACTORS AFFECTING Fe ABSORPTION • Acidity, ascorbic acid and cysteine promote iron absorption. • In iron deficiency anemia, iron absorption is increased to 2-10 times that of normal. • Small peptides and amino acids favor iron uptake. • Phytate and oxalate interfere with iron absorption.
  55. 55. TOTAL IRON BINDING CAPACITY (TIBC) • Each transferrin molecule can bind with two atoms of ferric ion (Fe+++). • The plasma transferrin ( concentration 250 mg/ dl) can bind with 400 mg of iron / dl plasma. This is known as TIBC.
  56. 56. CLINICAL ASPECT A. Iron deficiency: Three stages 1) Iron storage depletion 2) Iron deficiency 3) Iron deficiency anaemia B. Iron overload: 1) Haemochromatosis 2) Haemosiderosis
  57. 57. Riddles 1. The requirement of iron in diet is about 10 times the bodies normal requirements. Why is this so? 2. What are the common probable condition that increase physiological demands for dietary iron?