IRON METABOLISM,
IRON DEFICIENCY
AND DISORDERS OF HAEM SYNTHESIS
Guvera Vasireddy
Department of Pathology
Osmania Medical ...
INTRODUCTION
 Iron (atomic weight 55.85) is essential for many metabolic processes.
 It shares with other transition met...
NO EXCRETION!
 Body is limited in the adjustments it can make to
excessive loss of iron, which frequently occurs due to
h...
IRON IN DIET AND BODY
 The normal daily diet contains about 10 to 20 mg of iron,
mostly in the form of heme.
 About 20% ...
IRON DISTRIBUTION IN HEALTHY YOUNG ADULTS (MG)
Pool Men Women
Total 3450 2450
Functional
Hemoglobin 2100 1750
Myoglobin 30...
TRANSPORT OF IRON BETWEEN STORAGE AND
FUNCTIONAL POOLS
 Iron in the body is recycled extensively between the functional
a...
Iron
homeostasis
SEQUESTRATION OF IRON
 Free iron is highly toxic and it is important that iron be
sequestered.
 This is achieved by bind...
STORAGE OF IRON
 Intracellular ferritin is located in the cytosol and in
lysosomes.
 Partially degraded protein shells o...
IRON ABSORPTION
 Iron is absorbed in the proximal duodenum.
 As body iron stores rise, absorption falls, and vice versa....
NON HEME AND HEME IRON
 The absorption of nonheme iron is inhibited by
substances in the diet that bind and stabilize
Fe[...
DUODENAL EPITHELIAL CELL UPTAKE OF HEME AND NONHEME IRON.
FATE OF ABSORBED IRON
 Iron that enters the duodenal cells can follow one of two
pathways: transport to the blood or stor...
FERRIPORTIN AND DMT1
 DMT1 and ferriportin are widely distributed in the body
and are involved in iron transport in other...
REGULATION OF IRON ABSORPTION
 Iron absorption is regulated by hepcidin, synthesized by liver in
response to increases in...
ROLE OF HEPCIDIN IN DISEASES INVOLVING
DISTURBANCES OF IRON METABOLISM.
 Anemia of chronic disease is caused in part by i...
CAUSES FOR DIETARY IRON DEFICIENCY
• Infants, who are at high risk due to the
very small amounts of iron in milk.
• The im...
OTHER CAUSES OF IRON DEFICIENCY
 Impaired absorption is found in sprue, other causes
of fat malabsorption (steatorrhea), ...
PATHOGENESIS
 Whatever its basis, iron deficiency produces a
hypochromic microcytic anemia.
 At the outset of negative i...
MORPHOLOGY
 The bone marrow reveals a mild to moderate increase in
erythroid progenitors.
 Significant finding is the di...
HYPOCHROMIC MICROCYTIC ANEMIA OF IRON DEFICIENCY
(PERIPHERAL BLOOD SMEAR). NOTE THE SMALL RED CELLS
CONTAINING A NARROW RI...
DIAGNOSIS
 Both the hemoglobin and hematocrit are depressed,
usually to a moderate degree, in association with
hypochromi...
Iron metabolism, iron deficiency
Iron metabolism, iron deficiency
Iron metabolism, iron deficiency
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Iron metabolism, iron deficiency

  1. 1. IRON METABOLISM, IRON DEFICIENCY AND DISORDERS OF HAEM SYNTHESIS Guvera Vasireddy Department of Pathology Osmania Medical College
  2. 2. INTRODUCTION  Iron (atomic weight 55.85) is essential for many metabolic processes.  It shares with other transition metals two properties of particular importance in biology: the ability to exist in more than one relatively stable oxidation state and the ability to form many complexes.  Its ability to exist in both ferric and ferrous states underlies its role in critical enzyme reactions concerned with oxygen and electron transport and the cellular production of energy.  There are specialized proteins of iron transport and storage.  They are necessary to enable iron to remain in solution at neutral pH, at which ferric iron is insoluble, and to limit the potential toxicity of this reactive metal.
  3. 3. NO EXCRETION!  Body is limited in the adjustments it can make to excessive loss of iron, which frequently occurs due to haemorrhage, and iron deficiency is the most common cause of anaemia throughout the world.  The general need to conserve the metal is reflected in the absence of any physiological mechanism for excretion of iron, control of iron balance being at the level of iron absorption.  This is important in the rarer but potentially fatal disorders of iron overload
  4. 4. IRON IN DIET AND BODY  The normal daily diet contains about 10 to 20 mg of iron, mostly in the form of heme.  About 20% of heme iron and only 1% to 2% of non heme iron) is absorbable.  The total body iron content is normally about 2 gm in women and as high as 6 gm in men divided into functional and storage pools.  About 80% of the functional iron is found in hemoglobin; myoglobin and iron-containing enzymes such as catalase and the cytochromes contain the rest.  The storage pool (hemosiderin and ferritin) contains about 15% to 20% of total body iron.  Healthy young females have smaller stores of iron than do males.
  5. 5. IRON DISTRIBUTION IN HEALTHY YOUNG ADULTS (MG) Pool Men Women Total 3450 2450 Functional Hemoglobin 2100 1750 Myoglobin 300 250 Enzymes 50 50 Storage Ferritin, hemosiderin 1000 400
  6. 6. TRANSPORT OF IRON BETWEEN STORAGE AND FUNCTIONAL POOLS  Iron in the body is recycled extensively between the functional and storage pools.  It is transported in plasma by an iron-binding glycoprotein called transferrin, which is synthesized in the liver.  Transferrin is about one third saturated with iron, yielding serum iron levels that average 120 μg/dL in men and 100 μg/dL in women.  The major function of plasma transferrin is to deliver iron to cells, including erythroid precursors, which require iron to synthesize hemoglobin.  Erythroid precursors possess high-affinity receptors for transferrin, which mediate iron import through receptor- mediated endocytosis.
  7. 7. Iron homeostasis
  8. 8. SEQUESTRATION OF IRON  Free iron is highly toxic and it is important that iron be sequestered.  This is achieved by binding iron in the storage pool tightly to either ferritin or hemosiderin.  Ferritin is a ubiquitous protein-iron complex that is found at highest levels in the liver, spleen, bone marrow, and skeletal muscles.  In liver, most ferritin is stored within the parenchymal cells;  In spleen and bone marrow, it is found mainly in macrophages.  Hepatocyte iron is derived from plasma transferrin, whereas storage iron in macrophages is derived from the breakdown of red cells.
  9. 9. STORAGE OF IRON  Intracellular ferritin is located in the cytosol and in lysosomes.  Partially degraded protein shells of ferritin aggregate into hemosiderin granules.  Iron in hemosiderin is chemically reactive and turns blue- black when exposed to potassium ferrocyanide, which is the basis for the Prussian blue stain.  Normally only trace amounts of hemosiderin are found in macrophages in the bone marrow, spleen, and liver.  In iron-overloaded cells, most iron is stored in hemosiderin.
  10. 10. IRON ABSORPTION  Iron is absorbed in the proximal duodenum.  As body iron stores rise, absorption falls, and vice versa.  The pathways responsible for the absorption differ partially for nonheme and heme iron.  Luminal nonheme iron is mostly in the Fe[3]+ (ferric) state and must first be reduced to Fe[2]+ (ferrous) iron by ferrireductases, such as b cytochromes and STEAP3.  Fe[2]+ iron is then transported across the apical membrane by divalent metal transporter 1 (DMT1).
  11. 11. NON HEME AND HEME IRON  The absorption of nonheme iron is inhibited by substances in the diet that bind and stabilize Fe[3]+ iron.  Enhanced by substances that stabilize Fe[2]+ iron.  Heme iron is moved across the apical membrane into the cytoplasm through transporters that are incompletely characterized.  It is metabolized to release Fe[2]+ iron, which enters a common pool with nonheme Fe[2]+ iron.
  12. 12. DUODENAL EPITHELIAL CELL UPTAKE OF HEME AND NONHEME IRON.
  13. 13. FATE OF ABSORBED IRON  Iron that enters the duodenal cells can follow one of two pathways: transport to the blood or storage as mucosal iron.  Fe[2]+ iron destined for the circulation, is transported from the cytoplasm across the basolateral enterocyte membrane by ferriportin.  This process is coupled to the oxidation of Fe[2]+ iron to Fe[3]+ iron, which is carried out by the iron oxidases hephaestin and ceruloplasmin.  Newly absorbed Fe[3]+ iron binds rapidly to the plasma protein transferrin, which delivers iron to red cell progenitors in the marrow.
  14. 14. FERRIPORTIN AND DMT1  DMT1 and ferriportin are widely distributed in the body and are involved in iron transport in other tissues as well.  DMT1 also mediates the uptake of “functional” iron (derived from endocytosed transferrin) across lysosomal membranes into the cytosol of red cell precursors in the bone marrow,  Ferriportin plays an important role in the release of storage iron from macrophages.
  15. 15. REGULATION OF IRON ABSORPTION  Iron absorption is regulated by hepcidin, synthesized by liver in response to increases in intrahepatic iron levels.  Hepcidin inhibits iron transfer from the enterocyte to plasma by binding to ferriportin and causing it to be endocytosed and degraded.  As hepcidin levels rise, iron becomes trapped within duodenal cells in the form of mucosal ferritin and is lost as these cells are sloughed.  With low body stores of iron, hepcidin synthesis falls and this in turn facilitates iron absorption.  By inhibiting ferriportin, hepcidin reduces iron uptake from enetrocytes and suppresses iron release from macrophages.This, is important in the pathogenesis of anemia of chronic diseases.
  16. 16. ROLE OF HEPCIDIN IN DISEASES INVOLVING DISTURBANCES OF IRON METABOLISM.  Anemia of chronic disease is caused in part by inflammatory mediators that increase hepatic hepcidin production.  A rare form of microcytic anemia is caused by mutations that disable TMPRSS6, a hepatic transmembrane serine protease that normally suppresses hepcidin production when iron stores are low.  Affected patients have high hepcidin levels, resulting in reduced iron absorption and failure to respond to iron therapy.  Hepcidin activity is inappropriately low in both primary and secondary hemochromatosis.
  17. 17. CAUSES FOR DIETARY IRON DEFICIENCY • Infants, who are at high risk due to the very small amounts of iron in milk. • The impoverished, who can have suboptimal diets for socioeconomic reasons at any age. • The elderly, who often have restricted diets with little meat because of limited income or poor dentition. • Teenagers who subsist on “junk” food.
  18. 18. OTHER CAUSES OF IRON DEFICIENCY  Impaired absorption is found in sprue, other causes of fat malabsorption (steatorrhea), and chronic diarrhea.  Gastrectomy impairs iron absorption by decreasing hydrochloric acid and transit time through the duodenum.  Chronic blood loss is the most common cause of iron deficiency in the Western world.  Iron deficiency in adult men and postmenopausal women must be attributed to gastrointestinal blood loss until proven otherwise.
  19. 19. PATHOGENESIS  Whatever its basis, iron deficiency produces a hypochromic microcytic anemia.  At the outset of negative iron balance, reserves in the form of ferritin and hemosiderin may be adequate to maintain normal hemoglobin and hematocrit levels as well as normal serum iron and transferrin saturation.  Progressive depletion of these reserves first lowers serum iron and transferrin saturation levels without producing anemia.  In this early stage there is increased erythroid activity in the bone marrow.  Anemia appears only when iron stores are completely depleted and is accompanied by low serum iron, ferritin, and transferrin saturation levels.
  20. 20. MORPHOLOGY  The bone marrow reveals a mild to moderate increase in erythroid progenitors.  Significant finding is the disappearance of stainable iron from macrophages in the bone marrow, which is best assessed by performing Prussian blue stains on smears of aspirated marrow.  In peripheral blood smears, the red cells are small (microcytic) and pale (hypochromic).  In established iron deficiency the zone of pallor is enlarged;  Poikilocytosis in the form of small, elongated red cells (pencil cells) is also characteristically seen.
  21. 21. HYPOCHROMIC MICROCYTIC ANEMIA OF IRON DEFICIENCY (PERIPHERAL BLOOD SMEAR). NOTE THE SMALL RED CELLS CONTAINING A NARROW RIM OF PERIPHERAL HEMOGLOBIN. SCATTERED FULLY HEMOGLOBINIZED CELLS, PRESENT DUE TO RECENT BLOOD TRANSFUSION, STAND IN CONTRAST.
  22. 22. DIAGNOSIS  Both the hemoglobin and hematocrit are depressed, usually to a moderate degree, in association with hypochromia, microcytosis, and modest poikilocytosis.  The serum iron and ferritin are low, and the total plasma iron-binding capacity (reflecting elevated transferrin levels) is high.  Low serum iron with increased iron-binding capacity results in a reduction of transferrin saturation to below 15%.  In uncomplicated iron deficiency, oral iron supplementation produces an increase in reticulocytes in about 5 to 7 days.

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