Iron & Porphyrin Metabolism PDF

IRON & PORPHYRIN METABOLISM PATHOLOGIC CONDITIONS & LABORATORY TESTS 15-16/10/2024 Prof. Dr. Halil RESMİ  IRON METABOLISM & RELATED DISEASE 2   Iron is the most abudant element in the earth, but only trace amounts are present in living cells....

IRON & PORPHYRIN METABOLISM PATHOLOGIC CONDITIONS & LABORATORY TESTS 15-16/10/2024 Prof. Dr. Halil RESMİ  IRON METABOLISM & RELATED DISEASE 2   Iron is the most abudant element in the earth, but only trace amounts are present in living cells.  Most iron in the human body presents porphyrin ring of heme, which is incorporated into proteins such as hemoglobin, myoglobin, catalase, peroxidases and cytochromes. 3  Iron  An average man/woman has 4/2-3 g of iron in his/her body.  About,  65-70% in hemoglobin,  10% in myoglobin and other enzymes,  20-25% found in storage form. 4  Metabolism  Daily reqiurement of iron depends on person’s age, gender and physiological status.  About 1 mg of iron is lost daily through the normal sheeding of epithelial cells and cells that line gastrointestinal and urinary tracts.  Small number of erythrocyte are lost in urine and feces. 5  Daily need  Absorption of 1 mg of iron per day is sufficient for men and postmenopausal women,  The blood lost in each menstrual cycle has 20-40 mg of iron,  Women in their reproductive years need to absorb 2 mg iron per day. 6   The growing fetus during pregnancy, blood loss during delivery and feeding an infant need additional 1 g of iron.  This increases daily iron demand to 3-4 mg in pregnanat and lactating women. 7  Absorption  There are two types of absorbable dietary iron: heme and non-heme iron.  Heme iron, derived from hemoglobin and myoglobin of animal food sources (meat, seafood, poultry), is the most easily absorbable form (15% to 35%) and contributes 10% or more of our total absorbed iron.  Non-heme iron is derived from plants and iron- fortified foods and is less well absorbed. 8  Absorption  A healthy diet contains 10-20 mg of iron per day,  Only 5-10% of this amount is absorbed, mainly in duodenum and the upper small intestine,  Most dietary iron is in ferric (Fe3+) state and must be converted to ferrous (Fe2+) state before it can enter epithelial cells,  A brush border enzyme, ferric reductase converts ferric iron to ferrous iron. 9 10  Absorption  Ferrous iron then is transported into cell by a divalent metal transporter (DMP),  Substances that form insoluble complex with iron, such as phosphates (in eggs, cheese and milk), oxalates and phytates (in vegetable) and tannates (in tea) decrease iron absorption.  Heme iron is absorbed in different way,  Heme is directly absorbed by cells. 11  Absorption  In the epithelial cell, ring is split and iron is liberated.  This process is most efficient than the absorption of nonheme iron.  In intestinal epithelial cells, iron is incorporated into ferritin for storage,  Or it is transferred across its basolateral surface into blood. 12  Red Blood Cell Turnover  Absorbed iron represents only a fraction of the iron required for heme synthesis,  Most of iron (20-25 mg/day) comes from the destruction of old erythrocyte by tissue macrophage, primarily in the spleen,  Iron is bound to transferrin and then transported to bone marrow for heme synthesis. 13  Transport & Cell Uptake  Free iron is toxic to cells and biomolecules,  Iron is bound to specific proteins during transportation,  Transferrin is the transport protein for iron in blood,  Each transferrin has two binding sites for Fe3+, that normally are 20% to 50% saturated,  Transferrin carries iron to cells with specific surface receptor for these protein. 14 15  Transferrin  Transferrin binds this receptor and then transferrin-receptor complex is taken into cell by endocytosis,  This vehicle has a acidic medium and acidity results in releasing of iron from transferrin inside the cell,  Iron is used for heme synthesis or stored as ferritin. 16  Storage  Iron is stored in tissues in one of two forms; Ferritin or Hemosiderin.  Ferritin is present in most cells and is a readily mobilized form of storage iron.  Hemosiderin is an insoluble complex derived from ferritin, it is present in the granules.  Hemosiderin has a higher iron concentration than ferritin, but it releases iron more slowly. 17 About one-third of body’s iron reserve is in the liver, one-third in the bone marrow and remainder is in the spleen and other tissues. Dark hemosiderin granules in Kupffer liver cells (Prussian blue stain) 18 Clumping of ferritin particles with amorphous protein to form hemosiderin aggregates  Control of Iron Balance  Because iron loss is continuous and largely uncontrolled process, iron balance is controlled by change in absorption.  The major factors that affect iron absorption;  Body iron stores,  The rate of red blood cell production. 19  The absorption and tissue distribution of iron is principally controlled by the interaction of the hepatic hormone hepcidin with ferroportin. Ferroportin is expressed in iron-storing and iron- transporting tissues and functions both as the hepcidin receptor and the sole known cellular exporter of elemental 20 iron in multicellular organisms.   The conditions that stimulate iron absorption;  Iron deficiency,  Pregnancy,  Accelerated erythropoiesis. 21  PATHOLOGICAL CONDITIONS 22  Iron Deficiency  Iron deficiency is the most common nutritional disorder in humans, also is the most frequent cause of anemia.  Iron deficiency is more frequent;  Women,  People with low socioeconomics status,  After a gastrointestinal surgery,  Patient with chronic diarrhea. 23  Iron Deficiency  Iron deficiency develops in stages, when iron reserves has been exhausted, biochemical tests of iron metabolism become abnormal (even though anemia may not be seen).  Next steps;  A decrease in Hb concentration,  Red blood cells become paler (hypochromic).  In a fully developed iron deficiency anemia, MCV, MCH and MCHC also decreased. 26   Examination of peripheral blood smear shows;  Hypochromic,  Microcytic,  Anisocytosis (erythrocytes with abnormal size and shape). 27  Iron deficiency tests  Lab tests can distinguish iron deficiency from other causes of hypochrom, microcytic anemia;  Serum iron… low  Total Iron Binding Capacity (TIBC)… high  Transferrin saturation… low  Serum ferritin… low  Free Erythrocyte Protoporphrin (FEP)… high 28  [TIBC (total iron-binding capacity)— measures the total amount of iron that can be bound by proteins in the blood. Since transferrin is the primary iron-binding protein, the TIBC test is a reliable, indirect measurement of transferrin availability]  Although TIBC and transferrin are two different tests, they basically measure the same thing.  As transferrin is produced by the liver, TIBC value may also be low in a liver disease. 29   [Transferrin saturation— dividing the iron concentration by the TIBC produces an estimate of how many of transferrin iron- binding sites are occupied; this is called the transferrin saturation.] 30  Iron Overload  Hereditary hemochromatosis is a genetic disease charcterised by a progressive increase in iron stores, leading to organ impairment and damage.  Patient with hereditary hemochromatosis may absorbe 4 mg of iron or more per day, even on a usual diet.  Excessive amount of iron is deposited in liver, pancreas, heart, skin and other organs. 31   In hereditary hemochromatosis;  Serum iron…high  TIBC…low  Transferrin saturation… high  Iron overload can be an acquired disorder, called Acquired Hemochromatosis.  Ineffective erythropoiesis may result in acquired hemochromatosis (as in β-thalassemia major),  Blood transfusions can further increase iron overload,  Medicinal iron supplements do not cause 32 hemochromatosis.  CHANGE OF ANALYTE IN DISEASE 33  Lab tools for iron metabolism  The clinical laboratory can measure three iron compartment, which account for 90% of total body iron;  Hemoglobin (the largest pool, measured as a part of CBC),  Serum iron/transferrin,  Serum ferritin.  The combination of these tests enables one to identify disorder of iron metabolism. 34  Complete Blood Count (CBC)  A complete blood count gives the number of erythrocytes, hemoglobin concentration and red blood cell indices.  WHO defines anemia as a hemoglobin concentration; 