Hemoglobin-Iron Metabolism PDF

MEHMET OZANSOY, Ph.D. — The hematocrit is defined as the percentage of blood volume that is occupied by erythrocytes. — It is measured by centrifuging (spinning at high speed) a sample of blood, the erythrocytes being forced to the bottom of the centrifuge tube and the plasma to the top, the l...

MEHMET OZANSOY, Ph.D. — The hematocrit is defined as the percentage of blood volume that is occupied by erythrocytes. — It is measured by centrifuging (spinning at high speed) a sample of blood, the erythrocytes being forced to the bottom of the centrifuge tube and the plasma to the top, the leukocytes and platelets forming a very thin layer between them. — The normal hematocrit is approximately 45 percent in men and 42 percent in women — The volume of blood in an average-sized person (70 kg) is approximately 5.5 L. — If we take the hematocrit to be 45 percent, then — Erythrocyte volume = 0.45 x 5.5 L = 2.5 L — Since the volume occupied by the leukocytes and platelets is normally negligible, the plasma volume equals the difference between blood volume and erythrocyte volume — Therefore, in our average person — Plasma volume = 5.5 L - 2.5 L = 3.0 L Iron Metabolism — Because iron is important for the formation not only of hemoglobin but also of other essential elements in the body (e.g., myoglobin, cytochromes, cytochrome oxidase, peroxidase, catalase), it is important to understand the means by which iron is utilized in the body Quantity of Hemoglobin in the RBCs — Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells. — The concentration does not rise above this value, because this is the metabolic limit of the cell’s hemoglobin-forming mechanism. — Furthermore, in normal people, the percentage of hemoglobin is almost always near the maximum in each cell Hemoglobin Formation — The synthesis of hemoglobin begins in polychromatophil erythroblasts and continues even into the reticulocyte stage of the RBCs. — Therefore, when reticulocytes leave the bone marrow and pass into the blood stream, they continue to form minute quantities of hemoglobin for another day or so until they become mature erythrocytes Hemoglobin Formation Hemoglobin Formation Hemoglobin Formation Hemoglobin Formation — The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. — Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. — For example, in sickle cell anemia , the amino acid valine is substituted for glutamic acid at one point in each of the two beta chains. — When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the RBCs that are sometimes 15 micrometers in length. — These crystals make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes, leading to sickle cell anemia. Hemoglobin Combines Reversibly With Oxygen — The most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. — The primary function of hemoglobin in the body is to combine with oxygen in the lungs and then to release this oxygen readily in the peripheral tissue capillaries, where the gaseous tension of oxygen is much lower than in the lungs. Iron Metabolism — Iron is important for the formation not only of hemoglobin but also of other essential elements in the body (e.g., myoglobin, cytochromes, cytochrome oxidase, peroxidase, and catalase ). — The total quantity of iron in the body averages 4 to 5 grams, about 65% of which is in the form of hemoglobin. — About 4% is in the form of myoglobin, 1% is in the form of the various heme compounds that promote intracellular oxidation, 0.1% is combined with the protein transferrin in the blood plasma, and 15% to 30% is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin. Iron Metabolism Transport and Storage of Iron — When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. — The iron is loosely bound in the transferrin and, consequently, can be released to any tissue cell at any point in the body. — Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow. Transport and Storage of Iron — In the cell cytoplasm, iron combines mainly with a protein, apoferritin, to form ferritin. — Varying quantities of iron can combine in clusters of iron radicals with apoferritin. — Therefore, ferritin may contain only a small or a large amount of iron. This iron stored as ferritin is called storage iron . — Smaller quantities of the iron in the storage pool are in an extremely insoluble form called hemosiderin . — This is especially true when the total quantity of iron in the body is more than the apoferritin storage pool can accommodate. — Hemosiderin collects in cells in the form of large clusters that can be observed microscopically as large particles. — In contrast, ferritin particles are so small and dispersed that they usually can be seen in the cell cytoplasm only with an electron microscope. — When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed. — A unique characteristic of the transferrin molecule is that it binds strongly with receptors in the cell membranes of erythroblasts in the bone marrow. — Then, along with its bound iron, it is ingested into the erythroblasts by endocytosis. — There the transferrin delivers the iron directly to the mitochondria, where heme is synthesized. — In people who do not have adequate quantities of transferrin in their blood, failure to transport iron to the erythroblasts in this manner can cause severe hypochromic anemia (i.e., RBCs that contain much less hemoglobin than normal). Life Span and Destruction of Red Blood Cells — When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. — Once the red cell membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. — Many of the red cells self-destruct in the spleen, where they squeeze through the red pulp of the spleen. — There, the spaces between the structural trabeculae of the red pulp, through which most of the cells must pass, are only 3 micrometers wide, in comparison with the 8-micrometer diameter of the red cell. — When the spleen is removed, the number of old abnormal red cells circulating in the blood increases considerably. Destruction of Hemoglobin — When red blood cells burst and release their hemoglobin, the hemoglobin is phagocytized almost immediately by macrophages in many parts of the body, but especially by the Kupffer cells of the liver and macrophages of the spleen and bone marrow. — During the next few hours to days, the macrophages release iron from the hemoglobin and pass it back into the blood, to be carried by transferrin either to the bone marrow for the production of new red blood cells or to the liver and other tissues for storage in the form of ferritin Destruction of Hemoglobin — The porphyrin portion of the hemoglobin molecule is converted by the macrophages, through a series of stages, into the bile pigment bilirubin, which is released into the blood and later removed from the body by secretion through the liver into the bile Anemias — Anemia means deficiency of hemoglobin in the blood, which can be caused by too few RBCs or too little hemoglobin in the cells. Blood Loss Anemia — After rapid hemorrhage, the body replaces the fluid portion of the plasma in 1 to 3 days, but this response results in a low concentration of RBCs. — If a second hemorrhage does not occur, the RBC concentration usually returns to normal within 3 to 6 weeks. — When chronic blood loss occurs, a person frequently cannot absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. — RBCs that are much smaller than normal and have too little hemoglobin inside them are then produced, giving rise to microcytic hypochromic anemia Aplastic Anemia Due to Bone Marrow Dysfunction — Bone marrow aplasia means lack of functioning bone marrow. — For example, exposure to high-dose radiation or chemotherapy for cancer treatment can damage stem cells of the bone marrow, followed in a few weeks by anemia. — Likewise, high doses of certain toxic chemicals, such as insecticides or benzene in gasoline, may cause the same effect. — In autoimmune disorders, such as lupus erythematosus, the immune system begins attacking healthy cells such as bone marrow stem cells, which may lead to aplastic anemia. — In about half of aplastic anemia cases the cause is unknown, a condition called idiopathic aplastic anemia . — People with severe aplastic anemia usually die unless they are treated with blood transfusions—which can temporarily increase the numbers of RBCs—or by bone marrow transplantation. Megaloblastic Anemia — Loss of Vitamin B 12 , folic acid, or intrinsic factor from the stomach mucosa, can lead to slow reproduction of erythroblasts in the bone marrow. — As a result, the RBCs grow too large, with odd shapes, and are called megaloblasts . — Thus, atrophy of the stomach mucosa, as occurs in pernicious anemia , or loss of the entire stomach after surgical total gastrectomy can lead to megaloblastic anemia. — Also, megaloblastic anemia often develops in patients who have intestinal sprue , in which folic acid, vitamin B 12 , and other vitamin B compounds are poorly absorbed. — Because the erythroblasts in these states cannot proliferate rapidly enough to form normal numbers of RBCs, the RBCs that are formed are mostly oversized, have bizarre shapes, and have fragile membranes. — These cells rupture easily, leaving the person in dire need of an adequate number of RBCs. Pernicious Anemia — A common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. — This often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. — The parietal cells of the gastric glands secrete a glycoprotein called intrinsic factor, which combines with vitamin B12 in food and makes the B12 available for absorption by the gut Pernicious Anemia — Intrinsic factor binds tightly with the vitamin B12. — In this bound state, the B12 is protected from digestion by the gastrointestinal secretions. — Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border membranes of the mucosal cells in the ileum. — Then, vitamin B12 is transported into the blood during the next few hours by the process of pinocytosis, carrying intrinsic factor and the vitamin together through the membrane Pernicious Anemia — Once vitamin B12 has been absorbed from the gastrointestinal tract, it is first stored in large quantities in the liver, then released slowly as needed by the bone marrow — The minimum amount of vitamin B12 required each day to maintain normal red cell maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount. — Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia. Deficiency of Folic Acid — Folic acid is a normal constituent of green vegetables, some fruits, and meats (especially liver). — However, it is easily destroyed during cooking. — Also, people with gastrointestinal absorption abnormalities, such as the frequently occurring small intestinal disease called sprue (Coeliac disease), often have serious difficulty absorbing both folic acid and vitamin B12. — Therefore, in many instances of maturation failure, the cause is deficiency of intestinal absorption of both folic acid and vitamin B12. Hemolytic Anemia — Different abnormalities of the RBCs, many of which are acquired through hereditary, make the cells fragile, so they rupture easily as they go through the capillaries, especially through the spleen. — Even though the number of RBCs formed may be normal, or even much greater than normal in some hemolytic diseases, the life span of the fragile RBC is so short that the cells are destroyed faster than they can be formed, and serious anemia results. — In hereditary spherocytosis , the RBCs are very small and spherical rather than being biconcave discs. — These cells cannot withstand compression forces because they do not have the normal loose, baglike cell membrane structure of the biconcave discs. — On passing through the splenic pulp and some other tight vascular beds, they are easily ruptured by even slight compression. — In sickle cell anemia , which is present in 0.3% to 1.0% of Black people in West Africa and the Americas, the cells have an abnormal type of hemoglobin called hemoglobin S , containing faulty beta chains in the hemoglobin molecule. — When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long crystals inside the RBC. — These crystals elongate the cell and give it the appearance of a sickle rather than a biconcave disc. — The precipitated hemoglobin also damages the cell membrane, so the cells become highly fragile, leading to serious anemia. — Such patients frequently experience a vicious circle of events called a sickle cell disease crisis , in which low oxygen tension in the tissues causes sickling, which leads to ruptured RBCs, which causes a further decrease in oxygen tension and still more sickling and RBC destruction. — In erythroblastosis fetalis , Rh-positive RBCs in the fetus are attacked by antibodies from an Rh-negative mother. — These antibodies make the Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with a serious case of anemia. — The extremely rapid formation of new RBCs to make up for the destroyed cells in erythroblastosis fetalis causes a large number of early blast forms of RBCs to be released from the bone marrow into the blood. Polycythemia — Whenever the tissues become hypoxic because of too little oxygen in the breathed air, such as at high altitudes, or because of failure of oxygen delivery to the tissues, such as in cardiac failure, the bloodforming organs automatically produce large quantities of extra RBCs. — This condition is called secondary polycythemia , and the RBC count commonly rises to 6 to 7 million/mm 3 , about 30% above normal. — A common type of secondary polycythemia, called physiological polycythemia , occurs in those who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low. — The blood count is generally 6 to 7 million/mm 3 , which allows these people to perform reasonably high levels of continuous work, even in a rarefied atmosphere. Polycythemia Vera (Erythremia) — In addition to physiological polycythemia, a pathological condition known as polycythemia vera exists, in which the RBC count may be 7 to 8 million/mm 3 and the hematocrit may be 60% to 70% instead of the normal 40% to 45%. — Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells. — The blast cells no longer stop producing RBCs when too many cells are already present. — This causes excess production of RBCs. — It usually causes excess production of white blood cells and platelets as well. — In polycythemia vera, not only does the hematocrit increase, but the total blood volume also increases, sometimes to almost twice normal. — As a result, the entire vascular system becomes intensely engorged. — Also, many blood capillaries become plugged by the viscous blood; the viscosity of the blood in polycythemia vera sometimes increases from the normal of 3 times the viscosity of water to 10 times that of water.