L7-IRON METABOLISM.pdf

L 7 IRON METABOLISM ILOs By the end of this lecture, students will be able to: 1. Appraise distribution and functions of iron in the human body 2. Describe absorption, transport, and storage of iron 3. Correlate iron excess and deficiency to clinical conditions 4. Outline markers used for assessment...

L 7 IRON METABOLISM ILOs By the end of this lecture, students will be able to: 1. Appraise distribution and functions of iron in the human body 2. Describe absorption, transport, and storage of iron 3. Correlate iron excess and deficiency to clinical conditions 4. Outline markers used for assessment of iron status Iron is an essential trace element (present in living tissues in small amounts) needed for various metabolic processes in in every cell of the body. Functions of Iron 1. O2 transport: Iron is an essential component of both hemoglobin and myoglobin. 2. Cellular respiration: Iron is present in the iron–sulfur clusters of the electron transport chain proteins and therefore plays an important part in the generation of energy from cellular respiration. 3. Antioxidant mineral: Catalase is a heme enzyme that is present in nearly all aerobic cells. Catalase converts the reactive oxygen species hydrogen peroxide to water and oxygen and iron is a cofactor for this antioxidant enzyme. N.B. Aided by the fact that it may exist in two stable states; ferrous (Fe2+) and ferric (Fe3+), iron participates in the formation of hydroxide and hydroxyl radical by a reaction between Iron (II) (Fe2+) and hydrogen peroxide (H2O2) known as “Fenton reaction” this reaction is the most dangerous in free radical–mediated toxicity in cells. Iron Balance, Daily Requirements and Dietary Sources The total body content of iron in normal adults is about 4 g. Approximately 30 mg/day is required for hemoglobin synthesis in new red cells and the majority of this is supplied from the reticuloendothelial macrophages that recycle the iron from senescent red cells. About 1mg per day is lost (mostly in stools, by bleeding and shedding epithelial cells of the mucosa and skin). Women of childbearing age have additional loss of 0.5 mg per day from menses. 1 This iron loss is balanced by absorption of iron. Around 10% of the dietary iron is absorbed. Therefore, the adult recommended daily allowance in males is about 10 mg and in females is about 18 mg. Infants, adolescents and pregnant females require additional iron during periods of rapid growth. Dietary iron comes in two forms: heme and non-heme. Heme iron is derived from hemoglobin and myoglobin of animal food sources like meat, poultry, and seafood. Non-heme iron is found in plant foods like nuts, seeds, legumes, and green vegetables as spinach. Heme iron is better absorbed by the body than non-heme iron. Iron Absorption Absorption of ferrous iron occurs in the proximal duodenum. It is aided by the low pH of the hydrochloric acid secreted into the gastric lumen and the presence of reducing agents such as ascorbic acid (vitamin C), which help maintain the iron in the more soluble ferrous form. In contrast, other agents such as tannins (found in tea), phytates (found in grains such as oats) and phosphates bind the iron within the intestinal lumen, inhibiting its absorption. Also, lowered gastric acidity (hypochlorhydria and achlorhydria) decrease iron absorption. Once ferric iron is reduced to ferrous iron in the intestinal lumen, a protein on the apical membrane of enterocytes called Divalent Metal Cation Transporter 1 (DMT1) transports iron across the apical membrane and into the cell. Once inside the enterocyte, iron can be oxidized and stored as Ferritin or transported through the basolateral membrane and into circulation bound to Ferroportin. The body has no mechanism for excreting iron, so controlling its absorption into the mucosal cells is crucial. No other nutrient is regulated in this manner. This control is achieved by the action of Hepcidin, an iron-regulating hormone made in the liver. It controls the delivery of iron to blood from intestinal cells. Hepcidin acts by binding to and inactivating ferroportin. In a classical feedback system, hepcidin production is stimulated by increased plasma iron which leads to decreased iron absorption, matching iron supply to demand. Iron Transport and Storage Absorbed Iron and that released from hemoglobin in the reticuloendothelial macrophages is bound to proteins for storage in cells and for transport in the blood. Important proteins in this context are:  Ferritin: Ferritin oxidizes Fe2+ to Fe3+ for storage of normal amounts of Fe3+ in tissues. 2    Under conditions of iron overload (e.g., hemorrhage), Hemosiderin is generated from ferritin denaturation. Hemosiderin binds excess Fe3+ to prevent its escape into the blood, where it is toxic. Ferroxidase: (also known as ceruloplasmin, a Cu2+ protein) oxidizes Fe2+ to Fe3+ for transport Transferrin: carries Fe3+ in blood and delivers it to tissues for synthesis of heme. Iron Absorption, Transport and Storage Abnormal Iron Metabolism Failing to maintain iron levels within the healthy limits can lead to clinical consequences including the following: I. Iron Deficiency Anemia Iron deficiency anemia is one of the commonest causes of anemia worldwide. It is a hypochromic microcytic anemia with clinical features including pallor, fatigue, koilonychia (a spoon-shaped malformation of the nails), and brittle hair causing alopecia (Hair loss). - Causes: 1. Increased iron loss: Iron deficiency is most commonly secondary to excessive bleeding, usually from gastrointestinal or menstrual sources. In the developing world, hookworm 3 infestation resulting in gastrointestinal blood loss is the commonest cause of iron deficiency anemia. 2. Decreased iron uptake: e.g., Diet low in iron rich foods or malabsorption due to diseases associated with flattening of the duodenal mucosal villi. b a c d e Clinical features of iron deficiency anemia: a) microcytic hypochromic anemia, b) fatigue, c) pallor, d) koilonychia and e) alopecia II. Iron Overload Systemic iron overload leads to pathological increase in iron body stores, leading to iron deposition diseases. - Causes: 1. Hemochromatosis: is due to a genetic disorder caused by hepcidin deficiency and is characterized by excessive intestinal absorption of dietary iron, resulting in systemic deposition of iron in the liver, pancreas, heart, and other organs causing serious tissue damage. Primary hemochromatosis is sometimes referred to as bronze diabetes because it can lead to darkening of the skin. 2. Hemosiderosis: is deposition of hemosiderin in the reticuloendothelial system, which includes the reticuloendothelial cells of the spleen and bone marrow and the Kupffer cells of the liver, usually due to multiple blood transfusion, or hemorrhage. When the reticuloendothelial system is saturated, deposition occurs in other body tissues leading to secondary hemochromatosis 4 Treatment of both conditions includes iron chelation therapy using Deferoxamine Hemochromatosis Laboratory Determination of Iron Status - Serum iron level Measures the amount of iron in the blood - Serum ferritin Ferritin is a cytoplasmic iron storage protein. Small amounts are secreted into the serum where it functions as an iron carrier providing an accurate reflection of iron stores. - Transferrin and Total Iron Binding Capacity In the plasma, each molecule of transferrin binds up to two atoms of ferric iron (Fe3+) and serum Transferrin are normally only one third saturated with iron. The total iron binding capacity (TIBC) of plasma reflects the amount of transferrin in blood that's available to attach to iron. Therefore, in case of iron deficiency where iron level is expected to be low, TIBC will be high and in iron overload where iron level is high, the TIBC will be low. 5