Iron Metabolism & Hypochromic Anemia PDF

22/10/2022 Iron Metabolism & Hypochromic Anemias Chapter 6 Week 8 Rania Ab Seir, Ph. D. Associate Professor of Hematology...

22/10/2022 Iron Metabolism & Hypochromic Anemias Chapter 6 Week 8 Rania Ab Seir, Ph. D. Associate Professor of Hematology Clinical Hematology I (0202306) Harmening DM. Clinical Hematology & Fundamentals of Hemostasis, 5th ed. Philadephia: F.A. Davis 2009. Objectives State the function of Iron in relation to hemoglobin Discuss normal Iron metabolism, distribution and requirements Discuss the absorption and transport of Iron Evaluate laboratory tests that are used to differentiate and identify categories of different types of anemia (IDA, Sideroblastic anemia) 2 1  22/10/2022 Normal Iron Metabolism Distribution and Requirements In food, it exists as Ferric Hydroxide compounds (liver, meat, green vegetables) Average requirement: 1mg/day in males Average total Fe in adult: 3.5-4.0 gm 2/3 of this is used in Hb synthesis 1/3 in the Hb 95% of Fe needed for Erythropoiesis is from recycled Fe from RBC destruction and Hb metabolism. 3 Normal Iron Metabolism Distribution and Requirements Total dietary Fe is 10-20 mg/day in the normal adult. Only 10% of this is reabsorbed (1-2 mg) to balance the loss of Fe in feces, sweat and urine. The remaining is stored within liver, spleen, bone marrow, Myoglobin, electron transport proteins and Myeloperoxidase 4 2  22/10/2022 Daily Requirements, Absorption, and Transport Min daily requirement for iron Infant: 1mg Child: 0.5 mg Menstruating woman:2 mg Pregnant or lactating woman: 3 mg Adult man or non-menstruating woman:1 mg Physiologic & pathologic factors affecting iron requirements Growth spurts Menstruation Pregnancy Lactation /breast-feeding Iron deficiency 5 Iron Absorption Fe is absorbed in the GIT mainly in the small intestines. In the stomach (dec. pH, redox substances ), Fe+3 of food is converted to Fe+2 Fe+2 traverses the intestinal cells to the bloodstream. It is converted to Fe+3 by serum Ferroxidase. Fe+3 is carried by a protein carrier Transferrin. Then it is transported to BM to the Rubriblasts for Heme synthesis & to muscles for Myoglobin. 6 3  22/10/2022 Figure 6-1 Daily iron turnover and body iron distribution. 7 Table 6–1 Minimum Daily Requirement (MDR) for Iron Individual MDR (mg) Infant 1.0 Child 0.5 Menstruating woman 2.0 Pregnant or lactating woman 3.0 Adult man or nonmenstruating 1.0 woman 8 4  22/10/2022 Table 6–2 Iron-Containing Foods Foods High in Iron Foods Moderate in Iron Organ meats Muscle meats (beef, fish, fowl) Wheat germ Prunes Brewer's yeast Cereals Legumes Green vegetables Whole grain breads Shrimp Oatmeal Oysters 9 Table 6–3 Substances that Increase and Decrease the Absorption of Iron Increased Decreased Ingestion of acidic foods Phosphates Ascorbic acid (vitamin C) Phytates Foods that form insoluble iron complexes 10 5  22/10/2022 Iron Storage Iron is stored in mononuclear phagocytic system (MNP) and RE of BM, liver, and spleen. Over-needed Fe is stored as Ferritin (water soluble ), major, easily mobilized Hemosiderin (insoluble form) When Fe is absorbed in excess of Ferritin storage capacity, it is deposited in Macrophages as Hemosiderin. 11 Iron Storage In BM, erythroid nucleated cells with hemosiderin granules are called Sideroblasts. In PB, the granules are called Pappenheimer Bodies, and the cells are Siderocytes. Hemosiderin is stained by Prussian Blue stain. 12 6  22/10/2022 Bodily Iron Distribution & Turnover Average western diet contain ~15mg iron >> only 5-10% is absorbed or 1- 2mg Iron absorption can increase up to 20-30% in case of ID or pregnancy 13 Iron Absorption, Storage & Utilization Diet iron should be in ferrous state to absorbed and is inhibited by tannins (plant polyphenols in diet). Heme iron derived from meat is absorbed as heme and iron is freed inside enterocytes Figure 6-2 Schematic of iron intake and absorption through the mucosal cells in the small intestine. Absorbed iron is converted to ferritin for storage or transported bound to 14 transferrin for distribution to body tissues. 7  22/10/2022 Normal Iron Metabolism Total Body iron, in a 70-kg adult male Total % Male (mg) Female (mg) Hb iron 65 2400 1700 Storage iron (ferritin & hemosiderin) 30 1000 (30-1500) 300 (0-1000) Myoglobin in muscles 3.5 150 120 Heme enzymes (cytochromes, 0.5 20 15 catalse,..) Transferrin-bound iron (transport 0.1 4 3 iron) 100% ~3500 mg Total body iron in adult Male (Female) is 50 (40) mg/kg body weight 15 Table 6–4 Iron (Fe) Molecules and Compounds 16 Hemosiderin can be revealed by Prussian blue stain ;or by H&E stain as golden brown granules 8  22/10/2022 Table 6–5 Factors Affecting Iron Absorption Amount and type of iron accessible from food Functional state of gastrointestinal mucosa and pancreas Current iron stores Erythropoietic needs 17 Table 6–6 Proteins Involved in Iron Metabolism Protein Structure Function Single-chain glycoprotein with two iron binding Iron-binding transport protein in plasma Transferrin sites and extracellular fluid Transferrin Transmembrane glycoprotein diamer with two Receptor mediated ferric transferrin receptor transferrin binding sites Ferritin Spherical protein binds up to 4500 iron atoms Iron storage MHC class I glycoprotein complexes with B2- HFE binds with transferrin receptor HFE microglobulin reducing the affinity for transferrin Iron transport protein from GI lumen into DMT1 Single chain glycoprotein the duodenal enterocyte; from erythroblast endosome to cytoplasm Involved with iron metabolism. Increased Hepcidin Liver synthesized peptide in iron over-loading and decreased in iron deficiency HFE = hemochromatosis gene protein; MHC = major histocompatibility complex; DMT1 = divalent 18 metal transporter 1; GI = gastrointestinal. 9  22/10/2022 Table 6–8 High-Risk Groups Prenatal/Neonatal Infancy/Childhood Adolescent/Adult Social/Economic Premature birth Restricted diets Fad diets Low Low birth weight Lack of iron Menstruation socioeconomic Anemia during supplements Excessive weight groups pregnancy Growth spurts gain Recent Low iron formula Chronic infection Pregnancy immigration from Lack of iron Chronic or acute Lactation and developing supplements blood loss breast feeding countries after 6 months in Elderly breastfed infants Improper diet Chronic bleeding Gastrointestinal bleeding 19 Laboratory Evaluation of Iron Status The lab assessment of Iron includes: Serum Fe Total Iron Binding Capacity (TIBC) Transferrin Saturation (TsS) Ferritin level Transferrin Receptors (TsRs) Free Erythrocyte Protoporphyrin (FEP) and Zinc Protoporphyrin (ZPP) 20 10  22/10/2022 Laboratory Evaluation of Iron Status The lab assessment of Iron includes: Serum Fe: Is a measure of transferrin-bound iron Early morning specimens due to diurnal variation Total Iron Binding Capacity (TIBC) TIBC= amount of Fe in serum that transferrin can bind at any one time, this is limited by transferrin content. Each gm of T binds 1.4 mg iron 21 Laboratory Evaluation of Iron Status TIBC – Ser.Fe = Unsaturated Fe binding capacity (UIBC) amount of additional Fe that transferrin can bind above that which is already complexed. Transferrin Saturation = %saturation= Ser. Fe /TIBC x 100% 22 11  22/10/2022 Laboratory Evaluation of Iron Status Ferritin level Proportional to stored iron Better than serum iron and TIBC Good index for iron depletion It is an acute phase reactant, so inc in inflammatory states, malignancy, infections,… Transferrin Receptors (TsRs) Inversely proportional to the amount of iron Inc. when iron stores are depleted as regulatory proteins inc. its synthesis It is not inc. in anemia of chronic diseases 23 Laboratory Evaluation of Iron Status Free Erythrocyte Protoporphyrin (FEP) and Zinc Protoporphyrin (ZPP) FEP is a heme precursor In iron depletion, excess protoporphyrin is formed ZPP: zinc complexed with excess P Inc. in iron deficient erythropoiesis 24 12  22/10/2022 Laboratory Evaluation of Iron Status Reticulocyte Production Index (RPI ) = %reticulocytes x Patient Hct. Maturation time Normal average Hct(45%) (If >2.5---Hemolytic Anemia ) 25 Assessment of Body Iron Status Reverence range (adults) Measurement SI units Conventional units M 50-160 µg/dL Serum iron 10-30 µmol/L F 40-150 µg/dL TIBC 250-400 µg/dL 47-70 µmol/L Transferrin saturation (iron/TIBC 20-50% X100) ID 0-12 µg/L Serum Ferritin Borderline 13-20 µg/L Excess >400 µg/L Serum Transferrin receptor (sTfR) 2.8-8.5 mg/L Red cell zinc protoporphyrin (ZPP)