Transcript آهن و TIBC
ANEMIA & IRON METABOLISM Hossein Piri Department of Biochemistry and Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran September 2014 Classification of anemia Morphologic Normocytic: MCV= 80-100fL Macrocytic: MCV > 100 fL Microcytic : MCV < 80 fL Pathogenic (underlying mechanism) Blood loss (bleeding) Decreased RBC production Increased RBC destruction/pooling Normocytic Anemias Acute post-hemorrhagic anemia Hemolytic anemia (except thalassemia and some other Hb disorders) Endocrin diseases Renal failure Liver disease Chronic disease anemia Protein malnutrition Hypovitaminosis C Microcytic anemias Iron deficiency anemia Thalassemia Sideroblastic anemia Hereditary Chronic lead poisoning Anemia of chronic diseases (some cases) Megaloblastic Macrocytic Anemias Vit B12 deficiency Folic acid deficiency Other. Pathogenic classification (Causes of anemia) Relative (increased plasma volume) Decreased RBC production Blood loss Anemia due to acute bleeding Increased RBC destruction Pathogenic classification (Causes of anemia) Decreased RBC production – Decreased Hb production – Defective DNA synthesis – Stem cell defects Blood loss – Anemia due to acute bleeding Increased RBC destruction Relative(increased plasma volume) Decreased Hb production Iron deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning Defective DNA synthesis Vit B12 deficiency Folic acid deficiency Other. Anemias caused by increased RBC destruction (hemolytic anemias) Can be classified as; Hereditary hemolytic diseases Acquired hem. Diseases Iron & (TIBC) آهن عملکرد: انتقال اکسیژن تنفس متابولیسم اسیدهای آمینه و رادیکال آزاد ،لیپیدها ،فسفریلسیون اکسیداتیو جزئی از Hbو متالوآنزیم ها تركيبات آهن داربدن آهن هم()Heme Iron ترانسفرين هموسيدرين فريتين آهن غيرهم )(None heme Iron هموگلوبين)(Hb ميوگلوبين آهن بافتي (آنزيمهاي تنفس ي) Iron Transport into Plasma Duodenal cytochrome b Senescent Macrophages RBC Macrophage Hb Fe FerroFerroportin portin 1 1 Ferroportin 1 Adapted frlm Andrews, NEJM 1999;341:1986 Fe+2+2 Fe Ceruloplasmin Fe+3 Tf Receptor-Mediated Endocytosis Andrews N, NEJM 1999;341:1986 Food iron is predominantly in the ferric state. In the stomach, where the pH is less than 4, Fe3+ can dissociate and react with low-molecular weight compounds such fructose, ascorbic acid, citric acid, amino acids to form ferric complexes soluble in neutral pH of intestine fluid. A protein DMT1 (divalent metal transporter 1), which transports all kinds of divalent metals, then transports the iron across the cell membrane of intestinal cells. These intestinal lining cells can then store the iron as ferritin. The transfer of iron from the storage ferritin (as Fe3+ ) involves reduction to ferrous state – Fe2+ in order for it to be released from ferritine. The Fe2+ is subsequently again oxidized by ferroxidase ceruloplasmin and transported bound to plasma transferrin to storage sites in the bone marrow, liver muscle, other tissues. جذب ،انتقال و دفع آهن(متابوليسم آهن) اريتروپوئز و سنتز هم Bone marrow )RBC(blood خون ريزي و دفع از طرق ديگر اريتروپوئز غيرموثر Phagocytes تخريب RBC , Hb جذب روده اي & Plasma ECF ذخيره سازي به صورت فريتين و هموسيدرين Transferrin (TRF) TRF (sidrophilin) is a plasma transport protein for iron (β1) Single polypeptide chain ,79.6 kDa, 5.5% carbohydrate. Reversibly bind to divalent cations, TRF accounts for TIBC of plasma One TRF binds two Fe+3, TRF- Fe+3 complex transports iron to cells Every cell type has surface receptors of TRF TRF is synthesized by liver Plasma levels are regulated by iron availability (iron↓, TRF↑) One-half of TRF exists in extravascular spaces 4/8/2016 Plasma Proteins 19 Receptors for TRF After binding the TRF - Fe+3 -receptor complex is internalized, resulting in release of iron from TRF Free Fe+3, is cytotoxic, is reduced and incorporated into ferritin and hemosiderin, for synthesis of compounds, such as Hb, myoglobin, and cytochromes The receptor-apo TRF complex is recycled to the cell surface where the apo TRF is released and recycled, making the receptor available again for binding 4/8/2016 Plasma Proteins 20 Clinical Significance Differential diagnosis of anemia: In hypochromic microcytic anemia: Elevated TRF & less saturated : Iron deficiency (saturation normally 30% to 38%) Low or normal TRF & highly saturated: Iron nondependency Estrogen increases TRF synthesis, TRF is a negative APP 4/8/2016 Plasma Proteins 21 ناهنجاريهاي متابوليسم آهن آرتريت آريتمي قلبي كمبود آهن )(Iron deficiency افزايش آهن )(Iron overload هموسيدروز -هموكروماتوز(اوليه ،ثانويه) نارسايي قلبي سيروزكبدي هيپوتيروئيديسم سرطان كبد ديابت مليتوس هيپرپيگمانتاسيون آهن اثرات کمبود: آنمی هیپوکرومیک میکروسیت التهاب دهانی دیستروفی ناخن دست اثرات سمیت: هموکروماتوز اولیه علل عمده افزايش Fe افزايش تخريب RBCيا هموليز افزايش رها سازي آهن و يا فريتين ازبافتها (نكروزحاد كبد) كاهش توليد ( Hbمسموميت با ، pbكمبود پيريدوكسين) اريتروپوئز غير موثر)(Ineffective erythropoesis افزايش جذب آهن)(Iron overload مصرف قرصهاي آهن ترانسفوزيون مكرر مصرف داروهاي ضد حاملگي پروژستروني آلودگي سرنگ يا ظرف نمونه علل عمده كاهش Fe سندرم سوءتغذيه و سوءجذب خونريزي مزمن و مكرر اختالل دررهاسازي آهن ازسيستم رتيكولواندوتليال(عفونت و اختالالت التهابي مزمن) بيماريهاي مزمن(عفونت و بدخيمي) بيماريهاي حاد(عفونت) كواشيوركور نفروز(سندرم نفروتيك) Porphyrines Heme Biosynthesis نقش ویتامين های B9و B12دراریتروپوئز بيوسنتزپورين ها ازمسيرتوليد داخلي CO2 Gly Asp MethenylTHF FormylTHF Amide Nitrogen of Gln dTMPسنتز suicide inhibitor Breast and colon cancer تیمیدیلت سنتاز Aminopterin Trimethoprim Essential Nutrients for Erythropoiesis Folic Acid Enzyme Function Thymidylate synthetase DNA synth. Cobalamin Methionine synthetase DNA synth. Iron Ferrochelatase Hb synth. Source Vegetables, fruit, liver Meats, milk, eggs Meats, fortification Absorp. Prox. Intest. Term. Ileum Prox. Intest. Storage Liver Liver, kidney Macrophages