ANEMIA & IRON METABOLISM

1. ANEMIA & IRON METABOLISM Hossein PiriDepartment of Biochemistry and Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran September 2014

2. 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

3. 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 Normocytic Anemias

4. Microcytic anemias • Iron deficiency anemia • Thalassemia • Sideroblastic anemia • Hereditary • Chronic lead poisoning • Anemia of chronic diseases (some cases)

5. Megaloblastic Macrocytic Anemias • Vit B12 deficiency • Folic acid deficiency • Other.

6. Pathogenic classification(Causes of anemia) • Relative (increased plasma volume) • Decreased RBC production • Blood loss • Anemia due to acute bleeding • Increased RBC destruction

7. 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)

8. Decreased Hb production • Iron deficiency anemia • Thalassemia • Sideroblastic anemia • Lead poisoning

9. Defective DNA synthesis • Vit B12 deficiency • Folic acid deficiency • Other.

10. Anemias caused by increased RBC destruction (hemolytic anemias) Can be classified as; • Hereditary hemolytic diseases • Acquired hem. Diseases

12. Iron& (TIBC)

13. آهن • عملکرد: • انتقال اکسیژن • تنفس • متابولیسم اسیدهای آمینه و رادیکال آزاد، لیپیدها، فسفریلاسیون اکسیداتیو • جزئی از Hb و متالوآنزیم ها

14. تركيبات آهن دار بدن • آهن هم(Heme Iron) ترانسفرين هموسيدرين فريتين • آهن غير هم(None heme Iron) هموگلوبين(Hb) ميوگلوبين آهن بافتي (آنزيمهاي تنفسي)

15. Duodenal Duodenal cytochrome cytochrome b b Senescent RBC Macrophages Macrophage Hb Fe Ferro- portin 1 Cerulo- plasmin Ferroportin 1 Tf Ferroportin Ferroportin 1 1 +2 Fe +2 Fe Fe+3 Adapted frlm Andrews, NEJM 1999;341:1986 Iron Transport into Plasma

16. Receptor-Mediated Endocytosis Andrews N, NEJM 1999;341:1986

17. 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.

18. جذب ، انتقال و دفع آهن(متابوليسم آهن) اريتروپوئز و سنتز هم Bone marrow جذب روده اي Plasma &ECF RBC(blood) اريتروپوئز غيرموثر Phagocytes تخريبRBC , Hb خون ريزي و دفع از طرق ديگر ذخيره سازي به صورت فريتين و هموسيدرين

19. 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 Plasma Proteins

20. 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 Plasma Proteins

21. Clinical Significance Differential diagnosis of anemia: • In hypochromicmicrocytic anemia: Elevated TRF & less saturated : Iron deficiency (saturation normally 30% to 38%) • Low or normal TRF & highly saturated: Iron non-dependency • Estrogen increases TRF synthesis, • TRF is a negative APP Plasma Proteins

22. ناهنجاريهاي متابوليسم آهن آرتريت آريتمي قلبي نارسايي قلبي سيروز كبدي هيپوتيروئيديسم سرطان كبد ديابت مليتوس هيپرپيگمانتاسيون كمبود آهن (Iron deficiency) افزايش آهن (Iron overload) - هموسيدروز - هموكروماتوز(اوليه، ثانويه)

23. آهن • اثرات کمبود: • آنمی هیپوکرومیک میکروسیت • التهاب دهانی • دیستروفی ناخن دست • اثرات سمیت: • هموکروماتوز اولیه

24. علل عمده افزايش Fe • افزايش تخريب RBC يا هموليز • افزايش رها سازي آهن و يا فريتين از بافتها (نكروز حاد كبد) • كاهش توليد Hb (مسموميت با pb ، كمبود پيريدوكسين) • اريتروپوئز غير موثر(Ineffectiveerythropoesis) • افزايش جذب آهن(Ironoverload) • مصرف قرصهاي آهن • ترانسفوزيون مكرر • مصرف داروهاي ضد حاملگي پروژستروني • آلودگي سرنگ يا ظرف نمونه

25. علل عمده كاهش Fe • سندرم سوءتغذيه و سوءجذب • خونريزي مزمن و مكرر • اختلال در رهاسازي آهن از سيستم رتيكولواندوتليال(عفونت و اختلالات التهابي مزمن) • بيماريهاي مزمن(عفونت و بدخيمي) • بيماريهاي حاد(عفونت) • كواشيوركور • نفروز (سندرم نفروتيك)

26. Porphyrines

27. Heme Biosynthesis

34. ALA X-linked hereditary sideroblastic anemia Porphobilinogen ALA Acute intermittent porphyria Glycine + succinyl CoA Hydroxymethylbilane Heme Congenital porphyria Erythropoietic protoporphyria Protoporphyrin IX Variegate porphyria Uroporphyrinogen III Protoporphyrinogen Porphyria cutanea tarda Hereditary coproporphyria Coproporphyrinogen III ALA = 5-aminolevulinate

40. نقش ویتامین های B9و B12 در اریتروپوئز

41. بيوسنتز پورينها از مسير توليد داخلي CO2 Gly Asp Methenyl-THF Formyl-THF Amide Nitrogen of Gln

42. سنتز dTMP suicide inhibitor Breast and colon cancer تیمیدیلات سنتاز Aminopterin Trimethoprim

43. Essential Nutrients for Erythropoiesis Folic Acid Cobalamin Iron Ferro-chelatase Enzyme Methionine synthetase Thymidylate synthetase Function Hb synth. DNA synth. DNA synth. Source Meats, fortification Vegetables, fruit, liver Meats, milk, eggs Prox. Intest. Absorp. Term. Ileum Prox. Intest. Macrophages Storage Liver, kidney Liver