ANEMIA & IRON METABOLISMHossein PiriHossein PiriDepartment of Biochemistry and Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

September 2014September 2014

Classification of anemiaClassification of anemia

MorphologicMorphologic Normocytic: MCV= 80-100fLNormocytic: MCV= 80-100fL Macrocytic: MCV > 100 fLMacrocytic: MCV > 100 fL Microcytic : MCV < 80 fLMicrocytic : MCV < 80 fL

PathogenicPathogenic (underlying mechanism) (underlying mechanism) Blood loss (bleeding)Blood loss (bleeding) Decreased RBC productionDecreased RBC production Increased RBC destruction/poolingIncreased RBC destruction/pooling

Normocytic AnemiasNormocytic Anemias

Acute post-Acute post-hemorrhagic anemiahemorrhagic anemia

Hemolytic anemia Hemolytic anemia (except thalassemia (except thalassemia and some other Hb and some other Hb disorders)disorders)

Endocrin diseasesEndocrin diseases Renal failureRenal failure Liver diseaseLiver disease Chronic disease Chronic disease

anemiaanemia Protein malnutritionProtein malnutrition Hypovitaminosis CHypovitaminosis C

Microcytic anemiasMicrocytic anemias

Iron deficiency anemiaIron deficiency anemia ThalassemiaThalassemia Sideroblastic anemiaSideroblastic anemia

HereditaryHereditary

Chronic lead poisoningChronic lead poisoning

Anemia of chronic diseases Anemia of chronic diseases

(some cases)(some cases)

Megaloblastic Macrocytic Megaloblastic Macrocytic AnemiasAnemias

Vit BVit B1212 deficiency deficiency Folic acid deficiencyFolic acid deficiency Other.Other.

Pathogenic classificationPathogenic classification(Causes of anemia)(Causes of anemia)

Relative (increased plasma volume)Relative (increased plasma volume) Decreased RBC productionDecreased RBC production Blood lossBlood loss

Anemia due to acute bleedingAnemia due to acute bleeding Increased RBC destructionIncreased RBC destruction

Pathogenic classificationPathogenic classification(Causes of anemia)(Causes of anemia)

Decreased RBC productionDecreased RBC production– Decreased Hb productionDecreased Hb production– Defective DNA synthesisDefective DNA synthesis– Stem cell defectsStem cell defects

Blood lossBlood loss– Anemia due to acute bleedingAnemia due to acute bleeding

Increased RBC destructionIncreased RBC destruction Relative(increased plasma volume)Relative(increased plasma volume)

Decreased Hb productionDecreased Hb production

Iron deficiency anemiaIron deficiency anemia ThalassemiaThalassemia Sideroblastic anemiaSideroblastic anemia Lead poisoningLead poisoning

Defective DNA synthesisDefective DNA synthesis

Vit BVit B1212 deficiency deficiency Folic acid deficiencyFolic acid deficiency Other.Other.

Anemias caused by increased Anemias caused by increased RBC destruction RBC destruction (hemolytic (hemolytic anemias)anemias)

Can be classified as;Can be classified as; Hereditary hemolytic diseasesHereditary hemolytic diseases Acquired hem. DiseasesAcquired hem. Diseases

IronIron & & (TIBC)(TIBC)

:عملکرد:عملکردانتقال اکسیژنانتقال اکسیژنتنفستنفس ،متابولیسم اسیدهای آمینه و رادیکال آزاد، متابولیسم اسیدهای آمینه و رادیکال آزاد

لیپیدها، فسفریالسیون اکسیداتیولیپیدها، فسفریالسیون اکسیداتیو جزئی از جزئی ازHbHbو متالوآنزیم ها و متالوآنزیم ها

آهنآهن

تركيبات آهن دار بدنتركيبات آهن دار بدن(آهن هم(آهن همHeme IronHeme Iron))

ترانسفرينترانسفرين هموسيدرين هموسيدرين

فريتين فريتين

آهن غير همآهن غير هم((None heme IronNone heme Iron)) ))HbHb((هموگلوبينهموگلوبين

ميوگلوبين ميوگلوبين آهن بافتي آهن بافتي

)آنزيمهاي تنفسي()آنزيمهاي تنفسي(

Iron Transport into Plasma

Ferroportin 1

Macrophages

Fe+2

Ferro-portin 1

Macrophage

Fe+2

SenescentRBC

Hb

Fe

Fe+3 TfCerulo-plasminFerroportin 1

Duodenal cytochrome b

Ferroportin 1

Duodenal cytochrome b

Adapted frlm Andrews, NEJM 1999;341:1986

Andrews N, NEJM 1999;341:1986

Receptor-Mediated Endocytosis

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.

اريتروپوئز و سنتز هماريتروپوئز و سنتز همBone marrowBone marrow

جذب ، انتقال و دفع آهن)متابوليسم آهن(جذب ، انتقال و دفع آهن)متابوليسم آهن(

RBC(blood)RBC(blood) اريتروپوئز اريتروپوئزغيرموثرغيرموثر

Plasma &Plasma & ECFECF

PhagocytesPhagocytes , RBC , RBC تخريبتخريب

HbHb

جذب روده جذب روده اياي

ذخيره سازي به ذخيره سازي به صورت فريتين صورت فريتين و هموسيدرينو هموسيدرين

خون ريزي و خون ريزي و دفع از طرق دفع از طرق

ديگرديگر

04/19/23 Plasma Proteins 19

Transferrin (TRF)Transferrin (TRF) TRF (sidrophilin) is a plasma transport protein for iron (TRF (sidrophilin) is a plasma transport protein for iron (ββ1)1) Single polypeptide chain ,79.6 kDa, 5.5% carbohydrate. Single polypeptide chain ,79.6 kDa, 5.5% carbohydrate. Reversibly bind to divalent cations, Reversibly bind to divalent cations, TRF accounts for TIBC of plasmaTRF accounts for TIBC of plasma One TRF binds two Fe+3, TRF- Fe+3 complex transports iron One TRF binds two Fe+3, TRF- Fe+3 complex transports iron

to cellsto cells Every cell type has surface receptors of TRF Every cell type has surface receptors of TRF TRF is synthesized by liverTRF is synthesized by liver Plasma levels are regulated by iron availability (iron↓, TRF↑)Plasma levels are regulated by iron availability (iron↓, TRF↑) One-half of TRF exists in extravascular spacesOne-half of TRF exists in extravascular spaces

04/19/23 Plasma Proteins 20

Receptors for TRFReceptors for TRF

After binding the TRF - Fe+3 -receptor complex is After binding the TRF - Fe+3 -receptor complex is internalized, resulting in release of iron from TRFinternalized, resulting in release of iron from TRF

Free Fe+3, is cytotoxic, is reduced and incorporated into Free Fe+3, is cytotoxic, is reduced and incorporated into ferritinferritin and and hemosiderinhemosiderin, for synthesis of compounds, , for synthesis of compounds, such as Hb, myoglobin, and cytochromessuch as Hb, myoglobin, and cytochromes

The receptor-apo TRF complex is recycled to the cell The receptor-apo TRF complex is recycled to the cell surface where the apo TRF is released and recycled, surface where the apo TRF is released and recycled, making the receptor available again for bindingmaking the receptor available again for binding

04/19/23 Plasma Proteins 21

Clinical SignificanceClinical Significance

Differential diagnosis of anemia:Differential diagnosis of anemia: In hypochromic microcytic anemia: In hypochromic microcytic anemia: Elevated TRF & less saturated : Iron deficiencyElevated TRF & less saturated : Iron deficiency (saturation normally 30% to 38%)(saturation normally 30% to 38%) Low or normal TRF & highly saturated: Iron non-Low or normal TRF & highly saturated: Iron non-

dependencydependency

Estrogen increases TRF synthesis, Estrogen increases TRF synthesis,

TRF is a TRF is a negativenegative APP APP

Iron Iron((كمبود آهن كمبود آهن deficiencydeficiency((

Iron Iron((افزايش آهن افزايش آهن overloadoverload((

- هموسيدروز- هموسيدروز

- هموكروماتوز)اوليه، - هموكروماتوز)اوليه، ثانويه(ثانويه(

ناهنجاريهاي متابوليسم آهنناهنجاريهاي متابوليسم آهن

آرتريتآرتريت

آريتمي قلبيآريتمي قلبي

نارسايي قلبينارسايي قلبي

سيروز كبديسيروز كبدي

هيپوتيروئيديسمهيپوتيروئيديسم

سرطان كبدسرطان كبد

ديابت مليتوسديابت مليتوس

هيپرپيگمانتاسيونهيپرپيگمانتاسيون

:اثرات کمبود:اثرات کمبودآنمی هیپوکرومیک میکروسیتآنمی هیپوکرومیک میکروسیتالتهاب دهانیالتهاب دهانیدیستروفی ناخن دستدیستروفی ناخن دست

:اثرات سمیت:اثرات سمیتهموکروماتوز اولیههموکروماتوز اولیه

آهنآهن

افزايش تخريب افزايش تخريبRBCRBCيا هموليز يا هموليز افزايش رها سازي آهن و يا فريتين از بافتها )نكروز افزايش رها سازي آهن و يا فريتين از بافتها )نكروز

حاد كبد(حاد كبد( كاهش توليد كاهش توليدHbHb مسموميت با )مسموميت با( pbpb كمبود ، كمبود ،

پيريدوكسين(پيريدوكسين(اريتروپوئز غير موثراريتروپوئز غير موثر((IneffectiveIneffective erythropoesiserythropoesis))افزايش جذب آهنافزايش جذب آهن((IronIron overloadoverload)) مصرف قرصهاي آهنمصرف قرصهاي آهنترانسفوزيون مكررترانسفوزيون مكررمصرف داروهاي ضد حاملگي پروژسترونيمصرف داروهاي ضد حاملگي پروژسترونيآلودگي سرنگ يا ظرف نمونهآلودگي سرنگ يا ظرف نمونه

FeFeعلل عمده افزايش علل عمده افزايش

سندرم سوءتغذيه و سوءجذبسندرم سوءتغذيه و سوءجذبخونريزي مزمن و مكررخونريزي مزمن و مكرر(عفونت و عفونت و اختالل در رهاسازي آهن از سيستم رتيكولواندوتليال)اختالل در رهاسازي آهن از سيستم رتيكولواندوتليال

اختالالت التهابي مزمن(اختالالت التهابي مزمن()بيماريهاي مزمن)عفونت و بدخيمي(بيماريهاي مزمن)عفونت و بدخيمي)بيماريهاي حاد)عفونت(بيماريهاي حاد)عفونتكواشيوركوركواشيوركور)نفروز )سندرم نفروتيك(نفروز )سندرم نفروتيك

FeFeعلل عمده كاهش علل عمده كاهش

PorphyrinesPorphyrines

Heme BiosynthesisHeme Biosynthesis

نقش ویتامین نقش ویتامین B12B12و و B9B9های های

در اریتروپوئزدر اریتروپوئز

ها از مسير توليد ها از مسير توليد بيوسنتز پورينبيوسنتز پورينداخليداخلي

AspAsp

Formyl-Formyl-THFTHF

CO2CO2 GlyGly

Amide Nitrogen of Amide Nitrogen of GlnGln

Methenyl-Methenyl-THFTHF

dTMPdTMPسنتز سنتز

تیمیدیالت سنتاز

AminopterinTrimethoprim

suicide inhibitor Breast and colon cancer

Essential Nutrients for Erythropoiesis

Folic Acid Cobalamin Iron

Enzyme

Function

Source

Absorp.

Storage

Thymidylate synthetase

Methionine synthetase

Ferro-chelatase

DNA synth. DNA synth. Hb synth.

Vegetables, fruit, liver

Meats, milk,eggs

Meats, fortification

Prox. Intest. Prox. Intest.Term. Ileum

Liver Liver, kidney Macrophages