(for heme synthesis)

(for storage)

Hemosiderin

Fe Fe

Fe Fe Fe

Fe

Fe

Enterocyte

Fe+2 Fe

DCYTB Tr

ansferrin

Endosome

Mitochondria

Ferritin

??Fe

Fe

Fe

Figure: Iron Absorption and StorageFigure: Iron Absorption and Storage

????

DMT1TR

DMT1

H

Blood Normoblast

Fe+2 Fe

FP1

Fe+3

Fe+3

TfR

TR: Transferrin receptor H: Hephaestin

DMT1: Divalent metal transporter

FP1: Ferroportin

Other proteins playing –uncertain- role in iron homeostasis: HFE, hemojuvelin, TfR2

Iron Metabolism and Iron Deficiency Anemia

Demir Metabolizması ve Demir Eksikliği Anemisi

Deficiency of iron Anemia

Hereditary deficiencies of enzymes of heme synthetic pathway Porphyrias

Men WomenFunctional iron

Hb 31 28Myoglobin 5 4Heme & Nonheme enzymes 2 2

Transport iron (transferrin,TF) 0.2 0.2Storage iron

Ferritin 8 4Hemosiderin 4 2

Total 50 40 mg/kg

Muscle, parenchymal cells

Monocyte/macrophagesystem

Circulating

RBCs(Hbiron)

Hepatocytes

Erythroblasts

TF

1-1,5 mg iron/day

1-1,5 mg iron/day

Fe+3

Fe+2Gastric acid

DEMİR İHTİYACI ve EMİLİMİ• Vücuda demir girişi barsak

mukozasının kontrolünde. Emilimi x10 değiştirebilir. Demir için itrahmekanizması yoktur.

• Günlük ihtiyaç erkeklerde 1, bayanlarda 1.5 mg

• Bu ihtiyaç Gİ kanal ve ciltten dökülen hücreler, fizyolojik Gİ gizli kan kaybı ve menstruasyon ile olan kaybı karşılamak için

• Normal batı diyeti yaklaşık 15 mg demir içerir. Yalnızca ihtiyaç kadar emilmelidir

• Heme demirinin biyoyararlanımı daha iyidir. Gereğinde % 20-30 oranında emilebilir. Oysa, heme yapısında olmayan demir yalnızca % 5 oranında emilir

• Fitat, tannat, fosfat özellikle heme dışı demir emilimini geciktirir. Askorbik asit ve aminoasitler emilimihızlandırır

(for heme synthesis)

(for storage)

Hemosiderin

Fe Fe

Fe Fe Fe

Fe

Fe

Enterocyte

Fe+2 Fe

DCYTB Tr

ansferrin

Endosome

Mitochondria

Ferritin

??Fe

Fe

Fe

Figure: Iron Absorption and Storage

????

DMT1TR

DMT1

H

Blood Normoblast

Fe+2 Fe

FP1

Fe+3

Fe+3

TfR

TR: Transferrin receptor H: Hephaestin

DMT1: Divalent metal transporter

FP1: Ferroportin

Other proteins playing –uncertain- role in iron homeostasis: HFE, hemojuvelin, TfR2

Fe

Fe

Fe

Fe

Fe

FeFe

Fe

Aconitase

TR geneFer gene

Fe

x

TF TR

IRP-1

Fer gene TR gene

IRP-1

REGULATION of INTRACELLULAR IRON METABOLISM

Healthy State Iron Deficiency

Sensors and Controllers of Intracellular Iron Supply= IRP-1 (Aconitase) & IRP-2

Fer

Unstable TR mRNA

Stable TR mRNA

Fe

Endotel

Kupffer

Fe

Fe

Fe IL-6Hepcidin

Men WomenFunctional iron

Hb 31 28Myoglobin 5 4Heme & Nonheme enzymes 2 2

Transport iron (transferrin,TF) 0.2 0.2Storage iron

Ferritin 8 4Hemosiderin 4 2

Total 50 40 mg/kg

Muscle, parenchymal cells

Monocyte/macrophagesystem

Circulating

RBCs(Hbiron)

Hepatocytes

Erythroblasts

TF1-1,5 mg iron/day

1-1,5 mg iron/day

Fe+3

Fe+2Gastric acid

x x

Hepatosit

DEMİR HOMEOSTAZINDA ROL OYNAYAN BİR HORMON VAR MIDIR ?

Hepatik

Sinüzoid

Fe

Fe

FP1Fe

FP1Fe

Hepcidin

Fe

Fe

x

x

Causes of Iron Overload• Primary

1) Hereditary hemochromatosis (HFE- and non-HFE)2) Hereditary atransferrinemia3) Aceruloplasminemia

• Secondary1) Ineffective erythropoiesis (thalassemia, sideroblastic anemia)

2) Transfusional hemochromatosis (aplastic anemia, MDS, sickle cell anemia, end-stage renal disease)

3) Chronic dietary or medicinal intoxication4) Alcoholic cirrhosis5) Porphyria cutanea tarda

Iron chelation therapy by DFO-infusion pump in a patientwith thalassemia

HEPCIDIN in HEREDITARY HEMOCHROMATOSIS

Surprisingly, serum hepcidin is decreased in HFE- and some kinds of non-HFE hereditary hemochromatosis. Probably, HFE plays a role in regulation of hepcidin production. Therefore, HFE disruption leads to decreased hepcidin production.

Hepcidin

FeFe

Fe

Fe

Fe

Iron sensingmechanism

HFEFerroportin

TfR2Increased iron

Iron Requirements in Males and Females of Various Ages

0

0,5

1

1,5

2

2,5

3

Infa

ncy

Chi

ldho

od

Ado

lesc

ence

You

ngw

omen

Pre

gnan

tw

omen

Men

apau

se

Daily IronRequirement: Children& Females, mg Males, mg

mg

(Iron Deficiency Anemia) Occurs If (Iron Intake < Iron Loss)

(I ron-Deficiency Anemia) Occurs I f (I ron I ntake < I ron Loss)

Causes of I ron-Deficiency Anemia:1. I nadequate I ron Supply:

Poor nutritional intakeMalabsorption (gastric surgery, achlorhydria, celiac disease, etc.)Abnormal transferrin f unction (congenital atransferrinemia,

autoantibodies to transferrin receptors)

2. I ncreased I ron RequirementsBlood loss

Extensive and prolonged mensesGastrointestinal disorders (hemorrhoids, peptic ulser, colonic cancer, etc.)Pulmonary disorders (hemoptysis, pulmonary hemosiderosis)Urologic disorders (hematuria)Nasal disorders (nose bleeds)Chronic blood donationsDialysisHookworm infestation

I ntravascular hemolysis with hemoglobinuriaParoxysmal nocturnal hemoglobinuriaCardiac valve protheses

Rapid growth (between ages 2 and 36 months, adolesance)Pregnancy and lactation

SYMPTOMS of IRON DEFICIENCY ANEMIA• NO COMPLAINT:• SYMTOMS of UNDERLYING DISEASE:• SYMPTOMS / SIGNS COMMON TO ALL ANEMIAS:

PALLOR

DIZZINESSWEAKNESSEASY FATIGABILITYHEADACHEPALPITATIONGROWTH RETARDATIONDECREASED INTELLECTUAL CAPACITY

• SYMPTOMS / SIGNS COMMON TO ALL NUTRITIONAL ANEMIAS (IRON, B12 and FOLATE DEFICIENCIES):

GLOSSITISANGULAR STOMATITIS

• SYMPTOMS / SIGNS SPECIFIC TO IRON DEFICIENCY ANEMIA (RARE):KOILONYCHIAESOPHAGEAL WEB (MAY LEAD TO ESOPHAGEAL CANCER)PICA (EATING SOIL, CLAY, ICE –PAGOPHAGIA-, etc.)BLUE SCLERAE

GLOSSITIS (SORE MOUTH), DYSPHAGIA (ESOPHAGEAL WEB) and IRON DEFICIENCY ANEMIA = “PLUMMER VINSON” or “PETERSON-KELLY” SYNDROME

PICA, SPLENOMEGALY, GROWTH RETARDATION and IRON DEFICIENCY ANEMIA= “TAYANÇ-REIMANN-PRASSAD” SYNDROME

CBC in IRON DEFICIENCY ANEMIA

• Hb: 10.7 g/dL (female 12-16; male 13.5-17.7)

• MCV: 72 fL (80-100)

• MCH: 26 pg (27.5-33.2)

• RDW: 15 (11.5-13.4)

• WBC: 4900/L (4 000-11 000) N

• Platelet count: 450 000/L (150 000-450 000) N

SERUM IRON PARAMETERS in IDA

PERIPHERAL SMEAR in IDA

Iron: 5 g/dL (60-150)

TIBC (transferrin level): 467 g/dL (250-435)

Transferrin saturation: % 7 (15-45)

Ferritin:2 ng/mL (15-200)

Transferrin receptor level

= microcytosis

= hypochromia

= anisocytosis

Total Demir Bağlama Kapasitesi= Serum Transferrin Aktivitesi (~Düzeyi)

Serum Demiri = Demir Bağlamış Olan Transferrin

Serbest Demir Bağlama Kapasitesi = Serbest Transferrin

Transferrin Saturasyonu = Serum Demiri / Total Demir Bağlama Kapasitesi

Transferrin Saturasyonu = Serum Demiri / (Serum Demiri + Serbest Demir Bağlama Kapasitesi)

Transferrin Saturasyonu, Total ve Serbest Demir Bağlama Kapasiteleri Nelerdir ?

Differential Diagnosis of IDAOther common causes of hypochromic microcytic anemia are;• Thalassemia trait• Anemia of chronic

disease (anemia of inflammation)

These two disordersmay be confused withIDA.Generally history, CBC, serum iron parameters are enough to differentiate between them. Occasionally, Hb electrophoresis & bone marrow iron staining may benecessary.

Iron TIBC TS Ferritin

Iron Deficiency Anemia

Anemia of Chronic Disease

N N N N

Thalassemia trait

N N N N

NormalTS= % 15-45

Demir EATS= % 5

Kronik Hst.AnemisiTS= % 14

Demir YüklenmesiTS= % 100

İnefektifEritropoezTS= % 85

Differential Diagnosis of Iron Deficiency Anemia

Treatment & Follow-up in IDA• Removal of the Underlying

Disease (if present)• Iron Supplementation (Iron pills,

200 mg/day on empty stomach in adults)

• Anemia generally resolves within 2 months, but iron pills should be continued until iron stores get full (~ 6-9 months)

• In the case of treatment failure one should consider: incorrect diagnosis, an additional cause of anemia, ongoing blood loss, bad patient compliance & malabsorption

Indications for Parenteral Iron:

• Malabsorption

• Patient intolerance of pills

• Bad patient compliance to PO treatment

• Ongoing heavy blood loss

INVESTIGATION of THE CAUSE of IDA

• If the patient is at increased risk of IDA (e.g., women with suboptimal nutrition, infants, adolescents, pregnant women, women with multiple previous pregnancies) careful history, PE GUIAC test for occult GI blood loss & microscopic exam of stool for parasites will be sufficient.

• If suspicion of an underlying disease condition appears after simple tests or if the patient is a man or a postmenapausal woman the bowel, urinary and respiratory tracts must be carefully investigated for any bleeding lesion (e.g. peptic ulcer, colonic cancer).

Bu nedenle demir eksikliği anemisi için risk altındaki kişilere (gebelik, bazı infantlar) proflaksi uygulanması gereklidir:

Demir eksikliği anemisi bir halk sağlığı sorunudur. Dünya Sağlık Örgütü’nün verilerine göre dünya nüfusunun yaklaşık % 30 kadarı anemiktir ve bunların çok büyük çoğunluğu demir eksikliği anemisidir.