Fe+3 Fe+2 DMT1

DCYTB

Fe ??

TfR

Fe+3 Transferrin Fe Fe+2

FP1

Fe Fe ( for storage Fe Fe DMT1 Fe TR Endosome ??

Fe ??

Fe Fe Fe Hemosiderin Fe Mitochondria ) (for heme synthesis) Blood Normoblast

H: Hephaestin DMT1: Divalent metal transporter FP1: Ferroportin Other proteins playing –uncertain- role in iron homeostasis: HFE, hemojuvelin, TfR2

Deficiency of iron



Anemia Hereditary deficiencies of enzymes of heme synthetic pathway



Porphyrias

RBCs Circulat ( Hb iron) ing Monocyte/macrophage system TF Muscle, parenchymal cells

Fe+3 Fe+2 Gastric acid 1-1,5 mg iron/day 1-1,5 mg iron/day

Erythrobla sts Hepatocytes Functional iron Hb Myoglobin Heme & Nonheme enzymes Transport iron (transferrin,TF) Storage iron Ferritin Hemosiderin Total Men 31 5 2 0.2

8 4 50 Women 28 4 2 0.2

4 2 40 mg/kg

• • • •

DEMİR İHTİYACI ve EMİLİMİ

Vücuda demir girişi barsak mukozasının kontrolünde. Emilimi x10 değiştirebilir. Demir için itrah mekanizması yoktur.

• Heme demirinin biyoyararlanımı daha iyidir. Gereğinde % 20-30 oranında emilebilir. Oysa, Günlük ihtiyaç erkeklerde 1, bayanlarda 1.5 mg Bu ihtiyaç Gİ kanal ve heme yapısında olmayan demir yalnızca % 5 oranında emilir ciltten dökülen hücreler, fizyolojik Gİ gizli kan kaybı • Fitat, tannat, fosfat özellikle heme dışı demir ve menstruasyon ile olan kaybı karşılamak için emilimini geciktirir. Normal batı diyeti yaklaşık Askorbik asit ve 15 mg demir içerir. Yalnızca ihtiyaç kadar emilmelidir aminoasitler emilimi hızlandırır

Fe+3 Fe+2 DMT1 Fe ??

Enterocyte Fe+3 Fe+2

FP1

Fe Fe Blood Fe Ferritin Fe Fe DMT1 Fe TR Endosome ??

Fe ??

Fe Fe Fe Fe Mitochondria (for heme synthesis)

Figure: Iron Absorption and Storage

Normoblast

TR: Transferrin receptor H: Hephaestin DMT1: Divalent metal transporter FP1: Ferroportin Other proteins playing –uncertain- role in iron homeostasis: HFE, hemojuvelin, TfR2

REGULATION of INTRACELLULAR IRON METABOLISM

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

Fe Fe Fe Fe Fe Fer Aconitase TF Fe IRP-1 TR Stable TR mRNA Fe Fe Fe Fe Fer gene TR gene Unstable TR mRNA IRP-1 x Fer gene TR gene Healthy State Iron Deficiency

DEMİR HOMEOSTAZINDA ROL OYNAYAN BİR HORMON VAR MIDIR ?

H e p a ti k S i n ü z o i d Fe Fe Fe Fe Fe Endotel IL-6 Kupffer Hepatosit Hepcidin RBCs Circulat ( Hb iron) ing Monocyte/macrophage system x Muscle, parenchymal cells x

Fe+3 Fe+2 Gastric acid 1-1,5 mg iron/day

TF

1-1,5 mg iron/day

Erythrobla sts Hepatocytes Functional iron Hb Myoglobin Heme & Nonheme enzymes Transport iron (transferrin,TF) Storage iron Ferritin Hemosiderin Total Men 31 5 2 0.2

8 4 50 Women 28 4 2 0.2

4 2 40 mg/kg

Fe

x FP1

Hepcidin

Fe

x FP1

Fe Fe

Causes of Iron Overload

• •

Primary

1) Hereditary hemochromatosis (HFE- and non-HFE) 2) Hereditary atransferrinemia 3) Aceruloplasminemia

Secondary

1) Ineffective erythropoiesis

(thalassemia, sideroblastic anemia)

2) Transfusional hemochromatosis

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

3) Chronic dietary or medicinal intoxication 4) Alcoholic cirrhosis 5) Porphyria cutanea tarda Iron chelation therapy by DFO-infusion pump in a patient with 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 Iron sensing mechanism HFE Ferroportin TfR2 Fe Fe Fe Fe Increased iron Fe

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

Iron Requirements in Males and Females of Various Ages 3

mg

2,5 2 1,5 1 0,5 0

Daily Iron Requirement: Children & Females, mg Males, mg

(Iron-Deficiency Anemia) Occurs If (Iron Intake < Iron Loss) Causes of Iron-Deficiency Anemia: 1. Inadequate Iron Supply: Poor nutritional intake Malabsorption ( gastric surgery, achlorhydria, celiac disease, etc.

) Abnormal transferrin function ( congenital atransferrinemia, autoantibodies to transferrin receptors) 2. Increased Iron Requirements Blood loss Extensive and prolonged menses Gastrointestinal disorders ( hemorrhoids, peptic ulser, colonic cancer, etc.

) Pulmonary disorders ( hemoptysis, pulmonary hemosiderosis ) Urologic disorders ( hematuria ) Nasal disorders ( nose bleeds ) Chronic blood donations Dialysis Hookworm infestation Intravascular hemolysis with hemoglobinuria Paroxysmal nocturnal hemoglobinuria Cardiac 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 DIZZINESS WEAKNESS EASY FATIGABILITY HEADACHE PALPITATION GROWTH RETARDATION DECREASED INTELLECTUAL CAPACITY

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

GLOSSITIS ANGULAR STOMATITIS

SYMPTOMS / SIGNS SPECIFIC TO IRON DEFICIENCY ANEMIA (RARE):

KOILONYCHIA ESOPHAGEAL 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)  = microcytosis • MCH: 26 pg (27.5-33.2)  = hypochromia • RDW: 15 (11.5-13.4)  = anisocytosis • WBC: 4900/  L (4 000-11 000) N • Platelet count: 450 000/  L (150 000-450 000) N 

PERIPHERAL SMEAR in IDA SERUM IRON PARAMETERS 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 

Transferrin Saturasyonu, Total ve Serbest Demir Bağlama Kapasiteleri Nelerdir ?

Serbest Demir Bağlama Kapasitesi = Serbest Transferrin Serum Demiri = Demir Bağlamış Olan Transferrin Total Demir Bağlama Kapasitesi = Serum Transferrin Aktivitesi (~Düzeyi) Transferrin Saturasyonu = Serum Demiri / Total Demir Bağlama Kapasitesi Transferrin Saturasyonu = Serum Demiri / (Serum Demiri + Serbest Demir Bağlama Kapasitesi)

Differential Diagnosis of IDA

Other common causes of hypochromic • • microcytic anemia are;

Thalassemia trait Anemia of chronic disease (anemia of inflammation)

These two disorders may be confused with IDA.

Generally history, CBC, serum iron parameters are enough to differentiate between them. Occasionally, Hb electrophoresis & bone marrow iron staining may be necessary.

Differential Diagnosis of Iron Deficiency Anemia

Iron Deficiency Anemia Anemia of Chronic Disease Iron

 

N Thalassemia trait N



TIBC

 

N N TS

 

N N

 Ferritin 

N



N



Normal TS= % 15-45 Demir EA TS= % 5 Kronik Hst.

Anemisi TS= % 14 Demir Yüklenmesi TS= % 100 İnefektif Eritropoez TS= % 85

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).

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.

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