IRONIRON

Iron in the body is used primarily for the synthesis of Hemoglobin and normal erythropoiesis requires 20-25 mg of iron per day.

• All iron required for red cell production is acquired through the recycling of iron extracts from the senescent red cells.

• Only 5% of the iron needed for erythropoiesis, or 1 mg /d, is absorbed from GIT to balance losses in the urine, stool, sweat , and de-sequamated skin

• IRON STORAGETwo different configurations : Ferritin : water soluble, hydroxyl iron, & protein (Apoprotein).Hemosiderin : insoluble Aggregate of ferritin molecules that have been stripped of apoprotein.

Metabolic pathway of IRONPhagocytic macrophages in the liver, spleen, BM

take RBC that have complete their 120-day life span. Hemoglobin is broken down into its constituents and iron is stored as ferritin or hemosiderin.

1. Erythroid precursors in the marrow develop around the macrophages and take up the ferritin.

2. Macrophages in the marrow and spleen remove excess ferritin and hemosiderin.

3. Transferrin mediate iron transport from macrophages and gastro-intestinal mucosa to the immature RBC and for storage in the liver.

Iron transport• Transferrin is the principle means for moving

iron and is a transport protein with two iron binding site. transferrin picks up iron from the mucosal cells of the intestine then deliver iron to receptors on surface of nucleated RBCs and reticulocytes .the macrophages then transport the iron-free transferrin back to the place .

• The amount of transferrin in the serum is measured directly as the total iron binding capacity(TIBC).

Absorption sites : maximal absorption occur in the

duodenum and upper jejunum.

The acidic gastric juice reduces insoluble ferric iron to its soluble ferrous state.

Factors influence iron absorption• Increase Fe absorption Decrease Fe absorption• - Acids : HCl ,vit.C -Alkalis, antacids • - ferrous iron (Fe+2) pancreatic secretion • - Agents that solubilize iron organic iron, Ferric iron• as(sugars, amino acids) Agents precipitate Iron

as• - Iron deficiency (Phytate in the tea and

- Increased demand as in phosphate in the bran)• pregnancy, infancy , excess iron utilization adolescence,Hemolysis (infection&inflammation) or bleeding disorder • -primary hemochromatosis

• a. Depletion of tissue iron. in negative iron balance, and to preserve the level of iron

in the serum and RBC, results in Depleting the tissue iron stores and this results in:

IRON DEFICIENCY ANAEMIA (IDA)Stages of iron deficiency

Reduced levels of

Ferritin and hemosiderin

Reduced levelsof serum ferritin

In tissue macrophage

IDAIDA• b. Changes in serum iron are indicative of depletion of the iron

stores : • Serum iron are usually low.• TIBC increase. • c. Progressive anaemia : • initially normochronic, normocytic• eventually hypochromic, microcytic • tissue changes occur.

CAUSES OF IRON DEFICIENCY

• Chronic blood loss:• uterine blood loss.• GIT blood loss. • * Benign conditions:• peptic ulcer.• esophageal varicies.• hiatus hernia.• colonic diverticula or polyp.• hemorrhoids.• chronic aspirin use.• Parasites (hook worm).• *Malignancy:• colonic ;colorectal Ca.• Gastric Ca.• Esophageal Ca.• small intestinal Ca

Causes of IDA contCauses of IDA cont..• pulmonary accumulation lead to hemosiderosis. Hypernephroma.• urinary tract Bladder Ca. paroxysmal nocturnal

hemoglobinuria (PNH).

• Increase iron requirement• Iron malabsorption• Poor diet

SYMPTOMS OF IRON SYMPTOMS OF IRON DEFICIENCYDEFICIENCY

• symptoms and signs pertaining to anaemia :• 1. Non-specific symptoms :fatigue, weakness , dyspnoea, symptoms of

CHF• 2. Signs : Pallor, tachycardia, splenomegaly (minority of cases) • b. Symptoms and signs specific to iron deficiency : • 1. atrophic changes in the epithelium results from levels of heme-

containing enzymes (cytochrome, succinate dehydrogenase, catalase, peroxidase, xanthine oxidase) :

• a. oral lesions : • angular cheilosis • Atrophy of the tongue papilla with intermittent glossitis, and stomatitis. • Dysphagia : post-cricoid esophageal webbing (Plummer Vinson

syndrome).• Nail lesions : (Koilonychias) Flattening , thinning lead to brittle, spoon-

shaped nail. • 2. Pica : Compulsive ingestion of non nutritive substances.• Children : craving for & ingestion of clay, dirt, paint• Adult : to eat ice (pagophagia) clay.

Nutritional deficiency anaemiaNutritional deficiency anaemiaclinical applicationclinical application

Angular Cheilosis

Koilonychia

Glossitis

Marrow iron storesPlummer-Vinson

syndrome

Low Hb=AnemiaMCV

Low=microcytic Normal=normocytic High=macrocytic

Ferritin

Fe deficient Fe normal

Establishcause

Anemia ofchronic diseaseorhemoglobinopathy

Reticulocyte count

high low Anemia of chronic diseaseRenal failureMarrow failure

Hemolysis or blood loss

Measure B12 + folate

Low -Establish cause

Normal

Obvious cause

Cause not obviousConsider bone marrow

DIAGNOSISDIAGNOSIS:: • Laboratory studies :a. peripheral blood : 1. RBC indices : MCV (55-74 fl) MCH (25-30 g/dL) RDW > 16 • 2. Peripheral blood smears : microcytic hypochromic poikilocyte = abnormally shaped RBCs. Anisocyte = vary in size of RBCs.• 3. Blood count : normal or low reticulocytes • occasionally high platelet count.

IRON Deficiencyanaemia

Anaemia of chronic disorderesThalassaemia traitSideroblastic

anaemia

Transpart iron

壹 *plasma iron贰 *saturation of TIBC

Lowlow

LowNR or low

NN

N or highN or high

Storage iron

Plasma ferritinlowN or highNN or high

Plasma TIBChighN or lowNN or low

Marrow ironlowN or highNN or high

Differntial diagnosis of microcytic Differntial diagnosis of microcytic anaemiaanaemia

•DISEASES

Investigation-contInvestigation-cont..• b. serum iron studies : • the level of serum iron is low or normal depending

on what patient eat before the measurement. • TIBC > 400 µg/dL• Transferrin saturation <15 %• Serum Ferritin < 12 ng/ml.• Soluble transferrin receptor ; increased• C. Bone marrow studies :• Absence of iron in macrophage when the sample is

subjected to Perl's stain (Prussian blue stain)

TREATMENTTREATMENT• 1- Determine the cause of iron deficiency.• stool for occult blood loss from GIT bleeding.• radiological analysis of upper & lower GIT for occult

malignancy.• urine analysis for hematuria.• CXR for pulmonary Hemosiderosis.

Pelvic exam. In woman. Serum antiendomysial antibody or anti-

transglutaminase antibodies and possibly a duodenal biopsy are indicated to

detect coeliac disease. •.

Treatment-cont.Treatment-cont. 22--Treat the underlying causeTreat the underlying cause..

• 3- Initiate iron replacement therapy : • oral iron therapy : • Ferrous sulfate.• Ferrous fumarate and gluconate.• Dosage : • The adult dose of ferrous sulfate is 300 mg/day

gradually increased to 900 mg /day if tolerated.• Adverse effect : • GIT irritation : nausea, cramping, diarrhea.

INDICATION INDICATION OF parentral iron therapyOF parentral iron therapy

• can not tolerate the side effect of oral iron.

• Suffers from inflammatory bowel disease and peptic ulcers.• Does not comply with prescribed dosage.

• Iron mal-absoption.

• Suffers from condition such as hereditary hemorrhagic telengectasis (HHT) in which the rapid loss from continuous bleeding can not be compensated by oral iron.

• 4. Transfusion of whole blood or packed red cells is generally not indicated unless a rapid increase in haematocit is critical to the patient.

PREPARATIONSPREPARATIONS• 1- Iron dextran (imferon) Intramuscular injection. it may lead to

hypersensitivity reaction and anaphylaxis to the dextran and permanent stain with discoloration at the injection site. The later can be avoided by using the Z technique of IM injection.

• 2- Iron sorbitol (Jectofer) IV .A small test dose 0.25 ml of the drug should be administered before IM or IV to determine hypersensitivity to the agent

• Dose in ml = 0.0476 x weight (kg) x (Hb. deficit) + 1 ml/5kg to a maximum of 14 ml to replete iron stores.The total dose can be diluted in normal saline at 1:20 dilution and infused slowly over several hours.

• 3- Iron sucrose IV in patient who are allergic to dextran.

• .4-new preparations of iron isomaltose and iron•carboxymaltose have fewer allergic effects and are preferred .

Treatment-contTreatment-cont..

• Maintain iron replacement therapy : • the treatment should be extended to beyond the point

where the anaemia is corrected for a pertiod of usually 3-6 months in order to replenish depleted iron stores.

• - A failure to respond to iron therapy should suggest the following :

• incorrect diagnosis• continued loss of iron.• Presence of chronic infection or inflammation will suppress

BM activity .• Lack of pt. Compliance.• Inffective release of iron.• Malabsorption of iron.

LOW HB LOW HCT LOW MCV LOW MCH MCHC LOW / N LOW FERRITIN

LOW FE HIGH TIBC HIGH RDW

IDA CRITERIA

Anaemia of chronic diseaseAnaemia of chronic diseaseAnaemia of chronic disease (ACD) is a common type of

anaemia, particularly in hospital populations .It occursin the setting of chronic infection, chronic inflammation

or neoplasia .The anaemia is not related to bleeding,

haemolysis or marrow infiltration

, ,is mild, with haemoglobinis mild, with haemoglobinin the range of 85–115 g/L, and is usually in the range of 85–115 g/L, and is usually

associatedassociatedwith a normal MCV (normocytic, with a normal MCV (normocytic,

normochromic),normochromic),though this may be reduced in long-standing though this may be reduced in long-standing

inflammation.inflammation.The serum iron is low but iron stores are normal The serum iron is low but iron stores are normal

ororincreased, as indicated by the ferritin or increased, as indicated by the ferritin or

stainablestainable

marrow ironmarrow iron..

PathogenesisPathogenesisACD is The regulatory protein that accounts for the findings characteristic of

• which is produced by the liver Hepcidin production of hepcidin is induced by proinflammatory cytokines, especially

IL-6.Hepcidin binds to ferroportin on the membrane of iron-exporting cells,such as small intestinal enterocytes and macrophages,

internalising the ferroportin and thereby inhibiting theexport of iron from these cells into the blood .

The ironremains trapped inside the cells in the form of ferritin,

levels of which are therefore normal or high in the faceof significant anaemia. Inhibition or blockade of hepcidinis a potential target for treatment of this form of

Diagnosis and managementDiagnosis and managementIt is often difficult to distinguish ACD associated with alow MCV from iron deficiency.

Examination of the marrow may ultimately be required to assess iron storesdirectly.

A trial of oral iron can be given in difficult situations A positive response

occurs in true iron deficiency BUT not in ACD

Measures which reduce the severity of the underlying disorder generally help to improve ACD