Iron Deficiency AnemiaIron Deficiency Anemia

Reema Batra, MDReema Batra, MD George Washington UniversityGeorge Washington University

Essential Nutrients for ErythropoiesisEssential Nutrients for Erythropoiesis Folic AcidFolic Acid CobalaminCobalamin IronIron

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

Essential Nutrients, cont’d

Folic Acid Cobalamin Iron

DietarycontentDaily absorption

20 mg

0.2 mg 0.002 mg 1.0-1.5 mg

Stores 5-10 mg 1-10 mg 500-1000 mg

1.0 mg 0.01 mg

Iron- essential nutrientIron- essential nutrient

Reversible binding OReversible binding O22:: hemoglobinhemoglobinmyoglobinmyoglobin

Enzymes:Enzymes: heme (cytochromes)heme (cytochromes)iron sulfur cluster (aconitase)iron sulfur cluster (aconitase)other (ribonucleotide reductase)other (ribonucleotide reductase)

Immunity:Immunity: free radicals to destroy free radicals to destroy microbesmicrobes

Iron- potentially toxicIron- potentially toxic

Highly reactive with OHighly reactive with O22; can cause ; can cause fatal toxicity.fatal toxicity.– CardiomyopathyCardiomyopathy– Liver cirrhosisLiver cirrhosis– Endocrine abnormalitiesEndocrine abnormalities

Iron Metabolism: Broad ThemesIron Metabolism: Broad Themes Absorption of iron is highly Absorption of iron is highly

regulated to prevent excess iron regulated to prevent excess iron from being absorbed.from being absorbed.

No physiologic pathway for No physiologic pathway for excreting excess iron exists.excreting excess iron exists.

Body Iron CompartmentsBody Iron Compartments60 kg F 70 kg M

Functional compoundsHemoglobin 1750 mg 2300 mgMyoglobin 290 mg 320 mgEnzymes 160 mg 180 mgTransferrin 2.5 mg 3 mgStorage compoundsFerritin & hemosiderin 300 mg 1000 mgTotal 2500 mg 3800 mg

Iron Requirements

Men WomenObligatory losses 1.0 mg/d 1.0 mg/dMenstruation 0 mg/d 0.5 mg/dTotal losses 1.0 mg/d 1.5 mg/d

Iron absorbed 1.0 mg/d 1.5 mg/d

Iron AbsorptionIron Absorption1. Heme iron (meats) absorbed better than 1. Heme iron (meats) absorbed better than

non-heme iron (grains).non-heme iron (grains).2. Gastric acid keeps Fe reduced to Fe2. Gastric acid keeps Fe reduced to Fe++++ form form

that is absorbed.that is absorbed.3. Occurs in proximal small bowel3. Occurs in proximal small bowel4. Increases with: - high erythropoiesis 4. Increases with: - high erythropoiesis

- low iron stores- low iron stores5. Inhibited by inflammation, tea5. Inhibited by inflammation, tea

Fe from intestine

(1 mg/day)Erythroid precursors

in bone marrow produce hemoglobin

(18 mg Fe/day)

Macrophages in spleen remove and break down

senescent RBCs(18 mg Fe/day)

Transferrin in plasma carries Fe back to bone marrow

(17 mg/day)

Losses (1 mg Fe/day)

Iron MetabolismIron Metabolism1.1. Fe circulates in plasma bound to Fe circulates in plasma bound to transferrintransferrin

(approx 0.1% of body Fe)(approx 0.1% of body Fe)2.2. Fe stored intracellularly as Fe stored intracellularly as ferritinferritin. . 3.3. Serum Fe concentration and transferrin Serum Fe concentration and transferrin

saturation reflect Fe delivery to erythroid saturation reflect Fe delivery to erythroid precursors. precursors.

4.4. Serum ferritin concentration reflects stores Serum ferritin concentration reflects stores in macrophages.in macrophages.

Iron Transport into Plasma

Ferroportin 1

Macrophages

Fe +2

Ferro-portin 1

Macrophage

Fe +2

SenescentRBC

HbFe

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

Normal Peripheral Smear

H=hypochromic RBC; p=pencil RBC; T=target RBC; M=microcytic RBC

The Lancet 2000;355:1260

Iron Deficiency Anemia

Iron Deficiency Anemia

Iron Deficiency Anemia

Causes of Iron DeficiencyCauses of Iron Deficiency

1. 1. Chronic blood lossChronic blood loss– gastrointestinal (carcinoma, ulcers, gastrointestinal (carcinoma, ulcers,

diverticuli, a-v malformations, hookworm)diverticuli, a-v malformations, hookworm)– genitourinary (menorrhagia, bladder ca)genitourinary (menorrhagia, bladder ca)– pulmonary (hemoptysis, pulmonary pulmonary (hemoptysis, pulmonary

hemosiderosis)hemosiderosis)– frequent blood donors (220 mg Fe lost frequent blood donors (220 mg Fe lost

with each blood donationwith each blood donation

Causes of Iron DeficiencyCauses of Iron Deficiency

2.2. Dietary insufficiencyDietary insufficiency– rapidly growing childrenrapidly growing children– women of child-bearing age.women of child-bearing age.

3.3. MalabsorptionMalabsorption– s/p gastrectomys/p gastrectomy– s/p resection proximal small bowels/p resection proximal small bowel– Crohns diseaseCrohns disease– Celiac diseaseCeliac disease

Causes of Iron DeficiencyCauses of Iron Deficiency

4.4. Pregnancy and lactationPregnancy and lactation5.5. HemoglobinuriaHemoglobinuria

– secondary to intravascular hemolysis:secondary to intravascular hemolysis: paroxysmal nocturnal hemoglobinuriaparoxysmal nocturnal hemoglobinuria runner’s anemiarunner’s anemia

Fe Deficiency: Clinical Fe Deficiency: Clinical ManifestationsManifestations

Impaired growth, psychomotor Impaired growth, psychomotor developmentdevelopment

Fatigue, irritable, Fatigue, irritable, work productivity work productivity PicaPica Dysphagia, esophageal web Dysphagia, esophageal web (Plummer-(Plummer-

Vinson or Patterson-Kelly Sx)Vinson or Patterson-Kelly Sx) Koilonychiae, glossitis, angular stomatitisKoilonychiae, glossitis, angular stomatitis

Fe Deficiency: Lab FindingsFe Deficiency: Lab Findings CBCCBC

RDW, plateletsRDW, platelets MCV, MCH, MCHC, RBC, Hb, HctMCV, MCH, MCHC, RBC, Hb, Hct

Retic count not Retic count not Serum testsSerum tests

Fe , Tf Sat, Ferritin (< 12 Fe , Tf Sat, Ferritin (< 12 g/L)g/L) TIBC, transferrin, transferrin receptorTIBC, transferrin, transferrin receptor

Fe Deficiency: Lab Findings-II

•Bone marrow aspirate- Absent macrophage Fe- sideroblasts- Erythroid hyperplasia

BM aspirate: iron stain, increased macrophage iron

BM aspirate: iron stain, absent macrophage iron

Fe Deficiency: ManagementFe Deficiency: Management First, look for source of blood loss. Rule First, look for source of blood loss. Rule

out malignancy. out malignancy. Test stools for occult blood.Test stools for occult blood. GastrointestinalGastrointestinal GenitourinaryGenitourinary– ColorectalColorectal - Endometrial- Endometrial– GastricGastric - Cervical- Cervical– EsophagealEsophageal - Bladder- Bladder– HepatomaHepatoma

Second, correct cause of blood loss.Second, correct cause of blood loss.

TreatmentTreatment General principlesGeneral principles

– Iron absorption occurs at the duodenum Iron absorption occurs at the duodenum and proximal jejunumand proximal jejunum

Extended release capsules or enteric coated Extended release capsules or enteric coated capsules get absorbed lower parts of the GI capsules get absorbed lower parts of the GI tract and are not very effectivetract and are not very effective

– Iron salts should not be given with food Iron salts should not be given with food because the salts bind the iron and impair because the salts bind the iron and impair absorptionabsorption

TreatmentTreatment Iron should be given two hours before or four Iron should be given two hours before or four

hours after the ingestion of antacidshours after the ingestion of antacids Iron is best absorbed as the ferrous salt in a Iron is best absorbed as the ferrous salt in a

mildly acidic medium mildly acidic medium – Can give with tablet of Vitamin CCan give with tablet of Vitamin C

Iron preparation used should be based upon Iron preparation used should be based upon cost and effectiveness with minimal side cost and effectiveness with minimal side effectseffects– Cheapest is iron sulfate (65 mg of elemental iron)Cheapest is iron sulfate (65 mg of elemental iron)

TreatmentTreatment GI tract symptoms is directly related to GI tract symptoms is directly related to

the amount of elemental iron ingestedthe amount of elemental iron ingested– These symptoms may be less in the iron These symptoms may be less in the iron

elixir preparation.elixir preparation.

Oral Iron TherapyOral Iron Therapy Most appropriate oral iron therapy is use of a Most appropriate oral iron therapy is use of a

tablet containing ferrous saltstablet containing ferrous salts– Ferrous fumarate, 106 mg elemental iron/tabFerrous fumarate, 106 mg elemental iron/tab– Ferrous sulfate, 65 mg elemental iron/tabFerrous sulfate, 65 mg elemental iron/tab– Ferrous gluconate, 28-36 mg iron/tabFerrous gluconate, 28-36 mg iron/tab

Recommended daily dose= 150-200 mg/day Recommended daily dose= 150-200 mg/day of elemental ironof elemental iron– No evidence that one preparation is better than No evidence that one preparation is better than

anotheranother

Side effectsSide effects 10-20% patients nausea, constipation, 10-20% patients nausea, constipation,

epigastric distress and/or vomitingepigastric distress and/or vomiting– TreatmentTreatment

Smaller dose of elemental iron, or switch to Smaller dose of elemental iron, or switch to elixir formelixir form

Slow increase in dose from 1 tablet to 3 tablets Slow increase in dose from 1 tablet to 3 tablets per dayper day

Take tablet with meals (may decrease Take tablet with meals (may decrease absorption)absorption)

Duration of TreatmentDuration of Treatment Depends on physicianDepends on physician

– May discontinue when hgb level is normalMay discontinue when hgb level is normal– Some continue for six months after the hgb Some continue for six months after the hgb

is normalis normal

Treatment FailuresTreatment Failures Incorrect diagnosisIncorrect diagnosis Pressure of coexisting disease (ACD)Pressure of coexisting disease (ACD) NoncomplianceNoncompliance Difficulty with absorption (antacids, enteric-Difficulty with absorption (antacids, enteric-

coated tablets)coated tablets) Iron loss > amount ingestedIron loss > amount ingested Iron malabsorption (Celiac disease, H. Iron malabsorption (Celiac disease, H.

Pylori)Pylori)

Parenteral Iron TherapyParenteral Iron Therapy IndicationsIndications

– Rarely given when patients cannot tolerate Rarely given when patients cannot tolerate oral formoral form

– If iron loss exceeds oral iron replacementIf iron loss exceeds oral iron replacement– Inflammatory bowel diseaseInflammatory bowel disease– Dialysis patientsDialysis patients– Anemic cancer patients Anemic cancer patients

Available PreparationsAvailable Preparations Iron dextran (INFeD, Dexferrum)Iron dextran (INFeD, Dexferrum)

– 50 mg elemental iron/mL, given either IM or IV50 mg elemental iron/mL, given either IM or IV INFeD is low molecular weight, Dexferrum is high INFeD is low molecular weight, Dexferrum is high

molecular weightmolecular weight– Side effects: Usually in ~ 5% patientsSide effects: Usually in ~ 5% patients

Local rxns: Pain, muscle necrosis, phlebitisLocal rxns: Pain, muscle necrosis, phlebitis Systemic: Anaphylaxis seen in 1%, fever, urticaria, Systemic: Anaphylaxis seen in 1%, fever, urticaria,

arthritic flaresarthritic flares Side effects seen more with high molecular weight Side effects seen more with high molecular weight

preparations.preparations.

Available PreparationsAvailable Preparations Ferric Gluconate (Ferrlecit, 12.5 mg Ferric Gluconate (Ferrlecit, 12.5 mg

iron/mL)iron/mL) Iron sucrose (Venofer, 20 mg iron/mL)Iron sucrose (Venofer, 20 mg iron/mL)

– Both can only be used in IV formulationBoth can only be used in IV formulation– Ferric gluconate has less allergic reactions as Ferric gluconate has less allergic reactions as

compared to Iron dextran (3.3 vs. 8.7 allergic compared to Iron dextran (3.3 vs. 8.7 allergic events per 1 million doses per year)events per 1 million doses per year)

– Iron sucrose also has less side effects, even if Iron sucrose also has less side effects, even if there is a prior history of rxn to Iron dextranthere is a prior history of rxn to Iron dextran

Faich, G. Am J Kidney Dis 1999; 33:464

IM IronIM Iron Usually slow iron mobilization and Usually slow iron mobilization and

occasionally incompleteoccasionally incomplete– Therefore usually not used, even though Therefore usually not used, even though

available in the Iron dextran formavailable in the Iron dextran form

IV IronIV Iron Most commonly used in dialysis settingMost commonly used in dialysis setting If Ferric gluconate used, test dose not If Ferric gluconate used, test dose not

recommended anymorerecommended anymore– 2 mL of ferrlecit, diluted in 50 mL of NS and 2 mL of ferrlecit, diluted in 50 mL of NS and

infused over 60 min. infused over 60 min. If no reaction seen, up to 10 mL is given in any If no reaction seen, up to 10 mL is given in any

setting, diluted in 100 mL of NS and given over setting, diluted in 100 mL of NS and given over 60 minutes60 minutes

Calculation of IV Iron DoseCalculation of IV Iron Dose Calculate iron defecitCalculate iron defecit

– 1 gram of hemoglobin = 3.3 mg of elemental iron1 gram of hemoglobin = 3.3 mg of elemental iron 60 kg woman with hgb of 8 g/dL needs IV iron 60 kg woman with hgb of 8 g/dL needs IV iron

in the form of iron sucrose (20 mg/mL)in the form of iron sucrose (20 mg/mL)– Normal blood vol 65 mL/kg, thus her blood Normal blood vol 65 mL/kg, thus her blood

volume is 3900 mLvolume is 3900 mL– Normal hgb is 14 g/dL, therefore hgb deficit is 6 g Normal hgb is 14 g/dL, therefore hgb deficit is 6 g

dL, with a total of 234 grams (6 x 39 dL)dL, with a total of 234 grams (6 x 39 dL)

Calculation of IV iron DoseCalculation of IV iron Dose Each gram of hemoglobin = 3.3 mg of Each gram of hemoglobin = 3.3 mg of

ironiron– Total RBC iron deficit is 772 mg (234 g x Total RBC iron deficit is 772 mg (234 g x

3.3)3.3) Iron sucrose has 20 mg/mL, therefore, Iron sucrose has 20 mg/mL, therefore,

this would require a total of 38.6 mLthis would require a total of 38.6 mL

Oral Iron TherapyOral Iron Therapy1.1. DoseDose

– 100-200 mg elemental Fe/d (adults)100-200 mg elemental Fe/d (adults)– 5.0 mg elemental Fe/kg per day (children)5.0 mg elemental Fe/kg per day (children)– administer on empty stomach if tolerated administer on empty stomach if tolerated

2.2. DurationDuration– 1-2 months to correct anemia1-2 months to correct anemia– 2-4 additional months to replenish stores2-4 additional months to replenish stores

3.3. Side effects- Side effects- diarrhea, constipation, crampsdiarrhea, constipation, cramps

Oral Iron TherapyOral Iron Therapy

4. Preparations4. Preparations– FeSOFeSO4 4 (325 mg FeSO(325 mg FeSO44 = 65 mg Fe) = 65 mg Fe)

one tab tidone tab tid GI side effectsGI side effects risk of poisoning in small childrenrisk of poisoning in small children

– Carbonyl ironCarbonyl iron elemental Fe powder- 150 mg/delemental Fe powder- 150 mg/d Similar side effects; saferSimilar side effects; safer

Parenteral Iron TherapyParenteral Iron Therapy

1.1. Indications (rare)Indications (rare)– Unable to absorb oral ironUnable to absorb oral iron– Intractable non-compliance to oral ironIntractable non-compliance to oral iron

2.2. PreparationsPreparations– Fe dextran (risk of anaphylaxis)Fe dextran (risk of anaphylaxis)

50 mg/ml, 100 mg/d im/iv50 mg/ml, 100 mg/d im/iv– Sodium ferric gluconate complex Sodium ferric gluconate complex

Given with EPO in hemodialysis pts.Given with EPO in hemodialysis pts.