IRON DEFICIENCY ANEMIA

Iron deficiency in the United States

National Health and Nutrition Examination Survey (NHANES)

Survey of sample US households: ferritin, % saturation, FEPMMWR 51(40); 897-9

CAUSES OF IRON DEFICIENCY

OVERT BLOOD LOSS

Hematemesis, melena

Severe menorrhagia

Hemoptysis, hematuria, traumatic hemorrhage

OCCULT BLOOD LOSS

Small bowel, vascular, inflammatory

Voluntary blood donations, post-op, iatrogenic

Menses

OBS: delivery, direct iron loss to fetus,

iron loss to the neonate during lactation

CAUSES OF IRON DEFICIENCY

UNCOMMON• Reduced GI absorption of iron: Celiac Disease, Atrophic Gastritis,

H Pylori • Gastric Bypass for obesity ; Billroth II• Diet deficient in iron (phytates) • Intravascular hemolysis — PNH, malfunctioning heart valve

prostheses, Intravascular Hemolysis (Cold Agglutinin)• Pulmonary Hemosiderosis• ( IRIDA ) Iron-refractory iron deficiency anemia-- TMPRSS6,DMT1

EMERGING

Response to erythropoietin — Mobilization of iron stores

Unexplained iron deficiency:“Gastrointestinal sideropenia”

• Consider in patients with relapsed/refractory iron deficiency:– Celiac disease– Atrophic body gastritis– H. pylori infection– Gastric bypass surgery

Body Iron Distribution and Storage

Dietary ironUtilization Utilization

Duodenum(average, 1 - 2 mg

per day)

Muscle(myoglobin)

(300 mg)

Liver(1,000 mg)

Bone marrow(300 mg)Circulating

erythrocytes(hemoglobin)

(1,800 mg)

Reticuloendothelialmacrophages

(600 mg)

Sloughed mucosal cellsDesquamation/Menstruation

Other blood loss(average, 1 - 2 mg per day)

Storageiron

Plasmatransferrin

(3 mg)

Iron loss

Iron Cycling

Erythrocytes

2500 mg

Plasma

4 mgBody Stores

500-1000 mg

Myoglobin

and Respiratory Enzymes

300 mg

Monocyte-Macrophage System

RBC Production

Bone Marrow

20 mg Daily

RBC Destruction

20 mg Daily

Loss

1-2 mg

Daily

Absorption

1-2 mg

Daily

5 mg Daily

Hudson JQ, Comstock TJ. Clin Ther. 2001;23:1637-1671.

Eschbach JW et al. Kidney Int. 1992;42:407-416.

Fe-Transferrin

Fe-Transferrin

Fe-Transferrin

Fe-Transferrin

MetabolicHemoglobin 1800-2500 mgMyoglobin 300-500 mg

StorageIron storage 0-1000 mg

TransitSerum iron 3 mg

Total 3000-4000 mg

Major Iron Compartments

Iron Intake

Fairweather-Tait S.; Proc Nutrition Society (2004) 63:519-528

to the iron intake 1992-3

Bread11%

Cereals39%

Eggs3%

Meat15%

Vegetables16%

Other16%

Contribution of food groupsto the iron intake 1992-3

Bread11%

Cereals39%

Eggs3%

Meat15%

Vegetables16%

Other16%

• Mean iron intake 10-14 mg/d

• Historically, main source of iron intake has been meat

• Iron intake has stabilized over the past 25 years

• Not a marker of iron status• Not a marker of overall

nutrition

Effectors of Iron Absorption

Alleyne, M. Am J Med. (2008) 121:943-948

• Inhibiting Iron Absorption– Coffee, tea, milk, cereals, dietary fiber, carbonated

beverages– Dietary supplements with Ca, Zn, Mn, Cu– Antacids, H2 blockers, and PPI’s

• Facilitating Iron Absorption– Vitamin C– Acidic foods

Proteins Regulating Iron Absorption

Andrews N Engl J Med 353:2508

Lumen

Circulation

Hepcidin

Laboratory diagnosis of iron deficiency:Serum iron and transferrin (TIBC)

Parameter Sensitivity (%) Specificity (%) Accuracy (%)

Serum Iron 82 30 53

TIBC 60 63 54

Ferr

itin

µg/

l

Bone marrow iron stores

Laboratory Diagnosis of Iron DeficiencySoluble Transferrin Receptor (sTfR)

• Transferrin receptor located on surface of erythroid precursors in bone marrow

• Small amount of transferrin released into circulation (sTfR)

• Iron deficiency anemia associated with increased sTfR

sTfR: Distinguish Iron Deficiency from Other Hypoproliferative Anemias

Overall results of sTfR

Sensitivity ~100%

Specificity 69%

Accuracy 88%

Neurologic syndromes associated with iron deficiency

• Pica– Definition: Compulsive

ingestion of a non-food substance

– Pagophagia Ice eating– Occurs in women

more commonly then men

– Occurs in all causes of iron deficiency anemia

(~25%)

• Restless leg syndrome− Common neurologic

disorder− Criteria for diagnosis:

1. An urge to move the legs usually accompanied by uncomfortable sensations

2. Sensation begins or worsens during periods of rest

3. Sensations relieved by movement

4. Worse in the evening/night

− Occurs in ~10% of cases of iron deficiency anemia

Treatment With Iron: Principles

• Ferrous salts are absorbed better than ferric salts

• All ferrous salts are absorbed to the same extent

• Ascorbic acid increases absorption and toxicity

• Iron is absorbed best on an empty stomach; not given with antacids

• Prescription iron generally better tolerated than iron salts

• Reticulocytosis occurs <7days; Increase in Hgb 2-3 weeks

• Maximum iron dose ~200 mg/day

Available Oral Iron Supplements

Oral iron preparations

Typical dose (mg)

Elemental iron (mg)

Approx. cost to give 5000

mg

Ferrous sulfate 325 mg tid 65 $10.00

Ferrous gluconate 300 mg tid 36 $7-8.00

Ferrous fumarate 100 mg tid 33 $8.00-9.50

Iron polysaccharide

complex

150 mg bid 150 $11.00

Carbonyl iron 50 mg tid 50 $18.00

Inadequate Response to Oral Iron

Intolerance/Noncompliance (~30% discontinue)

Persistent blood loss Decreased iron absorption Chronic inflammation or bone marrow

damage Chronic kidney disease

Investigational agent(not FDA

approved)

Investigational agent(not FDA

approved)

Generic name High Molecular Wt Iron Dextran

Low Molecular Wt Iron Dextran

Ferric Gluconate

IronSucrose

Ferumoxtyol Iron Isomalto-

side

Ferric Carboxy-maltose

Trade nameDEXFERRUM INFeD Ferrlecit Venofer FERAHEME Monofer6 Injectafer

Manufacturer American Regent Watson Pharmaceuticals

Watson Pharmaceuticals

American Regent

AMAG Pharmaceuticals

Pharmacosmos A/S

American Regent

Carbohydrate High-molecular-weight iron dextran

Low-molecular-weight iron

dextran

Gluconate Sucrose Polyglucose sorbitol

carboxymethylether

Isomaltoside Carboxymaltose

Molecular weight measured by manufacturer (Da)

265,000 165,000 289,000-440,000 34,000-60,000

750,000 150,000 150,000

Total-dose or >500-mg infusion

Yes Yes No No No Yes Yes

Premedication TDI only TDI only No No No No No

Test dose required

Yes Yes No No No No No

Iron concentration (mg/mL)

50 50 12.5 20 30 100 30

Black box warning

Yes Yes No No Np NA NA

Intravenous Iron Preparations

IV Iron Agents are Spheroid Particles with an Iron Core and Carbohydrate Shell

iron

oxyhydroxide

core

carbohydrate

shell

Source of core sizes: Kudasheva and Cowman, J Biol Chem

IV Iron Agents Differ by Core Size and Shell Chemistry

Iron Sucrose Ferric Gluconatebound

sucrosebound

gluconate

&

weakly

associated

sucrose

core

Kudascheva, J Inorg Biochem. 2004 Nov; 98(11):1757-69

Plasma Kinetics of IV Iron Agents:Ionic Fe+3>SFGC > iron sucrose >> iron dextran

Dexferrum®

INFeD®

Iron sucrose

SFGC

Fe+3

Hours0 20 40 60 80

Plasma Iron Disappearance

50

10

100

% In

itial

Val

ue

Use of IV Iron Products

Notes: Ferric gluconate approved February 1999, iron sucrose approved November 2000Source: IMS Health National Sales Perspectives 1999-2008

2

4

6

8

10

12

14

16

18

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Venofer

Ferrlecit

Dexferrum

INFeD

Total IVIron

Millionsof

Units

0

2.0

4.0

6.0

15

25

35

45

Iron-Restricted Erythropoiesis

Eschbach JW et al. N Engl J Med. 1987;316:73-78.Eschbach JW et al. N Engl J Med. 1987;316:73-78.

Ret

icu

locy

tes

Co

rrec

ted

, %

Hem

ato

crit

, %

200 mLRBCs

1000 mgIV Iron Dextran

Anephric

-12 -8 -4 0 +4 +8 +12 +16 +20 +24

WeeksrHuEPO 50 U/kg 3 ×/wk

% Saturation 52 13 26Ferritin 885 578 1036

Percent Hypochromic Red Cells (%HYPO)

• Flow cytometry with 2 detectors– High angle for Hb content– Low angle for cell size– Allows construction of a histogram for Hb content

Depleted Iron Stores

Intense Erythropoietic

Stimulus, eg ESA

IronSucrose

FerricGluconate

IronDextran

Ferumoxytol

Push100 mg over 2-5 min

(HDD-CKD)

200 mg over 2-5 min (NDD-CKD)

125 mg over 10 min (HDD-CKD)

100 mg/ 2 minObserve patient for at least one hour after test dose for

signs and symptoms of anaphylaxis(Documented iron

deficiency in whom oral adminstration is unsatisfactory or

impossible)

510 mg/ 17 secObserve patient for at least 30 minutes after

administration for signs & symptoms of hypersensitivity

(CKD)

Infusion(0.9% NaCl)

100 mg/100 ml over 15 min (HDD-CKD)

300 mg/250 ml over 1.5hr (PDD-CKD)

400 mg/250 ml over 2.5hr (PDD-CKD)

125 mg/100 ml over 1 hr

(HDD-CKD)

1000 mg at 6 mg/min

(Not FDA-approved)

Not recommended

Recommended Dosing of IV Iron

Classification of Adverse Iron Reactions

Serious IV Iron Reactions: Three syndromes

• Anaphylaxis or anaphylactoid reaction– Sensitivity reaction, marked by allergic manifestations

♦ Hypotension with dyspnea, chest pain, angioedema, or urticaria

– Immediate, sudden, severe, usually with test dose or 1st dose

• Labile iron reaction– Non-allergic, commonly dose-related

• Intolerance reaction– Presumed sensitivity reaction of any kind, may not be

anaphylactic, preclude further treatment

– Incidence of adverse reactions increases with underlying autoimmune disease or infection

Iron Dextran: Boxed Warning due to the Risk of Anaphylaxis

IMPORTANT SAFETY INFORMATION

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection.

• Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during iron dextran administration.

• Administer a test dose prior to the first therapeutic dose.

• During all iron dextran administrations, observe for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran injection and in situations where the test dose was tolerated.

• Use iron dextran only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.

Incidence of Life-threatening Adverse Events (Anaphylaxis)

Chertow GM et al Nephrol Dial Transplant 2006;21:378-382

Product

Incidence ofAdverse event

(per 106 infusions) Comment

Iron dextran 3.3-11.3 HMW dextran>LMW dextran

Ferric gluconate 0.9

Iron sucrose 0.6

Labile iron reactions

• Incidence, severity varies by – Total dose administered– Rate of administration– Iron agent chemical class

• Findings include:– Cramping, flank pain, chest pain– Hypotension without allergic manifestations

– Lowering dose or slowing administration prevents recurrence (not a sensitivity reaction)

• Taste disturbance– “Minty” or “metallic” taste

• Flushing– Without hypotension

• Like labile iron reaction:– Transient– Abate after slowing infusion rate

Intolerance reactions: Common, Mild IV Iron Reactions

Tolerability of IV iron products

• Hemodialysis patients intolerant to iron dextran were shown to tolerate ferric gluconate

• Hemodialysis patients intolerant to iron dextran or ferric gluconate were able to tolerate iron sucrose