1. IRON DEFICIENCY ANEMIA

4. Iron deficiency in the United States
National Health and Nutrition Examination Survey (NHANES)
MMWR 51(40); 897-9 Survey of sample US households: ferritin, % saturation, FEP

5. 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

6. 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

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

8. Body Iron Distribution and Storage
Duodenum Dietary iron
(average, 1 - 2 mg
Utilization Utilization
per day)
Plasma
transferrin
(3 mg)
Bone
Muscle marrow
(myoglobin) Circulating (300 mg)
(300 mg) erythrocytes
Storage
iron (hemoglobin)
(1,800 mg)
Sloughed mucosal cells
Desquamation/Menstruation
Other blood loss
(average, 1 - 2 mg per day) Reticuloendothelial
Liver
(1,000 mg) macrophages
Iron loss (600 mg)

9. Iron Cycling
Erythrocytes
RBC
2500 mg Production
Monocyte-
Macrophage System
Bone Marrow
RBC
Destruction Fe-Transferrin
20 mg
20 mg Daily
Fe-Transferrin Fe-Transferrin
Daily
Plasma Loss
4 mg 1-2 mg
Body Stores
500-1000 mg Daily
5 mg Daily
Fe-Transferrin
Absorption Myoglobin
1-2 mg and Respiratory
Enzymes
Daily
300 mg
Hudson JQ, Comstock TJ. Clin Ther. 2001;23:1637-1671.
Eschbach JW et al. Kidney Int. 1992;42:407-416.

10. Major Iron Compartments
Metabolic
Hemoglobin 1800-2500 mg
Myoglobin 300-500 mg
Storage
Iron storage 0-1000 mg
Transit
Serum iron 3 mg
Total 3000-4000 mg

11. Iron Intake
• Mean iron intake 10-14
mg/d Contribution iron intake 1992-3
to the of food groups
• Historically, main source of to the iron intake 1992-3
iron intake has been meat Other Bread
Other Bread
11%
• Iron intake has stabilized 16%
16% 11%
over the past 25 years Vegetables
Vegetables
16%
• Not a marker of iron status 16%
Cereals
Cereals
• Not a marker of overall Meat
39%
39%
Meat Eggs
nutrition 15% Eggs
15% 3%
3%
Fairweather-Tait S.; Proc Nutrition Society (2004) 63:519-528

12. Effectors of Iron Absorption
• 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
Alleyne, M. Am J Med. (2008) 121:943-948

13. Proteins Regulating Iron Absorption
Lumen
Hepcidin
Circulation
Andrews N Engl J Med 353:2508

14. Laboratory diagnosis of iron deficiency:
Serum iron and transferrin (TIBC)
Parameter Sensitivity (%) Specificity (%) Accuracy (%)
Serum Iron 82 30 53
TIBC 60 63 54

15. Ferritin µg/l
Bone marrow iron stores

16. Laboratory Diagnosis of Iron Deficiency
Soluble 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

17. sTfR: Distinguish Iron Deficiency from
Other Hypoproliferative Anemias
Overall results of sTfR
Sensitivity ~100%
Specificity 69%
Accuracy 88%

18. Neurologic syndromes associated
with iron deficiency
• Pica • Restless leg syndrome
– Definition: Compulsive − Common neurologic
ingestion of a non- disorder
food substance − Criteria for diagnosis:
– Pagophagia Ice eating 1. An urge to move the legs
usually accompanied by
– Occurs in women more uncomfortable sensations
commonly then men 2. Sensation begins or
– Occurs in all causes of worsens during periods of
iron deficiency anemia rest
3. Sensations relieved by
(~25%) movement
4. Worse in the evening/night
− Occurs in ~10% of cases of
iron deficiency anemia

19. 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

20. Available Oral Iron Supplements
Approx. cost
Oral iron Typical Elemental
to give 5000
preparations dose (mg) iron (mg)
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
150 mg
polysaccharide 150 $11.00
bid
complex
Carbonyl iron 50 mg tid 50 $18.00

21. Inadequate Response to Oral Iron
 Intolerance/Noncompliance (~30%
discontinue)
 Persistent blood loss
 Decreased iron absorption
 Chronic inflammation or bone marrow
damage
 Chronic kidney disease

22. Investigati Investigati
onal agent onal agent
Intravenous Iron Preparations (not FDA (not FDA
approved) approved)
Generic name High Molecular Low Ferric Iron Ferumoxtyol Iron Ferric
Wt Iron Dextran Molecular Wt Gluconate Sucrose Isomalto- Carboxy-
Iron Dextran side maltose
Trade name
DEXFERRUM INFeD Ferrlecit Venofer FERAHEME Monofer6 Injectafer
American Regent Watson Watson American AMAG Pharmacosmo American
Manufacturer
Pharmaceuticals Pharmaceuticals Regent Pharmaceuticals s A/S Regent
Carbohydrate High-molecular- Low-molecular- Gluconate Sucrose Polyglucose Isomaltoside Carboxymalt
weight iron dextran weight iron sorbitol ose
dextran carboxymethyl
ether
Molecular weight 265,000 165,000 289,000-440,000 34,000- 750,000 150,000 150,000
measured by 60,000
manufacturer
(Da)
Total-dose or Yes Yes No No No Yes Yes
>500-mg
infusion
Premedication TDI only TDI only No No No No No
Test dose Yes Yes No No No No No
required
Iron 50 50 12.5 20 30 100 30
concentration
(mg/mL)
Black box Yes Yes No No Np NA NA
warning

23. IV Iron Agents are Spheroid Particles with
an Iron Core and Carbohydrate Shell
iron carbohydrate
oxyhydroxide shell
core
Source of core sizes: Kudasheva and Cowman, J Biol Chem

24. IV Iron Agents Differ by
Core Size and Shell Chemistry
Iron Sucrose Ferric Gluconate
bound
bound
sucrose
gluconate
&
weakly
associated
sucrose
core
Kudascheva, J Inorg Biochem. 2004 Nov; 98(11):1757-69

25. Plasma Kinetics of IV Iron Agents:
Ionic Fe+3>SFGC > iron sucrose >> iron dextran
100
% Initial Value Dexferrum®
50
Plasma Iron
Disappearance
INFeD®
Iron sucrose
10 SFGC
Fe+3
0 20 40 60 80
Hours

26. Use of IV Iron Products
18
16
14
Venofer
12
Millions
of Ferrlecit
Units 10
Dexferrum
8
INFeD
6
Total IV
4 Iron
2
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Notes: Ferric gluconate approved February 1999, iron sucrose approved November 2000
Source: IMS Health National Sales Perspectives 1999-2008

27. Iron-Restricted Erythropoiesis
Hematocrit, %
45 Anephric 1000 mg
IV Iron Dextran
35
200 mL
25 RBCs
15
6.0
Reticulocytes
Corrected, %
4.0
2.0
0
-12 -8 -4 0 +4 +8 +12 +16 +20 +24
Weeks
rHuEPO 50 U/kg 3 /wk
% Saturation 52 13 26
Ferritin 885 578 1036
Eschbach JW et al. N Engl J Med. 1987;316:73-78.

28. 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

29. Recommended Dosing of IV Iron
Iron Ferric Iron
Ferumoxytol
Sucrose Gluconate Dextran
100 mg/ 2 min
Observe patient for
510 mg/ 17 sec
at least one hour
Observe patient for at
after test dose for
100 mg over 2-5 min 125 mg over signs and symptoms
least 30 minutes after
administration for signs
Push (HDD-CKD)
200 mg over 2-5 min 10 min of anaphylaxis
(Documented iron & symptoms of
(HDD-CKD)
(NDD-CKD) deficiency in whom oral hypersensitivity
adminstration is (CKD)
unsatisfactory or
impossible)
100 mg/100 ml over 15 min
(HDD-CKD)
125 mg/100 1000 mg at 6
Infusion 300 mg/250 ml over 1.5hr
ml over 1 hr mg/min
Not
(0.9% NaCl)
(PDD-CKD)
(HDD-CKD) (Not FDA-approved)
recommended
400 mg/250 ml over 2.5hr
(PDD-CKD)

30. Classification of
Adverse Iron Reactions

31. 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

32. 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.

33. Incidence of Life-threatening
Adverse Events (Anaphylaxis)
Incidence of
Adverse event
Product (per 106 infusions) Comment
Iron dextran 3.3-11.3 HMW dextran>LMW dextran
Ferric gluconate 0.9
Iron sucrose 0.6
Chertow GM et al Nephrol Dial Transplant 2006;21:378-382

34. 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)

35. Intolerance reactions: Common,
Mild IV Iron Reactions
• Taste disturbance
– “Minty” or “metallic” taste
• Flushing
– Without hypotension
• Like labile iron reaction:
– Transient
– Abate after slowing infusion rate

36. 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