1. Iron Deficiency: Clinical Sequelae and Diagnosis
Photis Beris, MD
Professor of Clinical Haematology Department of Internal Medicine
Geneva University Hospital Geneva, Switzerland

2. Iron Deficiency—Definitions Successive Stages of Iron Deficiency
Iron-deficient erythropoiesis, or functional iron deficiency
Depletion of iron stores
Iron-deficiency anaemia
Grosbois B, et al. Bull Acad Natl Med. 2005;189:1649.

3. Iron Deficiency—Prevalence
World’s most common nutritional deficiency
2% in adult men (≤ 69 years old)
4% in adult men ≥ 70 years old*
10% in Caucasian, non-Hispanic women
19% in African-American women
*Value for 1994
CDC. MMWR. 2002;51:899.

4. Main Causes of Anaemia Others 9% Haemolysis 17.5% Iron Deficiency 29%
Acute Bleeding 17.5%
Chronic Disease 27%
Beris P, Tobler A. Schweiz Rundsch Med Prax. 1997;86:1684.
Reprinted from Lambert JF, et al. In C Beaumont, P Beris, Y Beuzard, C Brugnara, eds. Disorders of iron homeostasis, erythrocytes, erythropoiesis. Forum service editore, Genoa, Italy, 2006 page 73 figure 1, by permission of European School of Haemotology.

5. Iron Deficiency—Aetiology
Increased demand for iron and/or haematopoiesis
Iron loss
Decreased iron intake or absorption
Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005.

6. Iron Deficiency—Increased Demand for Iron and/or Haematopoiesis
Infancy and adolescence1,2
Pregnancy and lactation1,2
Low socioeconomic status and poverty greatly increase the prevalence of iron deficiency in this category of populations3
• In patients receiving erythropoietin therapy (= functional iron deficiency)2
1. Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005.
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed
CDC. MMWR. 2002;51:899.

7. Iron Deficiency—Iron loss
In physiologic conditions
Menstruation
In pathologic conditions
Surgery, delivery
Haemoglobinuria,haemoptysis
Gastrointestinal tract pathology
In therapeutic procedures
Phlebotomy
In blood donation
Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005: Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed

8. Iron Deficiency—Decreased Iron Intake or Absorption
Vegetarians or malnutrition (low-cost diet)1
Malabsorption syndromes
Sprue, UHC, and Crohn’s disease2
After gastric and intestinal surgery3
Intestinal parasitosis (ankylostomiasis)3
Helicobacter pylori infection2
Autoimmune atrophic gastritis2
CDC. MMWR. 1998;47(RR-3);1-36.
Annabale B, et al. Am J Med. 2001;111:439.
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed

9. Iron Deficiency Clinical Manifestations (I)
Fatigue
Decreased exercise tolerance
Tachycardia
Dermatologic manifestations
Decreased intellectual performance
Dysphagia
Depression, increased incidence of infections
Restless legs syndrome
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed
Trost LB, et al. J Am Acad Dermatol. 2006;54:824.

10. Iron Deficiency Clinical Manifestations (II)
Skin and conjuctival pallor
Koilonychia
Angular cheilosis
Burning tongue
Glossitis
Hair loss (alopecia areata)
Top figure accessed from: with permission from Nature Publishing Group.
Bottom figure accessed from: Modern Nutrition in Health & Disease. 9th ed. Editors: Shils, Olsen, Shike & Ross. Williams & Williams, pub.

11. Iron Deficiency Diagnosis
Laboratory tests for:
Iron depletion in the body
Iron-deficient erythropoiesis (functional iron deficiency)
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

12. Diagnosis of Iron Depletion in the Body—Haematology
Peripheral blood smear of a patient with severe iron deficient anaemia. Note the important microcytosis (compare red blood cells with lymphocyte) as well as hypochromia, target cells, and poikilocytosis.
Graphic courtesy of Dr. P. Beris.

13. Diagnosis of Iron Depletion in the Body—Haematology
Hypochromic, microcytic anaemia usually with high platelets
Differential diagnosis of microcytosis
Iron deficiency
Thalassaemia syndromes
Haemoglobinopathies (E,C,CS, Lepore…)
Anaemia of chronic diseases
Familial sideroblastic anaemia
Miscellaneous (lead intoxication…)
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed

14. Diagnosis of Iron Depletion in the Body—Clinical Chemistry
Serum iron
Transferrin (iron binding capacity)
Transferrin saturation
These parameters are modified by inflammation and by fasting state. They are thus of limited value.
Serum ferritin, soluble transferrin receptors (sTfR) and sTfR/log ferritin are excellent tools for screening iron stores
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

15. Serum Levels That Differentiate ACD from IDA
Variable
ACD
IDA
Both Conditions
Iron 
Transferrin
 To normal 
Transferrin saturation
Ferritin
Normal to 
sTfR
Normal
sTfR/log ferritin
Low (<1)
High (>2)
Cytokine levels

16. Iron Deficiency—Diagnosis
Bone marrow examination for stainable iron was regarded in the past as the gold standard for diagnosing iron deficiency
No longer recommended for routine evaluation
High inter- and intra-observer variability in evaluation
Discomfort associated with procedure
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

17. Iron Deficiency—Diagnosis
Microphotograph of bone marrow staining for iron. Iron is stained blue and it is mainly in the macrophages (lower left)
Graphic courtesy of Dr. P. Beris.

18. Iron Deficiency—Diagnosis
Patients with IDA and a high risk of underlying disease (eg, men of all ages and postmenopausal women) should be evaluated endoscopically for occult bleeding1
Video capsule endoscopy (VCE) should be considered in suspected small-bowel malignancy2
S Killip, et al. Am Fam Physician. 2007;75:671.
Urbain D, et al. Endoscopy. 2006;38:408.

19. Screening for Iron Deficiency
The US Preventive Services Task Force recommends screening only for pregnant women
There is insufficient evidence to support routine screening in other asymptomatic persons
S Killip, et al. Am Fam Physician. 2007;75:671.

20. Iron-Deficient Erythropoiesis (Functional Iron Deficiency)—Diagnosis
Normal or increased ferritin
Laboratory signs of iron-deficient erythropoiesis
Serum iron <60 μg/dL
Transferrin saturation <20%
Hypochromic RBC >5%
Reticulocyte Hb content (CHr) <29 pg
Soluble transferrin receptor > 7 mg/L
Beguin Y, et al. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

21. Main Conditions Characterized by Functional Iron Deficiency
EPO-stimulated red cell production (anaemia of chronic kidney disease)
Insufficient mobilization of iron from macrophages (anaemia in rheumatoid arthritis and in cancer)
Beguin Y, et al. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

22. Refractory Iron Deficiency Anaemia
In recent years, Helicobacter pylori has been implicated in several studies as a cause of iron deficiency anaemia (IDA) refractory to oral iron treatment, with a favorable response to H. pylori eradication
Another nonbleeding gastrointestinal condition that may result in IDA refractory to oral iron treatment is coeliac disease
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

23. Refractory Iron Deficiency Anaemia
Autoimmune atrophic gastritis or atrophic body gastritis has been associated with chronic idiopathic iron deficiency with no evidence of gastrointestinal blood loss and thus is another cause that leads to refractory IDA
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

24. Recommendations for the Diagnostic Work-Up of Refractory IDA
Screening for coeliac disease, autoimmune type A atrophic gastritis and for H. pylori should be performed in the following populations
Males and postmenopausal females with IDA and negative endoscopic and radiologic studies
Fertile females and children/adolescents refractory to oral iron treatment
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Forum service editore: Genoa, Italy; 2006.

25. Algorithm for Investigation of Microcytic Anaemia
RBC count ↓
RBC count normal or↑
CRP normal
CRP ↑
Ferritin normal
Ferritin < 50
Ferritin
Ferritin >150
sTfR/logFerr
≥1.55
sTfR/logFerr
<1.55
Ferritin <20
Ferritin normal
Anaemia of
chronic disease
Hb analysis
BM examination
Ring sideroblasts?
Familial sidero-
blastic anaemia
HbA2 ↑ or HbF ↑
Normal pattern
Lambert JF, Beris P. Pathophysiology and differential diagnsosis of anemia. In C Beaumont, P Beris, Y Beuzard, C Brugnara (editors) Disorders of iron homeostasis, erythrocytes, erythropoiesis. Forum service editore, Genoa, Italy,2006
Consider H.
pylori infection
Family studies,
chromosome 16 deletion search
Iron def anaemia
Aetiology?
No response to ttt
β-thalassaemia
Consider Hb analysis
α-thalassaemia
Reprinted from Lambert JF, et al. In C Beaumont, P Beris, Y Beuzard, C Brugnara, eds. Disorders of iron homeostasis, erythrocytes, erythropoiesis. Forum service editore, Genoa, Italy, 2006 page 73 figure 1, by permission of European School of Haemotology.

26. IDA—Conclusions
Iron deficiency causes not only anaemia but also extraerythroid symptoms
Diagnosis of iron deficiency may be difficult in the presence of a concommitant inflammatory state
Patients should be assessed for functional iron deficiency when erythropoietin is used to correct anaemia
IDA refractory to oral iron treatment is a new entity justifying a particular diagnostic work-up