Iron Deficiency: Clinical Sequelae and Diagnosis

Iron DeficiencyDefinitions
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.

Iron DeficiencyPrevalence
Worlds 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.

Main Causes of Anaemia

Haemolysis 17.5% Others 9% 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.

Iron DeficiencyAetiology
Increased demand for iron and/or haematopoiesis Iron loss Decreased iron intake or absorption

Adamson JW. In: Kasper DL, ed. Harrisons Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005.

Iron DeficiencyIncreased 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. Harrisons Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. 2. Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005. 3. CDC. MMWR. 2002;51:899.

Iron DeficiencyIron 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. Harrisons Principles Of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005: Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.

Iron DeficiencyDecreased Iron Intake or Absorption

Vegetarians or malnutrition (low-cost diet)1 Malabsorption syndromes
Sprue, UHC, and Crohns disease2

After gastric and intestinal surgery3 Intestinal parasitosis (ankylostomiasis)3 Helicobacter pylori infection2 Autoimmune atrophic gastritis2

1. CDC. MMWR. 1998;47(RR-3);1-36. 2. Annabale B, et al. Am J Med. 2001;111:439. 3. Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.

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. 2005. Trost LB, et al. J Am Acad Dermatol. 2006;54:824.

Iron Deficiency
Clinical Manifestations (II) Skin and conjuctival pallor Koilonychia Angular cheilosis Burning tongue Glossitis Hair loss (alopecia areata)

Top figure accessed from: www.nature.com/bdj/v194/n12/images/4810265f1, with permission from Nature Publishing Group. Bottom figure accessed from: www.dentistry.leeds.ac.uk/biochem/lectures/nutrition.org. Modern Nutrition in Health & Disease. 9th ed. Editors: Shils, Olsen, Shike & Ross. Williams & Williams, pub.

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.

Diagnosis of Iron Depletion in the BodyHaematology

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.

Diagnosis of Iron Depletion in the BodyHaematology

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. 2005.

Diagnosis of Iron Depletion in the BodyClinical 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.

Serum Levels That Differentiate ACD from IDA

Variable Iron Transferrin Transferrin saturation Ferritin ACD To normal Normal to IDA Both Conditions To normal

sTfR
sTfR/log ferritin Cytokine levels

Normal
Low (<1)

High (>2) Normal

Normal to
High (>2)

Iron DeficiencyDiagnosis
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.

Iron DeficiencyDiagnosis
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.

Iron DeficiencyDiagnosis
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
1. S Killip, et al. Am Fam Physician. 2007;75:671. 2. Urbain D, et al. Endoscopy. 2006;38:408.

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.

Iron-Deficient Erythropoiesis (Functional Iron Deficiency)Diagnosis Normal or increased ferritin Laboratory signs of iron-deficient erythropoiesis
Serum iron <60 g/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.

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.

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.

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.

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.

Algorithm for Investigation of Microcytic Anaemia

RBC count RBC count normal or CRP normal CRP Ferritin normal

Ferritin < 50

Ferritin 50-150

Ferritin >150

sTfR/logFerr 1.55 Ferritin <20 Ferritin normal BM examination Ring sideroblasts? Familial sideroblastic anaemia

sTfR/logFerr <1.55 Anaemia of chronic disease

Hb analysis

HbA2 or HbF Consider H. pylori infection -thalassaemia

Normal pattern Family studies, chromosome 16 deletion search -thalassaemia

Iron def anaemia

Aetiology? No response to ttt

Consider Hb analysis

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.

IDAConclusions
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