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

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.

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.

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.

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.

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. 2005. CDC. MMWR. 2002;51:899.

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. 2005.

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. 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 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.

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. 2005.

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.

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

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.

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.

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.

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 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.

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 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.

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