Chapter 10 Iron Deficiency Anemia and Anemia of Chronic Inflammation

Iron Deficiency Anemia and Anemia of Chronic Inflammation Scope of the problem A common false assumption is that iron deficiency anemia (IDA) due to inadequate nutrition is confined to developing or underdeveloped countries. It is not. Worldwide, more than 40% of children have an IDA that is frequently associated with infections.

Iron Deficiency Anemia Early diagnosis of iron deficiency is essential in nonanemic infants and toddlers (under 2 years of age). Early diagnosis of iron deficiency is equally important in pregnant women to reduce maternal–fetal morbidity.

Factors in Iron Deficiency Anemia Figure 10.1 Factors in iron deficiency.

Iron Deficiency Anemia (cont.) Etiology 1. Decreased iron intake, for example, meat-poor diets 2. Faulty or incomplete iron absorption, for example, resection of small bowel, celiac disease 3. Increased iron utilization, for example, growth spurt 4. Iron loss (pathological), for example, GI bleeding, malignancy 5. Iron loss (physiological), for example, pregnancy, menstruation

Iron Deficiency Anemia (cont.) Epidemiology Although a high prevalence of iron deficiency existed in the 1960s in the US population, intensified efforts to combat iron deficiency in this country appear to have successfully reduced anemia in some vulnerable age subgroups, such as infants.

Iron Deficiency Anemia (cont.) In the United States, iron deficiency continues to be common in Toddlers Adolescent girls Women of childbearing age

Iron Deficiency Anemia (cont.) Physiology Humans have 35 to 50 mg of iron per kilogram of body weight. The average adult has 3.5 to 5.0 g of total iron.

Iron Deficiency Anemia (cont.) Physiology Normal iron loss is very small, amounting to less than 1 mg/day. Iron is lost from the body through exfoliation of intestinal epithelial and skin cells, the bile, and through urinary excretion. To compensate for this loss, the adult male has a replacement iron need of 1 mg/day.

Iron Deficiency Anemia (cont.) Physiology Operational iron consists of iron used for oxygen binding and biochemical reactions. In humans, most operational iron is found in the heme portion of hemoglobin or myoglobin. Most operational iron is incorporated into the hemoglobin molecules of erythrocytes and is recycled. In normal adults, hemoglobin contains two thirds of the iron present in the body.

Iron Deficiency Anemia (cont.) Figure 10.2 Iron physiology.

Iron Deficiency Anemia (cont.) Iron needs in infants and children In the normal infant at term, iron stores are adequate to maintain iron sufficiency for approximately 4 months of postnatal growth. In premature infants, total body iron is lower than in the full-term newborn. They have a faster rate of postnatal growth than infants born at term, so unless the diet is supplemented with iron, they become iron- depleted more rapidly than full-term infants. Iron deficiency can develop by 2 to 3 months of age in premature infants.

Iron Deficiency Anemia (cont.) Breast milk and cow’s milk both contain about 0.5 to 1.0 mg of iron per liter, but its bioavailability differs significantly. The absorption of iron from breast milk is uniquely high, about 50% on average, and tends to compensate for its low concentration. By contrast, only about 10% of iron in whole cow’s milk is absorbed. About 4% of iron is absorbed from iron- fortified cow’s milk formulas that contain 12 mg of iron per liter. Reasons for high bioavailability of iron in breast milk are unknown.

Iron Deficiency Anemia (cont.) Dietary iron There are two broad types of dietary iron: Approximately 90% of iron from food is in the form of iron salts and is referred to as nonheme iron. The other 10% of dietary iron is in the form of heme iron, which is derived primarily from the hemoglobin and myoglobin of meat.

Iron Deficiency Anemia (cont.) Sequential phases of iron deficiency: Stage 1 (Prelatent) Decrease in storage iron Stage 2 (Latent) Decrease in iron for erythropoiesis Stage 3 (Anemia) Decrease in circulating red blood cell parameters & Decrease in oxygen delivery to peripheral tissues

Iron Deficiency Anemia (cont.) Clinical signs and symptoms The history and physical presentation are the typical initial observations in the diagnostic workup of a patient with symptoms of paleness, fatigue, and/or weakness.

Iron Deficiency Anemia (cont.) Clinical signs and symptoms Iron deficiency anemia in children is associated with psychomotor and mental impairment in the first 2 years of life. Currently, more than one third of children in the United States demonstrate evidence of iron insufficiency, 7% have iron deficiency without anemia, and 10% have iron deficiency anemia.

Iron Deficiency Anemia (cont.) Laboratory characteristicshematology studies Complete blood count including observation of the peripheral blood smear and a platelet count Platelet count and white blood cell count should be noted.

Iron Deficiency Anemia (cont.) Laboratory characteristicshematology studies Essential red blood cell parameters: Hemoglobin Microhematocrit Red blood cell count Calculation of the red blood cell indices (MCV=mean corpuscular volume, MCH=mean corpuscular hemoglobin, and MCHC=mean corpuscular hemoglobin concentration)

Iron Deficiency Anemia (cont.) The MCV can separate macrocytic, normocytic, and microcytic red blood cells. Approximately one third of patients with iron deficiency will present with normal red blood cell morphology because they are in an early phase of iron depletion.

Iron Deficiency Anemia (cont.) Another evaluation of mature erythrocyte indices as a new marker of iron status is the percentage of hypochromic red blood cells (% HYPO). This marker has been demonstrated to be the most sensitive and specific parameter of functional iron deficiency.

Iron Deficiency Anemia (cont.) A reticulocyte count is additionally helpful. A reticulocyte count equal to or greater than 2.5% demonstrates increased erythropoiesis. In the presence of a reticulocyte count of less than 2.5%, the red blood cell indices can form the algorithmic basis for separating anemias into categories. Reticulocyte hemoglobin content (CHr) is an effective early indicator of iron deficiency. Early alert is particularly important in infants and toddlers, who can suffer cognitive and psychomotor developmental problems as a result of inadequate iron in the synthesis of hemoglobin.

Iron Deficiency Anemia (cont.) Figure 10.3 Iron deficiency maturation drawing. (Reprinted with permission from Anderson SC, Poulsen KBV. Anderson's Atlas of Hematology, Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, Copyright 2003.)

Iron Deficiency Anemia (cont.) Figure 10.4 The blood in iron deficiency anemia. A: Normal blood smear. B: Blood smear in iron deficiency anemia. The red cells are small (microcytic) and pale (hypochromic). (Reprinted with permission from McConnell TH. The Nature Of Disease: Pathology for the Health Professions. Philadelphia, PA: Lippincott Williams & Wilkins, 2007.)

Iron Deficiency Anemia (cont.) Figure 10.5 A blood smear showing normal erythrocytes (A) compared with a blood smear revealing microcytic, hypochromic erythrocytes in a patient with iron deficiency anemia (B). (Reprinted with permission from Willis MC. Medical Terminology: A Programmed Learning Approach to the Language of Health Care. Baltimore, MD: Lippincott Williams & Wilkins, 2002.)

Iron Deficiency Anemia (cont.)

Iron Deficiency Anemia (cont.) Clinical chemistry studies Serum iron Transferrin saturation Serum ferritin Soluble transferrin receptor (sTfR)

Iron Deficiency Anemia (cont.)

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) Etiology Anemia of chronic diseases or disorder (ACD) or anemia of inflammation is another common form of anemia. Anemia results in illnesses as diverse as inflammation, infection, malignancy, or various systemic diseases. Approximately half of AOI/ACD cases are caused by subacute or chronic infections.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Microbial agents associated with anemia of inflammation Bacterial, for example, M. tuberculosis Fungal, for example, C. neoformans Viral, for example, HIV, Cytomegalovirus

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Other cases may be caused by the following: Neoplasms Rheumatoid arthritis Rheumatic fever Systemic lupus erythematosus (SLE) Uremia Chronic liver disease

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Pathophysiology AOI/ACD is a hypoproliferative defect not related to any nutritional deficiency. The principal pathogenesis of ACD is believed to be related to hepcidin, a small plasma protein, that is a key molecule in controlling iron absorption and recycling.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.)

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Characteristics of AOI associated with malignancy can be as follows: Decreased erythrocyte production because of direct bone marrow infiltration by malignant tumor cells or by primary marrow cell malignancies Production and release of TNF-α and IL-1 by macrophages Increased erythrocyte destruction present in immune or microangiopathic hemolytic anemia Acute and chronic blood loss Toxic effects of invasive therapy (e.g., chemotherapy or radiation therapy) Indirect multiple causes such as anemia associated with malignant disease, anemia associated with major organ failure, and various hemolytic anemias

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) The systemic diseases that produce AOI are accompanied by the release of acute-phase reactants in the blood. Elevated C-reactive protein (CRP) Fibrinogen Haptoglobin Ceruloplasmin

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) This response becomes unified in a common pathway of metabolic events initiated by interleukin-1 (IL-1-) from activated macrophages. IL-1- then initiates a cascade of events mediated by the cytokines released from macrophages, lymphocytes, and other numerous cells within the body. IL-1- is specifically responsible for production of fever, neutrophilia, leukocytosis, acute-phase protein synthesis, stimulation of production of lymphokines, and the release of lactoferrin from granulocytes.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Laboratory characteristics Laboratory assays that suggest inflammation or infection include the following: Elevated platelet counts Elevated total leukocyte counts Evidence of acute-phase reactants. C-reactive protein (CRP), an acute-phase protein, is frequently a surrogate marker that may or may not correlate with hepcidin levels.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Hematology studies This form of anemia is usually a mild hypoprolific anemia hematocrit usually fixed in the 28% to 32% range, in some cases (e.g., uremia), the hemoglobin may be as low as 5 g/dL.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) The peripheral blood smears usually show normochromic and normocytic erythrocytes, but one fourth to one third of patients display hypochromic and microcytic erythrocytes.

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Figure 10.6 Anemia of chronic diseases. (Reprinted with permission from Armitage JO. Atlas of Clinical Hematology, Philadelphia, PA: Lippincott Williams & Wilkins, 2004.)

Anemia of Inflammation (AOI) or Anemia of Chronic Disorders (ACD) (cont.) Clinical chemistry studies Serum iron Transferrin (iron-binding capacity) Total iron-binding capacity Transferrin saturation levels Serum ferritin Soluble transferrin receptor (sTfR)

Iron Deficiency Anemia and Anemia of Inflammation or Chronic Disorders

Iron Deficiency Anemia and Anemia of Inflammation or Chronic Disorders (cont.) Treatment of the underlying cause of anemia is the most direct approach.