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Diagnosis of case Iron Deficiency Anemia Iron deficiency anemia (IDA) has variably decreased hemoglobin caused by insufficient iron. In advanced cases the anemia is severe and markedly microcytic and hypochromic, but early on, hemoglobin and mean corpuscular volume (MCV) are only minimally decreased.

CLINICAL FEATURES A. Secondary to the Anemia Itself Because the anemia is insidious in onset, compensatory mechanisms usually prevent symptoms' until the hemoglobin falls to the range of 8 g/dL. Coexisting disease of the cardiopulmonary system may act jointly with less advanced anemia to produce symptoms typicoafl more severe anemia. When anemia is sufficiently advanced to be solely responsible for symptoms, the physical examination usually reveals pallor, and, occasionally, koilonychia, angular stomatitis, and glossitis, as well as splenomegaly.

B. Secondary to the Underlying Condition Iron deficiency anemia results from three abnormalities affecting iron: loss from abnormal bleeding, deficient diet, and malabsorption. 1. Blood Loss Blood loss is the most common causeo f IDA in adults livingin developed countries. Gastrointestinal blood loss is the most frequent cause in males and postmenopausal females. Heavy menstrual bleeding is a frequent cause of IDA in women of child-bearing age. Pregnancy, which requires approximately 1000 mg of iron, is also a common cause. Intestinal parasites, such as hookworms and schistosomes, often cause IDA in underdeveloped regions, but are rarely found in developed countries.

2. Deficient Diet In a broad sense, iron deficiency develops when intake does not keep pace with utilization and loss of iron. Worldwide, the most common cause is a low content of dietary iron, especially in readily absorbable forms such as in meat. In developed countries, dietary inadequacy is uncommon except when it is relative to increased need, as in the premature infant. Term infants may also develop iron deficiency, especially when bottle fed. Female adolescents, with increased need for iron because of both rapid growth and onset of menses, have a relatively high incidence of iron deficiency. 3. Malabsorbtion Malabsorption is an uncommon cause of IDA. Some patients with the short bowel syndrome, nontropical sprue, or a history of gastrectomy cannot absorb iron normally. Increased blood loss contributes to their anemia, and the majority have symptom a history of gastrointestinal disease.

2. Why diagnosis of case about iron deficiency anemia When the anemia is severe, the routine blood count providest he information needed for diagnosis, and additional studies are needed only to establish the etiology of the deficiency. The medical history and physical findings relative to the gastrointestinal tract and, in women, to the genital tract will most often reveal the reason for anemia. Endoscopic and/or radiographic evaluation of the gastrointestinal tract is frequently required to reveal the source of blood loss. When the anemia is mild to moderate, more extensive evaluation is necessary to establish that iron deficiency is its cause. Serum ferritin is the key test for making this determination, but the acute-phase reaction may interfere with its interpretation, necessitating a bone marrow examination or a trial of iron therapy to establish the presence of iron deficiency.

LABORATORY FINDINGS Laboratory tests are essential for detecting or confirming anemia and for determining that it is caused by iron deficiency, but they are of limited value in ascertaining the deficiencys cause. The latter is determined by the history and physical examination, supplemented by endoscopic and radiographic evaluation of the gastrointestinal tract. Followinigs a discussion of laboratory tests commonly used for evaluating IDA. A. Hemoglobin Level In severe, chronic iron deficiency, the hemoglobin may be as low as 3-4 gldL. The degree of anemia is related directly to the severity and duration of deficiency, and the spectrum of hemoglobin values ranges downward from normal. Hemoglobin is the key test for detecting the presence of anemia and for following its response to treatment. B. Red Cell Indices, Including RDW The MCV is of great importance in determining that iron deficiency is causing anemia. As with hemoglobin, the MCV varies downward from normal, depending on the severity of anemia. When hemoglobin is in the 3 to 4-gldL range, the MCV will be 50-60 fl. A discordance between the two values, for example, a hemoglobin of 6 g/dL associated with an MCV that is only mildly decreased, is indicative of IDA complicated by another process, such as significant acute blood loss, or of an entirely different type of anemia. The MCH and MCHC are less important, especially the latter. Most laboratories use automated cell counters that do not detect decreased MCHC until there is marked hypochromia and microcytosis. The RDW appears not to be a valuable discriminator between IDA and other causes of microcytic anemia. A normal value tends to exclude IDA, but an elevated value lacks specificity. C. Reticulocyte Count The reticulocyte counti s not an important test in the evaluatiofn IDA. It is usually essentially normal, as it is in the disorders from which iron deficiency must be differentiated.

D. White Cell and Platelet Counts There are no characteristic or diagnostically important changes in white cells or Elevated white cell and platelet counts occasionally occur, and, rarely, the latter rnillion. There may also be thrombocytopenia, which in rare cases may be severe. E. Red Cell Morphology Microcytosis, anisocytosis, poikilocytosis, and hypochromia are readily seen in the peripheral blood smear of individuals with moderate to marked IDA. However, because of inconsistent and inaccurate interpretationof the blood smear, as well as the superior sensitivity and accuracy of automated determination of red cell indices, morphologic findings do not contribute significantly to the accurate diagnosis of IDA. F. Serum Ferritin In a recent meta-analysis, Guyatt and associates found serum ferritin to be much more powerful than all other blood tests for diagnosing iron deficiency. In the absence of disorders that produce an acute-phase reaction, there is excellent correlation between the serum ferritin level and iron stores. Unfortunately, conditions such as malignancy, infection, and noninfectious inflammatory disorders cause serum ferritin to act as an acute-phase reactant producing false elevations that make interpretation difficult. With very rare exceptions, a subnormal ferritin level indicates absent iron stores, eveni f the acute phase reactioni s present. When the latter is occurring, values in iron deficiency may range upward to 100 ng/nL, with decreasing likelihood of iron deficiency as the value approaches 100. G. Serum Iron, Transferrin, and Transferrin Saturation Before the serum ferritin test was available, these were the preferred blood tests for assessing iron stores. However, the acute-phase reaction decreases serum iron to less than normal and also frequently decreases transferrin. These tests have less diagnostic power than the serum ferritin and should no longebr e used to test for iron deficiency, especially in sick, hospitalized patients.

H. Serum Transferrin Receptor Elevated concentrations of serum transferrin receptor are found in both iron deficiency and erythroid hyperplasia. There is indication that this test, which is currently used only in research settings, may help evaluate iron stores when the acute-phase reaction is present. I. Red Cell Protoporphyrin Iron deficiency,l ike lead poisoning, increases redce ll protoporphyrin. The availability of accurate and easily operated hematoflourometers has increasedt he use of this test in screening for these two conditions. However, redc ell protoporphyrin levels lack the sensitivity and specificity of serum ferritin for iron deficiency. J. Fecal Occult BIood Because gastrointestinal bleeding frequently leads to anemia, testing the stool for blood has a time-honored place in the investigation of IDA. However, many foods, such as meat, broccoli, and bananas, as well as liquid stool samples and oral iron therapy, may cause false positive reactions. Administration of ascorbic acid, as well as degradation of hemoglobin when there is upper gastrointestinal bleeding, may cause false negative reactions. In addition, many lesions probably bleed only intermittently, producing negative reactions on stools from nonbleeding intervals. For these reasons, the sensitivity and specificity of tests for occult blood are relatively low. Negative tests should not be a deterrent from endoscopic or radiographic evaluation of the gastrointestinal tract in patients with unexplained microcytic anemoiar other indications for such examination. K. Bone Marrow Examination Erythrocytic hyperplasia and deficient hemoglobinization of red cell precursors are usually found in the marrow, particularly in more advanced cases. However, these changes have only modest diagnostic significance, and the pivotal finding is the absence of marrow iron stores.

This is the gold standard for determining iron deficiency. Marrow examination is not required for most patients but should be carried out when the diagnosis is in doubt, especially when the serum ferritin has an equivocal value, or when a trial of iron therapy fails. Normal infants and children have little or no stainable iron stores, and evaluation of marrow iron does not distinguish depleted from normal stores.

3. Differential Diagnosis DIFFERENTIAL DIAGNOSIS A. Anemia of Chronic Disease IDA and anemia of chronic disease (ACD) are both very common, and they frequently coexist. Also, microcytosis is frequent in ACD. Therefore, it is often necessary to determine whether a patient has IDA, ACD, or both. Differentiation hinges on the serum ferritin Ilenv ae l .p atient who may have both IDA and ACD, a value below the usually quoted normal, 10-12 ng/nL, confirms iron deficiency. If, as is more likely, the level is in the normal range, the closer it is to the lower limit of normal, the more likely is iron deficiency. Some authors state that a normal RDW argues against iron deficiency, because the test has a high sensitivity for IDA. However, the preponderance of evidence suggests that the test lacks sufficient sensitivity to supplement the diagnostic power of serum ferritin. In some cases a clear-cut distinctioncan not be madoen the basis of clinical and laboratory findings, and a trioafl iron therapy or a bone marrow examination may be required. B. Thalassemia Heterozygous alpha and beta thalassemia are common microcytic anemias. The combination of low normal to slightly decreased hemoglobin, high normal to slightly increased red cell count, moderately decreased MCV, and target cells is characteristic of thalassemia minor. In iron deficiency when the hemoglobin is comparable to that typical of thalassemia minor, the MCV is usually less abnormal. Serum ferritin and hemoglobin A2 levels usually suffice to make the distinction.

C. Hemoglobinopathy Hemoglobin E, common in Southeast Asians, causes microcytosis thaits mild in heterozygotes and marked in homozygotes (17). Heterozygotes are usually not anemic and homozygotes only mildly so. Hemoglobin electrophoresis is diagnostic. D. Lead Poisoning In the past, lead poisoning was considered in the differential diagnosis of microcytic anemia, but it is now thought that both anemia and microcytsis are secondary to coexisting iron deficiency, which is common in underprivileged children, a group in which plumbism is often found.

4. Pathophysiology of iron deficiency anemia PATHOPHYSIOLOGY A. Iron Metabolism The major portion of body iron is in hemoglobin, myoglobin, and various enzymes. Nearly of the remainder is in storage in the reticuloendotheli~ system, primarily in the bone marrow, liver, and spleen. 1. Absorption Normally, dietary absorptionis limited to the amounto f iron necessary to produce hemoglobin, myoglobin, and enzymes, to compensate for losses, and to build stores. When losses increase or there are other causes of increased need, absorption may not keep pace because it can increase only modestly. 2. Loss Adults daily lose approximately 1 mg of iron, mainly in desquamated epidermal, urinary, and gastrointestinal cells. Menstrual bleeding adds, on average, slightly more than 1 mg to the daily loss, as does lactation.

3. t r a n s p ort Transferrin is the primary vehicle for transporting iron entering the plasma. Essentially all proliferating cells have on their surfaces transferrin receptors whose affinity increases with the latters iron content and whose synthesis and release into the blood increases with decreasing availability of iron. Erythroid precursors and hepatic and placental cells have more receptors than other cells. 4. Storage Ferritin is the primary storage protein for iron, and its production and cellular content, as well as the amount circulating in plasma, are increased by increasing amounts of cellular iron. Ferritin, present in essentiallya ll cells, readily gives up iron and serves as the storage compartment for cellular utilization. Hemosiderin, a more stable storage form, holds most of the iron in the reticuloendothelial systems macrophages.

B. Progression of Iron Deficiency When absorption does not keep pace with utilization and loss, iron stores are used. As stores become depleted, the individual passes through three stages of iron deficiency. 1. Latent Stage Iron stores are depleted, and marrow contains no stainable iron. However, hemoglobin production has not yet decreased, and there is no anemia or microcytosis. Serum ferritin, reflecting body iron stores, is decreased. Serum transferrin receptors, serum iron, transferrin, transferrin saturation, and red cell protopophyrin are normal. 2. Early Stage As the imbalance between absorption and need continues, insufficient iron is available for hemoglobin synthesis, and the various markers of deficiency begin to be established. The hemoglobin decreases through the normal range into the subnormal. Red cells being produced are smaller and have decreased content of hemoglobin and increased zinc protoporphyrin.

However, early in this stage, because abnormal cells are mixed int he peripheral blood with a much larger number of normal cells, routine studies of red cell parameters continue to be normal. Therefore, especially if the patients baseline MCV is in the upper portion of the normal range, early IDA can be normocytic. Serufemrr itin, already below normal during latent deficiency, can undergo no further measurable decrease, and thuiss not helpful in determining the degree of deficiency. Serum transferrin receptors, however, become increased in the early stage of iron lack and progressively increase as the deficiency worsens. 3.Established Stage As the deficiency progresses, under the stimulation of increasing amounts of erythropoietin, erythroid precursors are more numerous in the marrow, and the lack of iron causes the more mature forms to have visibly less cytoplasm that has deficient hemoglobinization. Anemia worsens, and progressively smaller red cells with lesser amountosf hemoglobin become more numerous in the peripheral blood. As the duration and severity of deficiency increase, and as more of the previously produced normal cells become senescent and are removed, the RDW increases and red cell histogram widens. The MCV and MCH decrease and become progressively more abnormal, in proportion with the decrease in hemoglobin. Likewise, there is a proportionate increase in serum transferrin receptors.