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Editors: Torre, Dario M.; Lamb, Geoffrey C.; Van Ruiswyk, Jerome J.; Schapira, Ralph M. Title: Kochar's Clinical Medicine for Students, 5th Edition Copyright 2009 Lippincott Williams & Wilkins
> Table of Contents > Part I - Key Manifestations and Presentations of Diseases > Chapter 5 - Anemia

Chapter 5 Anemia
Gwen O'Keefe Dario Torre Anemia is a frequent laboratory finding in medical patients, often incidentally found during evaluation for other conditions. It is defined as hemoglobulin <13.5 g/dL or hematocrit <41.0% in men and <12.0 g/dL or <36.0%, respectively, in women. Approximately 5% of the population will have values out of the range of normal without true abnormalities. Women and black men have values that are typically 1 to 2 g/dL lower than in white men. Only occasionally do patients present with symptoms related to low blood counts. Signs and symptoms of acute blood loss will develop with rapid losses of 10% to 15% of total blood volume, but in chronic blood loss, patients may not present with symptoms until the hemoglobin is 50% of normal because of mechanisms that allow compensation over time. Such mechanisms involve increased cardiac output and shift of the oxygen-hemoglobin dissociation curve to the right, leading to increased oxygen (O2) delivery and shunting of O 2 from organs rich in blood supply (kidneys, gastrointestinal tract, skin).

Differential Diagnosis
The differential diagnosis of anemia is quite broad and extensive, but is initially narrowed when the red cell indices are evaluated. One preferred way to categorize anemias is by the mean corpuscular volume (MCV), the key measure of the size of the cells (Table 5.1). All causes of anemia can be found in one of three categories: microcytic, normocytic, and macrocytic. An additional classification of anemia, based on a defect in formation, survival, and maturation of red cells, includes three major classes: decreased production (hypoproliferative bone marrow), increased peripheral destruction (hemolysis or blood loss), and a defect in red cell maturation (ineffective erythropoiesis). A complete history and physical examination can often provide clues to the cause of anemia. The patient's background and ethnic origin can provide clues to the presence of inherited hemoglobinopathies (sickle cell anemia, thalassemia major), toxic exposures (due to medications such as metotrexate or other chemotherapeutic agents), and nutritional deficits (such as poor intake of iron, B12, or folate). History of travel in areas where malaria is endemic may be a clue to the diagnosis of hemolytic anemia caused by infection. The occurrence of episodes of anemia, precipitated by drugs such as sulfanomides or antimalarials, suggests glucose-6-phosphate dehydrogenase deficiency. The presence of hereditary anemia associated with pain crises (acute chest syndrome, bone and joint pain due to vaso-occlusive episodes), splenomegaly early in the disease, and inability to concentrate urine (hyposthenuria) suggests sickle cell anemia. Blood loss is the most common cause of anemia, and one of the most common causes of iron deficiency anemia. Blood loss may be caused by gastrointestinal bleeding (manifested by hematemesis and or melena), trauma, genitourinary (presenting with menometrorrhagia or hematuria), postsurgical blood loss, and (less commonly) bleeding due ruptured spleen or retroperitoneal bleed. Symptoms such as onset of new fatigue or dyspnea, or noticeable bleeding, can help determine P.26

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the timing of onset of anemia. Obtaining old values for comparison can help to determine if a slightly low value is the norm for that patient or date the onset of the anemia.

Table 5.1 Anemia: classification by microcorpuscular volume

Microcytic (MCV <80 fL) Normocytic (MCV 80 to 100 fL) Macrocytic (MCV >100 fL)

Iron deficiency

Anemia of chronic disease

B12, folate deficiency

Thalassemias

Anemia of renal disease

Myelodysplastic syndrome

Anemia of chronic disease

Hemolytic anemias

hypothyroidism liver disease

Sideroblastic anemias Medications Toxins Lead poisoning

Iron deficiency (early stage)

Toxins, medications Hydroxiurea Azidovidine Alcohol Methotrexate

On physical examination start with examination of vital signs; hypotension and tachycardia may be signs of acute blood loss or very severe levels of anemia. Orthostatic hypotension will be present when the anemia overcomes the body's compensatory mechanisms in chronic states or severe blood loss in acute bleeding. Most patients with chronic anemia will have normal vital signs. Pale mucous membranes, particularly in the palmar creases, suggest hemoglobin <10 mg/dL. The presence of purpura may indicate anemia associated with thrombotic thrombocytopenic purpura or hemolytic uremic syndrome (Chapter 97). Splenomegaly is found in immune hemolytic anemia, hereditary spherocytosis, thalassemia major, leukemia, lymphoma, and myelofibrosis. Icterus may indicate hemolysis. A systolic flow murmur due to a hyperdynamic left ventricle may be best heard at the second left intercostal space. Koilonychia (spooning of nails), glossitis, and pica (craving for ice) can indicate iron deficiency. History of dementia, ataxia, and neurologic abnormalities such as paresthesias, decreased vibration, and proprioception may reflect vitamin B12 deficiency. Guaiac-positive stool suggests a gastrointestinal source of bleeding.

Microcytic Anemias
In microcytosis, the ferritin level should be checked. A ferritin level <10 ng/ml is very specific for iron deficiency states, the most common cause of microcytic anemia. A low ferritin level is diagnostic and can be reinforced by the aforementioned peripheral smear findings. The two other most common causes are thalassemias (Chapter 94), either alpha or beta. These are diagnosed by hemoglobin electrophoresis and anemia of chronic disease (although this is usually a normocytic anemia). Rarely, sideroblastic anemia is found.

Normocytic Anemias
Anemia of chronic disease (Chapter 92) can be associated with low iron and transferrin saturations, but is distinguished by normal or high ferritin levels from iron deficiency. It is thought to be due to a cytokine-mediated process that interferes with erythropoietin production and leads to altered iron homeostasis (Chapter 90). Anemia of chronic disease is frequently found in patients with diabetes, chronic infections, inflammatory diseases, or

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malignancies. The peripheral smear is usually normal. Anemia of renal disease is manifested by a normal peripheral smear and a normal or low erythropoietin level in the presence of anemia. Even mild to moderate renal insufficiency may be associated with anemia. P.27

Table 5.2 Classification of hemolytic anemias

Intracorpuscular defect

Disorders of the red cell membrane

Hereditary spherocytosis

Disorders resulting from enzyme abnormalities

Glucose-6-phosphate dehydrogenase deficiency Pyruvate kinase deficiency

Hemoglobinopathies

Sickle cell disease Thalassemias Hemoglobin C disease

Acquired

Paroxysmal nocturnal hemoglobinuria

Extracorpuscular defect (all are acquired)

Immune

Autoimmune hemolytic anemia

Warm-antibody type Cold-antibody type Mixed Drug mediated

Nonimmune

Resulting from chemical and physical damage Resulting from infections with microorganisms

Malaria Bartonella Babesia Clostridium perfringens

Drug induced

Hemolytic anemias (Table 5.2) are a group of diseases characterized by decreased erythrocyte survival time followed by anemia unless compensated by increased bone marrow production. Several general clues suggest hemolytic anemia: unexplained drop in the hemoglobin, sustained reticulocytosis, and elevated serum lactate dehydrogenase (LDH). Decreased haptoglobin levels are common and free serum hemoglobin can be present with intravascular red cell destruction (Table 5.3). Hemolytic anemias may show peripheral smear evidence of hemolysis: schistocytes and

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helmet cells in microangiopathic hemolytic anemia, spherocytes in hereditary spherocytosis (Chapter 95) or in autoimmune hemolytic anemia.

Primary Bone Marrow Disorders

There are several types of primary disorders that affect the bone marrow. Often the complete blood count will demonstrate abnormalities in all cell lines (white blood cells and platelets). Infiltrative processes may show immature myeloid cells and nucleated red cells in the peripheral smear; these disorders include myelofibrosis or metastatic cancer involving the bone marrow. Other classifications of primary disorders include primary bone marrow failureexhibited as pure red cell aplasia or aplastic anemiaand may include abnormalities of platelets and white blood cells as well. Myelodysplastic syndrome (Chapter 89) may exhibit an increased red cell distribution width (RDW) and various other cellular abnormalities. A bone marrow biopsy is necessary to make the final diagnosis of a primary bone marrow disorder.

Macrocytic Anemias
The first step in macrocytic anemia is to eliminate drugs and other toxic exposures as causes. The list if drugs that may cause macrocytosis is long, but the most common offenders include azidovidine, P.28 hydroxyurea, methotrexate, trimethoprim (in Bactrim), and alcohol. The second most common cause is a nutritional deficiency, namely vitamin B12 and/or folate deficiency (Chapter 91). The serum folate level is easily raised by recent dietary intake of folate, so the homocysteine level can be used to document folate deficiency. The homocysteine level is raised in low folate states as the metabolic conversion to methionine requires folate. Similarly, vitamin B12 levels are usually low in deficient states. If falsely low levels are suspected, methylmalonic acid levels can be obtained; a normal level makes B12 deficiency unlikely.

Table 5.3 Laboratory findings in hemolytic anemia

Feature Finding Comment

Degree of anemia

Variable

Hemoglobulin ranges from 11 to 12 g/dL in chronic compensated hemolytic anemia to <2 g/dL in severe cases

Type of anemia

Normocytic normochromic

Can be macrocytic due to reticulocytosis

Morphology

Variable

Spherocytosis in hereditary spherocytosis and autoimmune hemolytic anemia Sickle cells in sickle cell disease Target cells in thalassemias Schistocytes in microangiopathy

Reticulocytosis

Frequent

Sensitive but not specific for hemolysis

Normoblasts

Variable

Frequent in brisk hemolysis

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Serum lactate dehydrogenase

Increased

Nonspecific for hemolytic anemia

Serum hemoglobin

Variable

Increased in intravascular hemolysis

Serum haptoglobin

Low

Specific for hemolysis if no severe decompensated liver disease (haptoglobin is synthesized in the liver)

Urinary hemoglobin

Variable

Present and confirms intravascular hemolysis

Splenomegaly

Frequent

Present if red blood cells are destroyed primarily by phagocytosis in the splenic reticuloendothelial system

Evaluation
Initial laboratory evaluation should include (Fig. 5.1): 1. A complete blood count containing hemoglobin, hematocrit, red cell indices (MCV, MCHC, and MCH) white blood cell count and differential, and platelet count 2. A reticulocyte count 3. A careful examination of the peripheral smear 4. Iron studies The reticulocyte count is the percentage of total red cells that are reticulocytes (usually 0.5% to 1%). A more useful and accurate estimate of the reticulocytes response produced by the bone marrow is P.29 P.30 provided by the reticulocyte production index (RPI).To obtain the RPI, two steps are necessary. First, the reticulocyte count needs to be adjusted based on the degree of anemia to provide a reticulocyte count corrected for dilution. Second, the corrected reticulocyte count needs to be further adjusted based on the presence of reticulocytes using a predetermined correction factor. The RPI, which is normally about 1.0, gives an estimate of the reticulocytes produced by the bone marrow relative to normal. A low RPI indicates an underproduction state; a high RPI is seen in both hemolysis and in appropriate bone marrow response to anemia.

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Figure 5.1 Approach to diagnosis of anemia.

Table 5.4 Peripheral blood smear findings in selected hematologic disorders

Disorder Findings

Anemia of chronic disease

Unremarkable

Iron deficiency

Anisocytosis Poikilocytosis

Hemolysis

Schistocytes Spherocytes Bite cells

Primary bone marrow disorder

Rouleau formationmultiple myeloma Dimorphic red blood cells, oval macrocytes (myelodysplastic syndrome)

Thalassemia

Target cells

Liver disease, ethanol

Target cells

The peripheral smear can provide useful clues to narrow the differential diagnosis. Abnormal cell shapes can be characteristic. In iron deficiency, findings of anisocytosis (variation in size) and poikilocytosis (variations in shape) are common. Other cell lines can offer useful clues as well, such as hypersegmented polymorphonuclear leukocytes seen in B12 or folate deficiency (Table 5.4). Iron studies should include serum iron, total iron-binding capacity (TIBC), ferritin, and percent transferrin saturation = (serum iron 100)/TIBC. The RDW is a measure of the variability of the sizes of circulating red cells. Normal cells are fairly uniform in size, but in many anemias the RDW will be higher than normal as the bone marrow produces cells of varying sizes, such as in iron deficiency anemia. First to be evaluated should always be reversible causes of anemia, particularly deficiency states. A bone marrow examination is an invasive test and is likely not needed for the diagnosis of common forms of anemia (iron deficiency, anemia of chronic disease). However, when diseases such as aplastic anemia, bone marrow infiltration by a malignancy, myelofibrosis, chronic myelogenous leukemia, or myelodysplasia are suspected, a bone marrow examination may be warranted.

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