Anemia

Abstract

The diagnosis and initial evaluation of anemia is an important aspect of the internist’s office practice. This chapter provides an algorithm-based approach to help guide the internist through the differential diagnoses and decision-making process.

Introduction

The diagnosis and initial evaluation of anemia is an important aspect of the internist’s office practice. This chapter provides an algorithm-based approach to help guide the internist through the differential diagnoses and decision-making process.

Key History and Physical Exam

Primary care physicians should focus their evaluation toward obtaining clues useful for accurate diagnosis of anemia and its etiology. Key questions include the following: Any evidence of blood loss? What is the duration of the anemia? Is this genetic or acquired? Is infection or malignancy likely? Are there associated features or comorbidities known to cause anemia (e.g., renal failure, rheumatoid arthritis, and inflammatory bowel disease)? Does the patient’s ethnicity influence the differential? A careful review of medications, including the use of aspirin and nonsteroidal anti-inflammatory drugs, needs to be performed.

Classic symptoms that must be addressed include bleeding, fatigue, fever, weight loss, night sweats, and signs of infection.

Physical examination can reveal tachycardia, hypotension in acute blood loss, conjunctival pallor, jaundice, strong peripheral pulses, systolic blood flow murmur, lymphadenopathy, hepatosplenomegaly, bone tenderness, petechiae, and ecchymoses.

Diagnosis and Evaluation

• CBC (complete blood count) initial variables to review: hemoglobin (Hgb), hematocrit (Hct), corpuscular volumes [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC)], red blood cell (RBC) count, red cell distribution width (RDW), platelet count, and white blood cell (WBC) count with differential.

• Reticulocyte count to calculate the reticulocyte index and determine the nature of the anemia: hypoproliferative or hyperproliferative.

• Iron storage/supply [serum iron, total iron-binding capacity (TIBC), serum ferritin].

• Abnormalities in direct and indirect bilirubin, lactate dehydrogenase (LDH), and haptoglobin will suggest a hemolytic process.

• Peripheral blood smear: detailed evaluation for evidence of variations in cell size (anisocytosis) and cell shape (poikilocytosis).

• In some patients more advanced testing, such as hemoglobin electrophoresis and bone marrow examination (smear and aspirate), is warranted (Fig. 17.1).

  Fig. 17.1

  

  Anemia algorithm

Hypoproliferative Anemias

The reticulocyte index is <2% in hypoproliferative anemia.

Microcytic Anemias

These are characterized by smaller RBCs (MCV < 70) due to decreased production of hemoglobin. Common causes are lack of globin production (thalassemia), restricted iron delivery to the heme group (inflammation), lack of iron delivery to the heme group (iron-deficiency anemia), and defects in the synthesis of the heme group (sideroblastic anemia) [1]. Iron studies will guide us toward the most likely etiology, as shown in the following Table 17.1.

Table 17.1 Iron studies in microcytic anemia

Iron-Deficiency Anemia

Iron deficiency is the most common cause of anemia and is estimated to be present in 1–2% of the adult population. Iron deficiency in the absence of anemia is present in up to 11% of the adult population [2]. Decreased marrow iron and depleted iron stores cause decreased heme synthesis, leading to microcytosis and anemia.

In addition to general anemia symptoms, specific iron deficiency manifestations can include pica and pagophagia, brittle integument, and restless leg syndrome.

Serum ferritin level is the most sensitive and specific test used for the identification of iron deficiency (level of <12 ng/mL). In those with combined inflammation and iron deficiency, ferritin may be falsely elevated because it is an acute-phase reactant. Soluble transferrin receptor is not affected by inflammatory states and is a useful test to determine the presence of iron deficiency. If erythroid precursor cells have cellular iron deficiency, they express increased transferrin receptors to attract the iron-carrying transferrin. Some of these transferrin receptors then spill out in the blood and are detected [3]. A transferrin saturation level of less than 16% indicates an iron supply that is insufficient to support normal erythropoiesis [3].

The most frequent causes of iron-deficiency anemia are:

• Chronic GI bleeding, often subclinical, due to gastric ulcerations, GI malignancies.

• Decreased iron absorption: malnutrition, vegan diet, celiac sprue, inflammatory bowel disease (Crohn’s), gastrectomy/bariatric surgery, increased gastric pH, or use of chronic gastric acid suppressants.

• States with increased iron demand, i.e., pregnancy, rare iron refractory genetic disorders.

Treatment

Replacing iron and correcting the underlying etiology are the cornerstones of therapy. After 1 week of treatment, reticulocytosis should begin. In 3 weeks, Hgb should be 2 g/dL higher. Iron supplementation should continue not only until Hgb level is normalized, but until iron stores are repleted, typically after 6 months of therapy. Repletion can be confirmed when serum ferritin normalizes.

Oral supplementation is preferred; however, IV iron preparations can be given to patients with high Fe requirements, inability to absorb Fe from GI tract, or intolerance to oral iron preparations.

Preferred oral iron replacement:

• Ferrous sulfate 325 mg orally: For best absorption and tolerability, take 30 min before meals. Can start with 1 tab/day and increase up to three times per day. If unable to take three times per day, 1–2 times per day may be sufficient as long as the Hgb is recovering.

• Adverse effects: bloating, change in bowel habits, black stools.

Refractoriness to treatment should raise the concern of compliance issues, poor absorption, and possibly incorrect diagnosis (e.g., thalassemia, anemia of chronic inflammation).

Normocytic Anemia

There is an overlapping of some anemias with normal MCV which might be either hypoproliferative or hyperproliferative, but could also present as normocytic, microcytic, or macrocytic. This category includes acute blood loss/hemorrhagic anemia, anemia of renal disease, hypothyroidism, early stages of iron deficiency, anemia of chronic inflammation, sickle cell anemia, pure red cell aplasia as seen in thymomas, chronic lymphocytic leukemia, and parvovirus infection.

Anemia of Chronic Inflammation (ACI)

Previously known as anemia of chronic disease, this is the second most common form of anemia after iron deficiency. Classically, it was thought to be caused only by inflammatory, infectious, or malignant processes; however, diabetes and severe trauma have also been proposed etiologies. Major causes include malignancy, HIV infection, rheumatologic disorders, inflammatory bowel disease (Crohn’s), heart failure, renal insufficiency, and chronic obstructive pulmonary disease.

The underlying process is multifactorial. It involves increased pro-hepcidin, an acute-phase reactant, causing decreased intestinal absorption of iron and trapping of iron in the macrophages resulting in decreased availability for heme synthesis. Also, there is an inability to increase erythropoiesis, relative decrease in erythropoietin (EPO) production, and RBC survival. These changes are mediated by inflammatory cytokines, TNF-alpha, IL-1, IL-6, INF-b, and INF-g.

Patients with anemia of chronic disease and concomitant iron-deficiency anemia more frequently have microcytes, and their anemia tends to be more severe. The ratio of the concentration of soluble transferrin receptors to the log of the ferritin level of less than 1 suggests anemia of chronic disease, whereas a ratio of more than 2 suggests absolute iron deficiency coexisting with anemia of chronic disease [3].

The primary treatment of ACI is correction of the underlying disorder. Blood transfusions are only indicated in the setting of severe symptomatic anemia Hgb < 6.5 mg/dL or acute bleeding. Transfusion affords some benefit in survival for patients with myocardial infarction.

Iron supplementation might be beneficial if ferritin or TIBC saturation is low or low normal.

EPO can be administered if EPO level is < 500 mU/mL and Hgb <10 g/dL for cancer or chemo-related ACI .

Macrocytic Anemia

Macrocytic anemia is defined by an MCV > 100, and can be categorized as megaloblastic or non-megaloblastic depending on the presence of hypersegmented neutrophils in addition to macrocytic RBCs in the peripheral smear [4].

Megaloblastic Anemia

Resulting from impaired DNA synthesis, megaloblastic anemia is usually caused by folate or vitamin B12 (cobalamin) deficiency, which in turn could be due to chemotherapeutic agents that impair absorption or block enzymes during DNA synthesis.

Vitamin B12 Deficiency

Always establish a cause of vitamin B12 deficiency. Major causes include pernicious anemia, atrophic gastritis, bacterial overgrowth, pancreatic insufficiency, ileal resection or Crohn’s disease involving the ileum, chronic proton pump inhibitor or histamine 2-blocker use, HIV, Helicobacter pylori, and Diphyllobothrium latum (fish tapeworm) infections.

Common signs and symptoms of B12 deficiency include general symptoms of anemia, beefy tongue, and neurologic symptoms due to degeneration of the lateral and dorsal columns of the spinal cord known as subacute combined degeneration (SCD). Symptoms of SCD include paresthesias from axonal degeneration, cerebellar ataxia, proprioceptive deficit, and dementia.

Laboratory findings include low serum B12 level (<200 very suggestive, 200–400 borderline), along with elevated methylmalonic acid (MMA) and homocysteine levels, macrocytosis, pancytopenia, and hypersegmented neutrophils. If MMA is normal, significant B12 deficiency is unlikely.

Treatment of severe cases is supplementation of B12 by injection of 1000 mcg daily for 5 days, then monthly. Oral B12, dosed at 500–1000 mcg daily, is usually absorbed well enough even in patients with atrophic gastritis, gastric resection , or pernicious anemia.

Folate Deficiency

Folate deficiency is most commonly caused by poor dietary ingestion. Other causes are malabsorption (sprue), and hemolytic anemia.

In B12 deficiency neurologic abnormalities can be present and MMA is elevated.

However, in folate deficiency neurologic abnormalities are absent and MMA is normal, and homocysteine is increased. RBC folate levels rather than serum folate levels are more accurate for diagnosing deficiency.

Treatment is to give folate 1 mg/day even if deficiency is caused by malabsorption.

Non-megaloblastic anemia: Other causes of macrocytic anemias without megaloblastosis include:

• Liver disease

• Alcohol abuse (even in the absence of vitamin B12 or folate deficiency)

• Hypothyroidism

• Smoking

• Drugs (hydroxyurea, antiretrovirals, 5-FU, azathioprine, etc.)

• Primary bone marrow disorders

• Reticulocytosis

Hyperproliferative Anemias

Hyperproliferative anemias are the result of acute blood loss or increased RBC destruction such as in hemolysis, which may be due to congenital or acquired causes. Aside from blood loss, hyperproliferative anemias warrant a referral to a hematologist given the complexity of management.

Defects in Red Cell Membrane

Hereditary spherocytosis is characterized by osmotically fragile spherical red blood cells due to a deficiency of one of the membrane proteins. Spherocytes have diminished deformability, predisposing them to entrapment and destruction in the spleen.

Patients present with evidence of hemolysis (anemia, jaundice, reticulocytosis, gallstones, splenomegaly) with spherocytosis (spherocytes on the peripheral smear and increased osmotic fragility) and a positive family history.

Peripheral smears usually show easily identifiable spherocytes lacking central pallor.

Treatment includes folic acid supplementation (1 mg/day) and splenectomy for moderate to severe cases. Ultrasound should be carried out before splenectomy to exclude the presence of gallstones. If present, cholecystectomy is also indicated [5].

Defects in Red Blood Cell Metabolism

Glucose-6-phosphate dehydrogenase deficiency (G6PD) diminishes the reductive energy of the red cell affecting red cell integrity when exposed to certain drugs, infections, chemicals, and fava beans, resulting in hemolysis.

Oxidized hemoglobin precipitates to form Heinz bodies which are plucked out of the red cell leading to hemolysis and “bite cell” and “blister cell” morphology [6].

Patients require education about foods (e.g., fava beans) and drugs (e.g., quinolones, sulfa, and certain antimalarials) that should be avoided. Patients should be aware of the signs of hemolytic crisis (orange/dark urine, lethargy, fatigue, jaundice) and be hypervigilant during acute infections. Patients should be transfused with packed red blood cells if Hb level is below 7 g/dl or if hemoglobinuria persists and Hb is below 9 g/dL [7].

Hemoglobinopathies

Sickle Cell Disease

Sickle cell disease is the most commonly observed hemoglobinopathy in the United States, affecting 1:500 African-American births and 1:36,000 Hispanic-American births.

The defect is a Glu → Val substitution in the sixth amino acid of the β-globin gene producing mutant β-globins that form hemoglobin S which polymerizes resulting in deformed RBCs. Sickle cells are prematurely destroyed or hemolyzed which reduces nitric oxide (NO) bioavailability contributing to vasoconstriction and platelet activation. This cascade of events causes endothelial damage, production of inflammatory mediators, and overexpression of adhesion molecules producing vaso-occlusion and stasis [8].

Always be aware of the three main types of complications of sickle cell anemia:

• Hemolysis associated: severe anemia, cholelithiasis, acute aplastic episodes (parvovirus B19 infection), pulmonary hypertension

• Infectious complications: Streptococcus pneumoniae, E. coli sepsis, osteomyelitis (Salmonella)

• Vaso-occlusive: painful crises, acute chest syndrome, splenic sequestration/infarcts, stroke, osteonecrosis of the bone, priapism, leg ulcers, spontaneous abortion, renal insufficiency

Management of Common Acute Complications

Vaso-occlusive crisis (VOC) : In patients with mild-to-moderate pain who report relief with NSAIDS, continue the same treatment in the absence of contraindications. In severe pain, hospitalization for pain control is indicated.

Fever: If temperature ≥101.3 °F (38.5 °C), evaluate with H&P, CBC with differential, reticulocyte count, blood culture, and urine culture when urinary tract infection is suspected [9].

Hospitalize if acute chest syndrome (acute onset of lower respiratory tract disease with cough, shortness of breath, tachypnea, retractions, or wheezing with or without fever), stroke, priapism lasting >4 h, acute pain requiring parenteral opiates, or fever with temperature ≥103.1 °F (39.5 °C). Chronic complications include chronic pain, leg ulcers, avascular necrosis, pulmonary hypertension, and renal and ophthalmologic complications [9].

Outpatient treatment focuses on prevention of acute and chronic complications of sickle cell anemia.

Patients should be treated with hydroxyurea under the following conditions: three or more sickle cell severe pain crises in a 12-month period; pain that interferes with daily activities and quality of life, severe and/or recurrent ACS; or severe symptomatic chronic anemia. Hydroxyurea should be discontinued if the patient becomes pregnant or is breastfeeding. The starting dosage for adults (500 mg capsules) is 15 mg/kg/day. The dosage should be reduced to 5–10 mg/kg/day if the patient has chronic kidney disease [9].

Health maintenance includes vaccination against Streptococcus pneumoniae and regular screening for hypertension, proteinuria, and retinopathy [9].

Thalassemias

In this type of anemia, there is decreased synthesis of structurally normal globin proteins, characterized by low Hgb and unusually small and fragile RBCs (microcytosis), although the RBC count may be normal. In thalassemia minor, the RBC count is usually high and the Hgb and RDW will be normal or slightly abnormal. Subtypes of thalassemia involve imbalances in the four chains of amino acids that comprise hemoglobin (alpha- and beta-globins). This causes instability in the globin chains, which precipitate in RBC precursors in the bone marrow, leading to ineffective erythropoiesis and microcytic anemia:

• Decreased α synthesis = α thal → relative excess of β globins

• Decreased β synthesis = β thal → relative excess of α globins

Although thalassemia major is a serious disease, in adult medicine we see thalassemia minor, which requires no treatment:

• Beta thalassemia minor: generally asymptomatic; mild microcytic anemia

• Alpha thalassemia minor: lifelong mild microcytic anemia, microcytosis out of proportion to the degree of anemia, high RBC count [10]

Hemolytic Anemia

The reticulocyte index will be >2% (see algorithm). Based on the underlying pathophysiologic process, hemolytic anemias can be classified as immune and non-immune mediated:

• Immune mediated (Coombs positive)

  In addition to recent history of blood transfusions or specific drug use, further workup needs to be done to determine the following:

• 1. Autoimmune (warm or cold).

• 2. Alloimmune (acute or delayed transfusion reaction).

• 3. Drug induced (e.g., quinidine, phenacetin, INH, hydralazine, sulfa drugs, penicillin, methyldopa, dapsone, nitrites, rifampin). Patients with G6PD deficiency are particularly prone.

• Non-immune mediated (Coombs negative)—intravascular hemolysis due to:

• 1. Microangiopathic hemolytic anemia

• 2. Defects in RBC membrane/enzymes

• 3. Infections (bacterial, viral, or fungal)

Usually hemolytic anemia is normocytic, but can be macrocytic if there is significant reticulocytosis. Testing includes LDH, indirect bilirubin, haptoglobin, urinary-free hemoglobin (if brisk intravascular hemolysis, positive dipstick, but no RBC on urine analysis), and Coombs (direct antiglobulin test or DAT) test.

Microangiopathic hemolysis produces schistocytes on smear due to mechanical intravascular disruption of RBCs.

Always send a preliminary panel of hemolysis labs for any unexplained normocytic anemia (or macrocytic with high reticulocyte count). Without a high index of suspicion, subtle hemolysis can be missed.

Clinical Pearls

Categorize anemia based on reticulocyte index and cell size.

Anemia can have more than one etiology in the same patient.

Acute treatment of anemia should be based on symptoms, not Hgb level.

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