Continuing Education Activity

Macrocytosis refers to the finding of enlarged red blood cells (RBCs). The measurement of RBC size is reported in the complete blood count (CBC) as mean corpuscular volume (MCV). Most elevated MCV reports are accompanied by an elevated mean corpuscular hemoglobin (MCH). Elevation of MCV and/or MCH suggests macrocytosis. This activity reviews the evaluation and treatment of macrocytosis and highlights the role of the healthcare team in the care of patients with this condition.

Objectives:

• Identify the etiology of macrocytosis.
• Review the appropriate evaluation process for macrocytosis.
• Outline the management options available for macrocytosis.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the care of macrocytosis and improve outcomes.

Introduction

Macrocytosis refers to the finding of enlarged red blood cells (RBCs). The measurement of RBC size is reported in the complete blood count (CBC) as mean corpuscular volume (MCV). Most elevated MCV reports are accompanied by an elevated mean corpuscular hemoglobin (MCH). The elevation of MCV and/or MCH suggests macrocytosis. In some cases, the discovery of macrocytosis may not necessitate further testing or treatment. However, practitioners should understand the importance of macrocytosis in the potential development of clinically significant anemia (macrocytic anemia), and they should understand the range of pathology that macrocytosis may signify, often implicating extra-hematologic organ systems. Close attention to historical, physical exam, and laboratory findings is helpful in determining the underlying etiology, which, in turn, dictates management strategies for patients with macrocytosis.

Etiology

In most cases, the etiology of macrocytosis may be related to abnormal RBC development, abnormal RBC membrane composition, increased reticulocyte count, or a combination of these three factors.

Abnormal RBC development may occur in settings such as vitamin B12 or folate deficiency. Vitamin B12 deficiency may be related to prolonged, strictly vegan diets. B12 is dependent on normal gastric and small intestine function. Its absorption needs intrinsic factor from the stomach and normal small bowel absorption. Immune interference with the intrinsic factor results in no B12 absorption. Impaired vitamin B12 absorption may occur due to gastrointestinal abnormalities including pernicious anemia, gastritis, celiac disease, inflammatory bowel disease (IBD), as a late complication of gastrointestinal surgeries such as gastrectomy, gastric bypass, and ileal resection, as an adverse reaction to medications such as proton pump inhibitors and metformin, or as an adverse effect of nitrous oxide abuse. Folate deficiency may be dietary, especially in cases involving alcoholic or elderly patients. Folic acid absorption also depends on health good GI small bowel absorption.

Folic acid stores may be affected by alcohol as well. Impaired folate absorption may be related to a similar range of intestinal abnormalities, including celiac disease, IBD, and small bowel resection. Folate metabolism may be impaired by medications such as methotrexate, phenytoin, and trimethoprim. In addition to its association with poor nutritional intake, ethanol also impairs folate absorption and metabolism, as well as inducing changes in the RBC membrane via its metabolite, acetaldehyde.[1] Furthermore, folate deficiency may be induced by conditions that increase folate requirements, such as pregnancy and chronic hemolysis. Of note, these nuclear maturation deficits are often associated with MCV in the 116 to 130 range, compared to other causes that often elevate MCV to the 100 to 116 range. 

Increased reticulocyte count directly increases the MCV as these immature RBCs are, on average, significantly larger. Reticulocytosis may occur as a response to hemolytic or blood loss anemia. A low reticulocyte count is expected in anemic states caused by impaired RBC production. However, transient reticulocytosis may occur during recovery from these states once the factors causing the anemia are corrected (e.g., iron store repletion, hematopoietic cell transplant, or spontaneous recovery from parvovirus).

Additional etiologies of macrocytosis which are not completely understood but are presumed to be multifactorial include the following: hypothyroidism, pregnancy, liver disease, Down syndrome, HIV, myelodysplastic syndrome (MDS), multiple myeloma, and hereditary stomatocytosis. Common medications not already mentioned that may induce macrocytosis include the following: valproic acid, hydroxyurea, allopurinol, and reverse-transcriptase inhibitors such as zidovudine, stavudine, and lamivudine.

Artificial changes in MCV may be reflected in laboratory tests for various reasons. Cold agglutinins are associated with MCV clumping, which may result in the interpretation of an elevated MCV. Clumping may also occur to an extent due to inflammatory or neoplastic conditions. Severe leukocytosis or hyperglycemia may also result in MCV overestimation.[2][3]

Epidemiology

The prevalence of macrocytosis has been estimated from 1.7% to 3.9%.[4] Males are more commonly affected. Both macrocytosis and macrocytic anemia are associated with advanced age. Overall, about 40% of patients also have associated anemia. The presence of anemia is associated with a higher probability of primary bone marrow disease.[5]

Pathophysiology

As noted in the etiology section, macrocytosis is often associated with abnormalities of RBC nuclear maturation and cell development, and this process may be described as "megaloblastic change." This usually occurs as a result of impaired DNA synthesis. Vitamin B12 acts as an essential cofactor for the methylation of homocysteine to methionine, in which the methyl group is transferred from 5-methyl tetrahydrofolate to form tetrahydrofolate. Tetrahydrofolate then converts to methylenetetrahydrofolate, which is essential for the synthesis of thymidine, one of the nucleotides in DNA. Dietary folic acid is necessary to maintain the folate compounds used as substrates in these reactions. A deficit in either of these vitamins will limit thymidine available for DNA synthesis, resulting in impaired nuclear maturation.[6]

As also noted above, many medications are known to induce megaloblastic change by limiting vitamin absorption or vitamin metabolism, and others may do so by inhibiting nucleotide or protein synthesis through other mechanisms.

Histopathology

A maturation defect causes the developing cell to have an imbalance between the cytoplasm and the nucleus. The result will be an RBC precursor with more cytoplasm compared to the nucleus. Binucleate cells and macro-ovalocytes may be found on a peripheral smear. Large leukocytes and platelets may also be observed. Leukocytes may show nuclear abnormalities such as hypersegmentation.[7]

History and Physical

A thorough history and physical exam will reveal likely etiologies of macrocytosis and place it in a clinical context. Macrocytosis without anemia is unlikely to result in specific signs or symptoms, and in many cases, may have minimal clinical significance. Patients should be screened for symptoms of anemia, including fatigue, generalized weakness, dyspnea, palpitations, lightheadedness, and syncopal or near-syncopal events. Assess for pallor of the skin and mucous membranes, which may also suggest anemia. Tachycardia may be present in cases of significant anemia.

A medical history should be obtained and should include all current and recent medications, with attention to medications listed in the above sections, including anti-convulsants, biguanides, proton pump inhibitors, antihistamines, chemotherapeutic agents, and reverse-transcriptase inhibitors. Alcohol use should be quantified. Diet should be discussed to screen for the insufficient intake of folate and vitamin B12. 

Neurologic signs and symptoms, including paresthesia or impaired proprioception of the distal extremities, should be identified as suspicious for vitamin B12 deficiency. Glossitis may also be observed. Stigmata of cirrhosis, including jaundice, gynecomastia, telangiectasias, ascites, and asterixis may be elicited in cases of macrocytosis due to liver dysfunction, although these findings are not sensitive. Assess for lymphadenopathy, hepatosplenomegaly, and areas of bony tenderness as these may suggest a neoplastic cause such as multiple myeloma. Findings such as petechiae, ecchymosis, and epistaxis may indicate thrombocytopenia or platelet dysfunction, which is often associated with macrocytic anemia caused by primary bone marrow pathology.[4]

Evaluation

Macrocytosis is indicated by a high MCV on CBC. This is confirmed by the analysis of a peripheral blood smear. A peripheral blood smear may reveal findings of megaloblastic change, as discussed in the histopathology section. Target cells may suggest liver disease, although this is not a specific finding. 

Additional tests that help determine the etiology of macrocytosis include reticulocyte count, vitamin B12 and folate levels, methylmalonic acid and homocysteine levels, iron studies, TSH, and free T4 levels, liver and renal function tests. HIV antibody tests may be performed initially. Urinalysis may also be obtained to check for protein.

More specific tests may be undertaken when indicated to confirm a suspected etiology. Schilling test may be performed in patients with vitamin B12 deficiency to assess absorption and evaluate for conditions such as pernicious anemia. Serum protein electrophoresis may be performed if multiple myeloma is suspected based on initial testing. 

In cases in which the etiology is undetermined, or if pancytopenia is present, a bone marrow aspiration and biopsy may be indicated to evaluate for aplasia, dysplasia, or malignancy.[8]

Special precautions should be taken in evaluating patients susceptible to iron deficiency or anemia of chronic disease (e.g., those with chronic neoplastic or inflammatory conditions), as these processes may normalize the MCV, masking the pathology that would otherwise be responsible for macrocytosis.

Treatment / Management

Management of macrocytosis depends on the etiology and the presence or absence of associated anemia. If the macrocytosis is relatively mild with MCV < 115 without significant anemia and if no concerning features are identified on a thorough history, physical exam, and initial laboratory testing, then no treatment is necessary.

If the patient regularly consumes alcohol, macrocytosis, and macrocytic anemia may resolve several months after alcohol cessation.[9][10] Other bone marrow changes caused by alcohol have been shown to be reversible. While the macrocytosis may have little direct importance in this case, decreased alcohol use may prevent complications such as worsening liver disease, nutritional deficits, hypertension, pancreatitis, and psychiatric disease.

If significant anemia is present or if the MCV is 115 or greater, more investigation should be undertaken to determine the etiology, which in turn dictates the appropriate treatment strategy. Vitamin B12 may be supplemented orally or, if impaired, enteral absorption is present, given IM monthly. Daily oral folic acid may be prescribed. Offending medications should be adjusted or discontinued as clinically appropriate. Pathology responsible for gastrointestinal malabsorption should be identified and treated with referral to the appropriate specialist. Oncology referral may be necessary for cases of dysplasia or hematologic malignancy.

Differential Diagnosis

True macrocytosis carries a wide differential diagnosis, as discussed in the etiology section. A very common cause of pseudomacrocytosis is RBC clumping in the test tube and blood smear. This occurs with cold agglutinins, immune disorders, and anticoagulant malfunction in the drawing tube. These pseudomacrocytic rouleau changes are easily seen on a blood smear. Severe hyperglycemia or leukocytosis may also cause pseudomacrocytosis.

Prognosis

Prognosis varies depending on etiology and associated comorbidities. Patients with macrocytic anemia and associated chronic renal failure have the lowest survival rates (40% at five years). Nutritional deficiencies are also associated with poor survival (52%). Macrocytosis with multifactorial etiologies, including medication reaction, is associated with comparatively better survival rates. Macrocytosis related to alcohol use, in the absence of significant anemia and liver disease, is also comparatively benign.[11]

Complications

As with other etiologies of anemia, macrocytic anemia is associated with reduced exercise capacity and level of function, decreased physiologic reserve in cases of acute illness and injury, and increased all-cause mortality.[12] By itself, macrocytosis is not known to cause any direct complication.[4]

Deterrence and Patient Education

In the absence of anemia or other concerning findings on history, physical, and laboratory testing, the patient should be reassured that a mildly elevated MCV is relatively common in healthy patients. If the patient regularly consumes alcohol, even if the other laboratory tests are unremarkable and no other evidence of liver disease is present, patients should be cautioned that their macrocytosis may be an early sign of excessive use. Patients should be counseled regarding any other abnormal findings on their presentation and diagnostic testing, as these will dictate further management strategies.

Enhancing Healthcare Team Outcomes

The diagnostic laboratory team is essential for evaluating cases of macrocytosis. Hematology staff plays an important role in the processing and analysis of peripheral blood smears. The successful management of macrocytic anemia may require an interprofessional team effort involving primary care, gastroenterology, surgery, endocrinology, rheumatology, nephrology, hematology, and/or oncology. Specialists in nutrition, speech pathology, and addiction or social services may be important in managing vulnerable patient populations susceptible to malnutrition and excessive alcohol consumption.