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 3 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 factors 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 and induces 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 red blood cells 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 (eg, iron store repletion, hematopoietic cell transplant, or spontaneous recovery from parvovirus).

Additional etiologies of macrocytosis that 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. 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, essential for synthesizing thymidine, 1 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 limits the 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 is a RBC precursor with more cytoplasm than 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 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 skin pallor 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. A diet should be discussed to screen for insufficient folate and vitamin B12 intake. 

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, often associated with macrocytic anemia caused by primary bone marrow pathology.[4]

Evaluation

A high MCV on complete blood count indicates macrocytosis. The analysis of a peripheral blood smear confirms this. A peripheral blood smear may reveal findings of megaloblastic change, as discussed in the histopathology section. Target cells may suggest liver disease, although this finding is not specific. 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, free T4 levels, and 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. For example, a Schilling test may be performed in patients with vitamin B12 deficiency to assess absorption and evaluate for conditions such as pernicious anemia. If multiple myeloma is suspected based on initial testing, serum protein electrophoresis may be performed. In cases where 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 (eg, 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 no concerning features are identified on a thorough history, physical exam, and initial laboratory testing, 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 are reversible. While 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.(B3)

If significant anemia is present or the MCV is 115 or greater, more investigation should be undertaken to determine the etiology, which dictates the appropriate treatment strategy. Vitamin B12 may be supplemented orally, or enteral absorption is present if impaired, and IM is given 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 a 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 the etiology section discusses. A 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 5 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 acute illness and injury cases, and increased all-cause mortality.[12] By itself, macrocytosis is not known to cause any direct complication.[4]