eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Macrocytosis

Author: Wendy Brick, MD, Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Coauthor(s): Russell Burgess, MD, Department of Internal Medicine, Division of Hematology/Oncology, East Carolina Internal Medicine
Contributor Information and Disclosures

Updated: Aug 29, 2009

Introduction

Background

Macrocytosis is a term used to describe erythrocytes that are larger than normal, typically reported as mean cell volume (MCV) greater than 100 fL. The amount of hemoglobin in the cell increases proportionately, so the mean cell hemoglobin concentration (MCHC) remains within normal limits. Causes of macrocytosis are many and range from benign to malignant; thus, a complete workup to determine etiology is essential.¹

Pathophysiology

The most common cause of macrocytic anemia is megaloblastic anemia, which is the result of impaired DNA synthesis. Although DNA synthesis is impaired, RNA synthesis is unaffected, leading to a buildup of cytoplasmic components in a slowly dividing cell. This results in a larger-than-normal cell. The nuclear chromatin of these cells also has an altered appearance.²

Vitamin B-12 and folate coenzymes are required for thymidylate and purine synthesis; thus, their deficiency results in retarded DNA synthesis. In vitamin B-12 and folate deficiency, the defect in DNA synthesis affects other rapidly dividing cells as well, which may be manifested as glossitis, skin changes, and flattening of intestinal villi. The synthesis of DNA also may be delayed when certain chemotherapeutic agents are used. Examples of such agents include folate antagonists (methotrexate), purine antagonists (6-mercaptopurine), and pyrimidine antagonists (cytosine arabinoside [ara-C]).

Hydroxyurea, an agent now commonly used to decrease the number of vasoocclusive pain crises in patients with sickle cell disease, interferes with DNA synthesis, causing a macrocytosis by which compliance with therapy may be monitored. Patient compliance with zidovudine, an agent used in the treatment of patients with HIV, may be monitored in the same way.

Sternfeld et al assessed whether macrocytosis may be a marker of mitochondrial toxicity in antiretrovirally treated HIV-infected patients by using the¹³ C-methionine breath test to analyze the hepatic mitochondrial function in vivo in these HIV patients with macrocytosis.³  The investigators found a significantly negative correlation between mean corpuscular erythrocyte volume and the breath test results, concluding there is association between an increase of the mean corpuscular erythrocyte volume from treatment with nucleoside reverse transcriptase inhibitors and the hepatic mitochondrial function in vivo.³

Nonmegaloblastic macrocytic anemias are those in which no impairment of DNA synthesis occurs. Included in this category are disorders associated with increased membrane surface area, accelerated erythropoiesis, alcoholism, and chronic obstructive pulmonary disease (COPD).

Patients with hepatic disease and obstructive jaundice have a macrocytosis that is secondary to increased cholesterol and/or phospholipids deposited on the membranes of circulating RBCs. Similarly, in splenectomized patients, RBC membrane lipids that usually are removed during maturation in the spleen are not effectively removed, leading to a larger-than-normal cell.

In patients with hemolytic anemia or posthemorrhagic anemia, the reticulocyte count increases. The reticulocyte, an immature RBC, is approximately 20% larger than the more mature RBC. When released prematurely from the marrow, the volume of the reticulocyte is averaged with the volume of the more mature RBC, and the resultant MCV is increased.

Macrocytosis, sometimes without associated anemia, is often evident in persons with chronic alcoholism. Although the macrocytosis of alcoholism may be secondary to poor nutrition with a resulting folate or vitamin B-12 deficiency, it is more often due to a direct toxicity of the alcohol on the marrow. The macrocytosis of alcoholism usually reverses only after months of abstinence from alcohol.

The macrocytosis associated with COPD is attributed to excess cell water that is secondary to carbon dioxide retention.

Mortality/Morbidity

No complications are directly attributable to the increased size of the red cell. Complications are attributed to the condition causing the macrocytosis. Diagnosis of the etiology of macrocytosis is required before the morbidity and mortality can be determined.

Age

Macrocytosis may occur at any age, but it is more prevalent in older age groups because the causes of macrocytosis are more prevalent in older persons.⁴

Clinical

History

• Symptoms are attributable to the underlying condition causing the anemia or directly to the anemia. Symptoms may include the following:
  • Dyspnea
  • Headache
  • Fatigue
  • Sore tongue
  • Diarrhea or other gastrointestinal symptoms
  • Paresthesias
• A history of alcohol abuse may be an important clue as to the cause of the increased MCV.
• A thorough examination of the patient's medication regimen is also crucial in the workup of macrocytosis.
• Dyspnea is a consequence of anemia. In acute or severe anemia, the volume of hemoglobin in the blood is inadequate to provide appropriate oxygenation of the tissues.
• Fatigue may be attributed to underlying disease, if present, or to inadequate blood volume.
• Headache is a symptom of anemia due to decreased oxygenation of the tissues.
• A sore tongue may be glossitis or atrophy of the tongue, which are common findings in folate and vitamin B-12 deficiencies.
• Diarrhea or other gastrointestinal symptoms may be present in patients with tropical or celiac sprue. Sprue may cause folate or vitamin B-12 deficiencies.
• Long-term use of alcohol may have a direct toxic effect on the bone marrow, causing macrocytosis.
• A variety of medications may have an effect on the MCV.
• Paresthesia or gait disturbances suggest vitamin B-12 deficiency.
• Recent acute blood loss may signal that reticulocytosis is causing the MCV increase.

Physical

• Glossitis suggests that the macrocytosis stems from deficiency of vitamin B-12, folate, or both.
• Tachycardia is usually modest and is common in patients with severe anemia.
• Flow murmurs usually are noted only in patients with severe anemia.
• Splenomegaly may be quite remarkable when the macrocytosis is due to hemolysis, infiltrative disorders, or neoplasms.
• Jaundice suggests liver disease or hemolysis, both of which may lead to an increased MCV.
• Conjunctival pallor is evident in patients with severe anemia.
• Neurological disorders, such as ataxia, loss of posterior column sensations, loss of deep tendon reflexes (particularly ankle reflex), and confabulation, may suggest vitamin B-12 deficiency.

Causes

• Vitamin B-12 deficiency is a cause of macrocytosis. Because DNA synthesis requires cyanocobalamin (vitamin B-12) as a cofactor, a deficiency of the vitamin leads to decreased DNA synthesis in the erythrocyte, thus leading to macrocytosis. A dietary deficiency of vitamin B-12 is rare, although deficiency can result from the following:
  • Lack of intrinsic factor in patients with postgastrectomy status or who have pernicious anemia
  • Malabsorption of vitamin B-12 secondary to small bowel overgrowth, tapeworm, familial factors, drugs, ileal bypass, ileal enteritis, or sprue
• Folate also is needed as a cofactor in the synthesis of DNA. Folate deficiency may be caused by any of the following:
  • Dietary deficiency
  • Increased requirements of pregnancy
  • Congenital deficiency
  • Sprue
• Inherited disorders of DNA synthesis include the following:
  • Lesch-Nyhan syndrome
  • Deficient enzymes for folate metabolism
  • Homocystinuria
• Drug-induced macrocytosis is the most common cause in nonalcoholic patients. Usually, no associated anemia is present. The following categories of drugs are known to cause macrocytosis:
  • Folate antagonists (methotrexate)
  • Purine antagonists (6-mercaptopurine)
  • Pyrimidine antagonist (ara-C)
  • Alkylating agents (cyclophosphamide)
  • Azidothymidine (AZT)
  • Trimethoprim
  • Oral contraceptive pills (OCPs)
  • Dilantin
  • Arsenic
• Reticulocytosis may be due to posthemorrhagic blood loss or hemolysis. Reticulocytes are immature red cells released in response to decreased hematocrit levels.
• Long-term alcohol intake directly affects bone marrow. This effect is not related to the presence of liver disease or vitamin deficiency and resolves only after months of abstinence from alcohol.
• Refractory anemias
  • Myelodysplastic anemias
  • Myelophthisic anemias (marrow replacement by neoplasm, granuloma, or fibrosis)
  • Aplastic anemia
  • Acquired sideroblastic anemia
• Macrocytosis in patients with COPD is attributed to excess cell water secondary to carbon dioxide retention.
• Benign familial macrocytosis is an inherited syndrome in which patients have mild asymptomatic macrocytosis.
• Macrocytosis of liver disease is secondary to increased cholesterol and phospholipids deposited on membranes of circulating erythrocytes. This deposition effectively increases the surface area of the erythrocyte.
• Hypothyroidism
  • Hypothyroidism is a manifestation of hormone deficiency.
  • More commonly, hypothyroid patients exhibit a normocytic anemia.
  • Artifactually elevated MCVs must be considered in certain patients. This happens less frequently with newer counting machines.
  • Hyperglycemia and cold agglutinins may cause artificially elevated MCVs.

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