Macrocytosis 

Macrocytosis is a term used to describe erythrocytes that are larger than normal, typically reported as mean cell volume (MCV) greater than 100 fL. Because the amount of hemoglobin in the cell increases proportionately with the increase in size, 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] 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.^[2]

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.^[3]

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 deficiency and folic acid 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.

DNA synthesis also may be delayed when certain chemotherapeutic agents are used, including folate antagonists, purine antagonists, and pyrimidine antagonists.

Hydroxyurea, an agent now commonly used to decrease the number of vaso-occlusive 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 infection, may be monitored in the same way.

Sternfeld et al, in a study using the¹³ C-methionine breath test to analyze hepatic mitochondrial function in vivo in antiretroviral-treated HIV-infected patients with macrocytosis, found a significantly negative correlation between mean corpuscular erythrocyte volume and the breath test results.^[4] They concluded that there is an association between an increase in mean corpuscular erythrocyte volume from treatment with nucleoside reverse transcriptase inhibitors and the hepatic mitochondrial function in vivo.

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 deposition of cholesterol or phospholipids on the membranes of circulating red blood cells (RBCs). Similarly, in splenectomized patients, RBC membrane lipids that usually are removed during maturation in the spleen are not effectively removed, and the result is 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 the reticulocyte is released prematurely from the marrow, its volume 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.^[5] 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 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.

A murine study found that disruption of the Gardos channel (the erythrocyte Ca²⁺ -activated K⁺ channel [KCa3.1]) caused subtle erythrocyte macrocytosis and led to mild but progressive splenomegaly.^[6]

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 resulting in macrocytosis. A dietary deficiency of vitamin B-12 is rare, although deficiency can result from the following:

• Lack of intrinsic factor in patients who have undergone gastrectomy 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 (eg, methotrexate^[7] )
• Purine antagonists (eg, 6-mercaptopurine [6-MP])
• Pyrimidine antagonists (eg, cytosine arabinoside [ara-C])
• Alkylating agents (eg, cyclophosphamide)
• Zidovudine (AZT)
• Trimethoprim
• Oral contraceptive pills
• Phenytoin
• 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 of the following types may cause macrocytosis:

• 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.^[8]

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 is a manifestation of hormone deficiency. More commonly, hypothyroid patients exhibit a normocytic anemia. Artifactually elevated MCVs must be considered in certain patients. These are observed less frequently with newer counting machines. Hyperglycemia and cold agglutinins may cause artificially elevated MCVs.^[9]