AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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.

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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Liver disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete CBC with platelet count
• • The hemoglobin/hematocrit level may provide a guide to diagnosis, and it determines presence and severity of anemia.
  • WBC and platelet count may be decreased in primary marrow disturbances.
  • The MCV is a calculated average volume of the erythrocytes. An MCV greater than 100 fL is, by definition, macrocytosis. Because evaluation of the RBC size is key to the diagnosis of an anemia, the MCV is considered to be the most important of the RBC indices.
• Peripheral blood smear morphology may be helpful. Round macrocytes suggest liver or marrow infiltrative disease, whereas oval macrocytes tend to suggest a megaloblastic disorder.
• • This study provides clues to the etiology of macrocytosis.
  • Hypersegmented neutrophils and macro-ovalocytes strongly suggest megaloblastic anemia.
  • Nucleated RBCs, teardrop cells, decreased and/or large platelets, and immature WBCs are often present in myelophthisic disease and leukemias.
• Reticulocyte count
• • This study helps to determine if hemolysis is present; it also indicates malfunctioning bone marrow.
  • Expect marked reticulocytosis (>4) in hemolytic anemias.
  • Reticulocyte count less than 1% indicates inadequate marrow production.
  • Reticulocyte count must be corrected for degree of anemia.
• Coombs test
• • Perform this test if the reticulocyte count is elevated to aid in confirming the diagnosis of hemolysis.
  • Expect a positive direct Coombs test finding in autoimmune hemolytic anemias, hemolytic transfusion reactions, and some drug-induced anemias (eg, penicillin, methyldopa, some cephalosporins, sulfonamides).
• Lactate dehydrogenase (LDH) is elevated in both intravascular and extravascular hemolysis including the ineffective erythropoiesis that occurs in megaloblastic anemias.
• Because the haptoglobin binds free hemoglobin, a low or absent haptoglobin level indicates intravascular hemolysis.
• If macro-ovalocytes and hypersegmented neutrophils are noted on peripheral smear, the vitamin B-12 level may be low.
• RBC folate levels
• • If folate deficiency is the cause of the macrocytosis, the RBC folate level likely will be decreased.
  • As in vitamin B-12 deficiency, peripheral smear may reveal hypersegmented neutrophils and macro-ovalocytes.
• Homocysteine level: Serum total homocysteine levels almost always are elevated in patients with folate deficiency, because folate is required in the remethylation step converting homocysteine to methionine. Serum methylmalonic acid and homocysteine levels may be increased even in early vitamin B-12 deficiency.
• Serum unconjugated bilirubin is expected to be elevated in hemolysis.
• If vitamin B-12 deficiency is the cause of the macrocytosis, the serum vitamin B-12 level likely will be decreased. Serum methylmalonic acid and homocysteine levels are increased early in vitamin B-12 deficiency, even before hematologic manifestations or decreases in B-12 levels are noted.
• A Schilling test was previously considered the criterion standard to further investigate a low vitamin B-12 level. However, many institutions no longer offer the Schilling test. Alternative tests to the Schilling test are antibodies to parietal cells and intrinsic factor antibodies.
• A serum folate level may be obtained, although an RBC folate level is more reliable because it reflects the level over the lifespan of the RBC.

Procedures

• Bone marrow biopsy and aspirate
• • The bone marrow biopsy and aspirate determines if the marrow is functioning adequately and also may reveal replacement of marrow with tumor, granuloma, or fibrosis. Obtain the bone marrow prior to vitamin B-12 folate therapy or blood transfusion because megaloblastic changes may reverse rapidly.
  • The bone marrow in megaloblastic anemias is usually hypercellular with all cell lines proliferating. Marked erythroid hyperplasia may occur to the point at which the myeloid-erythroid ratio is reversed. Nuclear-chromatin dissociation with a young-appearing nucleus with abundant mature-appearing cytoplasm may occur. Granulocytic hyperplasia with giant metamyelocytes and bands often are noted.

Histologic Findings

• Blood: On peripheral smear, large RBCs are evident. Depending on the etiology of the macrocytosis, peripheral smear may reveal nucleated RBCs, target cells, RBC fragments, hypersegmentation of neutrophils, immature WBCs, large platelets, or pancytopenia.
• Marrow: Depending on the etiology of the macrocytosis, marrow may reveal hypercellularity, megaloblastic changes, fibrosis, infiltration by tumor or granulomatous disease, leukemic changes, or erythroid hyperplasia.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Evaluation usually can be performed on an outpatient basis.
• Medical treatment depends on the etiology of the macrocytosis, the presence and severity of an anemia, and the symptoms of the patient.
• • After the appropriate laboratory studies are obtained, the symptomatic anemic patient may be transfused with packed RBCs.
  • If a drug is thought to be the cause of the macrocytic anemia, especially if hemolysis is occurring, discontinue administration of the offending drug.
  • Patients deficient in vitamin B-12 or folate should receive replacement therapy.
  • Counsel patients suspected of abusing alcohol to abstain.
  • Treat malignancies, granulomatous diseases, and COPD according to standards for each.
• Hospitalization may be required to treat some causes of macrocytosis, especially acute leukemias.

Consultations

• Hematology
• Oncology

Diet

If folate or vitamin B-12 deficiency is the cause of the macrocytosis, modify the diet to include foods rich in these vitamins. Red meat is a good source of vitamin B-12, and green leafy vegetables are excellent sources of folate. Do not provide folate supplementation without vitamin B-12 replacement therapy in any patient with vitamin B-12 deficiency or with suspected vitamin B-12 deficiency, since this may precipitate subacute combined degeneration of the spinal cord.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Vitamins

In macrocytosis associated with vitamin deficiencies, the deficient vitamin is replaced.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Outpatient follow-up depends on the cause of the macrocytosis.

In/Out Patient Meds

• Folate 1 mg/d may be prescribed in patients with folate deficiency.
• Vitamin B-12 injections (100-1000 mcg IM per mo), continued indefinitely, may be prescribed.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose and treat the cause of the macrocytosis

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ali G, Pecoud A, Decrey H, Verdon F. [Vitamin B 12 deficiency: early diagnosis in ambulatory care medicine]. Schweiz Med Wochenschr. Nov 7 1998;128(45):1763-71. [Medline].
• Atony AC. Megaloblasctic anemias. Hematology Basic Principles and Practice. 1995;2nd ed:552-581.
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• Field EA, Speechley JA, Rugman FR, et al. Oral signs and symptoms in patients with undiagnosed vitamin B12 deficiency. J Oral Pathol Med. Nov 1995;24(10):468-70. [Medline].
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• Sechi LA, De Carli S, Catena C, et al. Benign familial macrocytosis. Clin Lab Haematol. Mar 1996;18(1):41-3. [Medline].
• Seppa K, Heinila K, Sillanaukee P, Saarni M. Evaluation of macrocytosis by general practitioners. J Stud Alcohol. Jan 1996;57(1):97-100. [Medline].
• Swain RA, St Clair L. The role of folic acid in deficiency states and prevention of disease. J Fam Pract. Feb 1997;44(2):138-44. [Medline].
• Thong KL, Hanley SA, McBride JA. Clinical significance of a high mean corpuscular volume in nonanemic patients. Can Med Assoc J. Oct 22 1977;117(8):909-10. [Medline].
• Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum. Dec 1989;32(12):1592-6. [Medline].
• Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. Lancet. May 4 1974;1(7862):829-31. [Medline].
• Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting. J Gen Intern Med. May-Jun 1990;5(3):192-7. [Medline].
• Zittoun J, Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. Semin Hematol. Jan 1999;36(1):35-46. [Medline].

Article Last Updated: Jun 27, 2006