The term macrocytosis refers to a blood condition in which red blood cells
(RBC) are larger than normal. Macrocytosis is reported in terms of mean
corpuscular volume (MCV). Normal MCV values range from 80 to 100 femtoliters
(fl) and vary by age and reference laboratory.1MCV is calculated according to the
MCV (fl) = [Hematocrit (percent) x 10]/[RBC count (106/µL)]
Macrocytosis can be identified by reviewing peripheral blood smears and/or by
automated RBC indices. The peripheral blood smear is more sensitive than RBC
indices for identifying early macrocytic changes because the MCV represents the
mean of the distribution curve and is insensitive to the presence of small numbers of
macrocytes.2However, compared to the peripheral blood smear, MCV may
underestimate macrocytosis in over 30% of cases.3
Although determination of the MCV by automated blood cell counter is rarely
inaccurate, hyperglycemia, marked leukocytosis and cold agglutinins may result in
false elevations of the MCV.4-6Moreover, partial occlusion of the instrument
aperture and/or leaving the blood sample at room temperature for several hours may
also result in false elevations of the MCV value.
Macrocytosis is a relatively common finding in the era of automated blood cell
counters, with prevalence estimates ranging from 1.7% to 3.6%.3,7,8Its significance
tends to be underestimated by physicians, since about 60% of patients present without
associated anemia,8unless there are other accompanying abnormalities noted.
No complications arise from macrocytosis itself as an isolated finding. However, its
identification can provide important information regarding the presence of an
underlying disease state. Thus, in the appropriate clinical setting, MCV values above
the upper limit of normal or those that differ significantly from the patient’s baseline
values may require further clinical and laboratory assessment to determine the
underlying cause of the macrocytosis.9
Clinical Medicine & Research
Volume 4, Number 3: 236-241
©2006 Marshfield Clinic
Steven H.Yale, MD
Department of Internal Medicine
1000 North Oak Avenue
Megaloblastic Anemia and Other Causes of Macrocytosis
Florence Aslinia, MD; Joseph J. Mazza, MD, MACP; and Steven H. Yale, MD, FACP
Received: December 12, 2005
Revised: May 11, 2006
Accepted: June 19, 2006
18. Bain BJ. Diagnosis from the blood smear. N Engl J Med
19. Torres Gomez A, Casano J, Sanchez J, Madrigal E, Blanco F,
Alvarez MA. Utility of reticulocyte maturation parameters in
the differential diagnosis of macrocytic anemias. Clin Lab
20. Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein
LE, McGlave P, eds. Hematology: basic principles and practice.
4thed. New York, NY: Churchill Livingston; 2005.
21. Harris JW, Kellermeyer RW. The red cell. rev ed. Cambridge,
MA: Harvard University Press; 1970. 387.
22. Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ,
Silberstein LE, McGlave P, eds. Hematology: basic principles
and practice. 2nded. New York, NY: Churchill Livingston;
23. Ward PC. Modern approaches to the investigation of vitamin
B12 deficiency. Clin Lab Med 2002;22:435-445.
24. Snow CF. Laboratory diagnosis of vitamin B12 and folate
deficiency: a guide for the primary care physician. Arch
Intern Med 1999;159:1289-1298.
25. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB,
Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blickle
JF. Vitamin B12 (cobalamin) deficiency in elderly patients.
26. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam
27. Ashraf MJ, Goyal M, Hinchey K, Cook JR. Clinical utility of
folic acid testing for anemia and dementia screen. J Gen
Intern Med 2004;19(s1):130.
28. Chanarin I. The megaloblastic anaemias. 2nded. Oxford,
England: Blackwell Scientific Publishers; 1979.
29. Handin RI, Lux SE, Stossel TP. Blood: principles and practice
of hematology. 1sted. Philadelphia, PA: Lippincott Williams
& Wilkins; 1995; 1406.
30. Handin RI, Lux SE, Stossel TP. Blood: principles and practice
of hematology. 1sted. Philadelphia, PA: Lippincott Williams
& Wilkins; 1995; 1421.
31. Lindenbaum J, Allen RH. Clinical spectrum and diagnosis of
folate deficiency. In: Bailey LB, ed. Folate in health and
disease. New York, NY: Marcel Dekker; 1995. 43-73.
32. Antony AC. Megaloblastic anemias. In: Hoffman R, Benz EJ Jr,
Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P,
eds. Hematology: basic principles and practice. 3rded. New
York, NY: Churchill Livingston; 2000. 446-485.
33. Jaffe JP, Schilling RF. Erythrocyte folate levels: a clinical study.
Am J Hematol 1991;36:116-121.
34. Barney-Stallings RA, Heslop D. What is the clinical utility of
obtaining a folate level in patients with macrocytosis or
anemia? J Fam Pract 2001;50:544.
35. Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers
GM, eds. Wintrobe’s clinical hematology. 10thed. Baltimore:
Williams & Wilkins; 1999.
36. Tisman G, Herbert V. B12 dependence of cell uptake of serum
folate: an explanation for high serum folate and cell folate
depletion in B12 deficiency. Blood 1973;41:465-469.
37. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG,
Lindenbaum J. Elevation of total homocysteine in the serum
of patients with cobalamin or folate deficiency detected by
capillary gas chromatography-mass spectrometry. J Clin
38. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of
cobalamin deficiency I: usefulness of serum methylmalonic
acid and total homocysteine concentrations. Am J Hematol
39. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of
cobalamine deficiency: II. Relative sensitivities of serum
cobalamine, methylmalonic acid, and total homocysteine
concentrations. Am J Hematol 1990;34:99-107.
40. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of
serum methylmalonic acid and total homocysteine
determinations for diagnosing cobalamin and folate
deficiencies. Am J Med 1994;96:239-246.
41. Alpers DH. What is new in vitamin B(12)? Curr Opin
42. Lloyd-Wright Z, Hvas A, Moller J, Sanders TA, Nexo E.
Holotranscobalamin as an indicator of dietary vitamin B12
deficiency. Clin Chem 2003;49:2076-2078.
43. Nilsson K, Isaksson A, Gustafson L, Hultberg B. Clinical
utility of serum holotranscobalamin as a marker of cobalamin
status in elderly patients with neuropsychiatric symptoms.
Clin Chem Lab Med 2004;42:637-643.
44. Solomon LR. Cobalamin-responsive disorders in the
ambulatory care setting: unreliability of cobalamin,
methylmalonic acid, and homocysteine testing. Blood
45. Robinson AR, Mladenovic J. Lack of clinical utility of folate
levels in the evaluation of macrocytosis or anemia. Am J
46. Shojania AM. Protein synthesis-megaloblastic disorders. In:
Gross S, Roath S, eds. Hematology. A problem-oriented
approach. Baltimore: Williams & Wilkins. 1996. 25-54.
47. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S,
Nightingale P, Fegan C. Oral vitamin B12 can change our
practice. Postgrad Med J 2003;79:218-220.
48. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S,
Senturk T. Oral versus intramuscular cobalamin treatment in
megaloblastic anemia: a single-center, prospective,
randomized, open-label study. Clin Ther 2003;25:3124-3134.
49. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP,
Lindenbaum J. Effective treatment of cobalamin deficiency
with oral cobalamin. Blood 1998;92:1191-1198.
50. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for
vitamin B12 deficiency: comparison between the sublingual
and oral route. Br J Clin Pharmacol 2003;56:635-638.
51. Latif T, Hsi ED, Rybicki LA, Adelstein DJ. Is there a role for
folate determinations in current clinical practice in the USA?
Clin Lab Haematol 2004;26:379-383.
52. Smellie WS, Wilson D, McNulty CA, Galloway MJ, Spickett
GA, Finnigan DI, Bareford DA, Greig MA, Richards J. Best
practice in primary care pathology: review 1. J Clin Pathol
Florence Aslinia, MD, Department of Internal Medicine,
Marshfield Clinic, 1000 N. Oak Avenue, Marshfield,
Joseph J Mazza, MD, MACP, Department of
Hematology/Oncology, Marshfield Clinic, 1000 N. Oak
Avenue, Marshfield, Wisconsin 54449.
Steven H. Yale, MD, FACP, Department of Internal Medicine,
Marshfield Clinic and Clinical Research Center, Marshfield
Clinic Research Foundation, 1000 N. Oak Avenue,
Marshfield, Wisconsin 54449.
Aslinia et al.
CM&R 2006 : 3 (September)