Macrocytosis

INTRODUCTION

When a complete blood count is obtained, there is now the virtually uniform use of an automated cell count that, by several different methods, measures a parameter that reflects the red blood cell (RBC) volume. This measurement is reported as mean corpuscular volume (MCV) in units of femtoliters (10-15 liters) per RBC. (See "Mean corpuscular volume".) With automated methods, a MCV above 100 femtoliters (fL) is flagged as a high value and is called macrocytosis. Examination of the peripheral smear will confirm the diagnosis, as macrocytic cells are larger than the size of the nucleus of a small lymphocyte (picture 1).

This topic review will discuss the differential diagnosis of an elevated MCV. Such patients may not be anemic but, if they are, the presence of macrocytosis can help to direct the subsequent evaluation. (See "Approach to the adult patient with anemia".)

PATHOPHYSIOLOGY AND ETIOLOGY

Red blood cells (RBCs) enter the circulation from the bone marrow as reticulocytes, which are macrocytic. All other macrocytic RBCs are formed as a consequence of congenital or acquired abnormalities in nucleic acid metabolism of erythroid precursors, changes in membrane structure, alterations in pathways governing cell water content, or other factors (table 1) [1-3]. Conditions causing the production of macrocytic RBCs are broadly grouped into those associated with megaloblastic (eg, folate or cobalamin deficiency) or normoblastic (eg, alcoholism, liver disease, and certain drugs) RBC precursors.

Reticulocytosis — During normal erythropoiesis, when the orthochromic normoblast extrudes its nucleus, the remaining reticulocyte has a volume of 120 to 150 fL. This cell remains in the marrow for approximately three days and then is released into the peripheral blood where it undergoes remodeling with loss of cell water and membrane. Reticulocytes in the peripheral blood have a mean corpuscular volume (MCV) of 103 to 126 fL, a mean corpuscular hemoglobin concentration (MCHC) of 23.5 to 28.7 g/dL, and a mean cell hemoglobin (MCH) of 25.9 to 30.6 (picture 2). These values should be contrasted to normal RBC values:

MCV = 80 to 96 fL

                

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Literature review current through: Jun 2014. | This topic last updated: May 21, 2014.
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References
Top
  1. Hoffbrand V, Provan D. ABC of clinical haematology. Macrocytic anaemias. BMJ 1997; 314:430.
  2. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am 1992; 76:581.
  3. d'Onofrio G, Chirillo R, Zini G, et al. Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia. Blood 1995; 85:818.
  4. Houwen B. Reticulocyte maturation. Blood Cells 1992; 18:167.
  5. Seppä K, Sillanaukee P, Saarni M. Blood count and hematologic morphology in nonanemic macrocytosis: differences between alcohol abuse and pernicious anemia. Alcohol 1993; 10:343.
  6. Savage D, Lindenbaum J. Anemia in alcoholics. Medicine (Baltimore) 1986; 65:322.
  7. Girard DE, Kumar KL, McAfee JH. Hematologic effects of acute and chronic alcohol abuse. Hematol Oncol Clin North Am 1987; 1:321.
  8. Latvala J, Parkkila S, Melkko J, Niemelä O. Acetaldehyde adducts in blood and bone marrow of patients with ethanol-induced erythrocyte abnormalities. Mol Med 2001; 7:401.
  9. Wickramasinghe SN, Malik F. Acetaldehyde causes a prolongation of the doubling time and an increase in the modal volume of cells in culture. Alcohol Clin Exp Res 1986; 10:350.
  10. Hashimoto Y, Nakayama T, Futamura A, et al. Erythrocyte mean cell volume and genetic polymorphism of aldehyde dehydrogenase 2 in alcohol drinkers. Blood 2002; 99:3487.
  11. Karvellas CJ, Sawyer M, Hamilton M, Mackey JR. Effect of capecitabine on mean corpuscular volume in patients with metastatic breast cancer. Am J Clin Oncol 2004; 27:364.
  12. Snower DP, Weil SC. Changing etiology of macrocytosis. Zidovudine as a frequent causative factor. Am J Clin Pathol 1993; 99:57.
  13. Burns ER, Reed LJ, Wenz B. Volumetric erythrocyte macrocytosis induced by hydroxyurea. Am J Clin Pathol 1986; 85:337.
  14. Engström KG, Löfvenberg E. Treatment of myeloproliferative disorders with hydroxyurea: effects on red blood cell geometry and deformability. Blood 1998; 91:3986.
  15. Steele RH, Keogh GL, Quin J, et al. Mean cell volume (MCV) changes in HIV-positive patients taking nucleoside reverse transcriptase inhibitors (NRTIs): a surrogate marker for adherence. Int J STD AIDS 2002; 13:748.
  16. Woodson LC, Dunnette JH, Weinshilboum RM. Pharmacogenetics of human thiopurine methyltransferase: kidney-erythrocyte correlation and immunotitration studies. J Pharmacol Exp Ther 1982; 222:174.
  17. Gillessen S, Graf L, Korte W, Cerny T. Macrocytosis and cobalamin deficiency in patients treated with sunitinib. N Engl J Med 2007; 356:2330.
  18. Billemont B, Izzedine H, Rixe O. Macrocytosis due to treatment with sunitinib. N Engl J Med 2007; 357:1351.
  19. Rini BI, Choueiri TK, Elson P, et al. Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma. Cancer 2008; 113:1309.
  20. Schallier D, Trullemans F, Fontaine C, et al. Tyrosine kinase inhibitor-induced macrocytosis. Anticancer Res 2009; 29:5225.
  21. Rajaraman S, Davis WS, Mahakali-Zama A, et al. An allelic series of mutations in the Kit ligand gene of mice. II. Effects of ethylnitrosourea-induced Kitl point mutations on survival and peripheral blood cells of Kitl(Steel) mice. Genetics 2002; 162:341.
  22. Anttila P, Ihalainen J, Salo A, et al. Idiopathic macrocytic anaemia in the aged: molecular and cytogenetic findings. Br J Haematol 1995; 90:797.
  23. Rauw J, Wells RA, Chesney A, et al. Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis. Leuk Res 2011; 35:1335.
  24. Buckstein R, Jang K, Friedlich J, et al. Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: a retrospective study of 322 bone marrows. Leuk Res 2009; 33:1313.
  25. Christensen RD, Jopling J, Henry E, Wiedmeier SE. The erythrocyte indices of neonates, defined using data from over 12,000 patients in a multihospital health care system. J Perinatol 2008; 28:24.
  26. Dallman PR, Siimes MA. Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr 1979; 94:26.
  27. Pappo AS, Fields BW, Buchanan GR. Etiology of red blood cell macrocytosis during childhood: impact of new diseases and therapies. Pediatrics 1992; 89:1063.
  28. David O, Fiorucci GC, Tosi MT, et al. Hematological studies in children with Down syndrome. Pediatr Hematol Oncol 1996; 13:271.
  29. Borgna-Pignatti C, Azzalli M, Pedretti S. Thiamine-responsive megaloblastic anemia syndrome: long term follow-up. J Pediatr 2009; 155:295.
  30. Inelmen EM, D'Alessio M, Gatto MR, et al. Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: some results of an Italian multicentric study. Aging (Milano) 1994; 6:81.
  31. den Elzen WP, Westendorp RG, Frölich M, et al. Vitamin B12 and folate and the risk of anemia in old age: the Leiden 85-Plus Study. Arch Intern Med 2008; 168:2238.
  32. Lam AP, Gundabolu K, Sridharan A, et al. Multiplicative interaction between mean corpuscular volume and red cell distribution width in predicting mortality of elderly patients with and without anemia. Am J Hematol 2013; 88:E245.
  33. Davenport J. Macrocytic anemia. Am Fam Physician 1996; 53:155.
  34. Khawcharoenporn T, Shikuma CM, Williams AE, Chow DC. Lamivudine-associated macrocytosis in HIV-infected patients. Int J STD AIDS 2007; 18:39.
  35. Eyer-Silva WA, Arabe J, Pinto JF, Morais-De-Sá CA. Macrocytosis in patients on stavudine. Scand J Infect Dis 2001; 33:239.
  36. Planche V, Georgin-Lavialle S, Avillach P, et al. Etiologies and diagnostic work-up of extreme macrocytosis defined by an erythrocyte mean corpuscular volume over 130°fL: A study of 109 patients. Am J Hematol 2014; 89:665.
  37. Harkins LS, Sirel JM, McKay PJ, et al. Discriminant analysis of macrocytic red cells. Clin Lab Haematol 1994; 16:225.
  38. Hinchliffe RF, Bellamy GJ, Lilleyman JS. Use of the Technicon H1 hypochromia flag in detecting spurious macrocytosis induced by excessive K2-EDTA concentration. Clin Lab Haematol 1992; 14:268.
  39. Holt JT, DeWandler MJ, Arvan DA. Spurious elevation of the electronically determined mean corpuscular volume and hematocrit caused by hyperglycemia. Am J Clin Pathol 1982; 77:561.
  40. van Duijnhoven HL, Treskes M. Marked interference of hyperglycemia in measurements of mean (red) cell volume by Technicon H analyzers. Clin Chem 1996; 42:76.
  41. Weiss GB, Bessman JD. Spurious automated red cell values in warm autoimmune hemolytic anemia. Am J Hematol 1984; 17:433.
  42. Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol 1980; 74:797.
  43. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994; 69:144.