History

The symptoms of macrocytosis are attributable either to the anemia itself or to the underlying condition causing the anemia. They may include the following:

Dyspnea – This 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
Headache – This is a symptom of anemia due to decreased oxygenation of the tissues
Fatigue – This may be attributed to underlying disease, if present, or to inadequate blood volume
Sore tongue – This may reflect glossitis or atrophy of the tongue, which are common findings in folate and vitamin B12 deficiencies^[20]
Diarrhea or other gastrointestinal (GI) symptoms – These may be present in patients with tropical or celiac sprue; sprue may cause folate or vitamin B12 deficiencies^[21]
Paresthesia or gait disturbances – These suggest vitamin B12 deficiency

A history of alcohol abuse may be an important clue to the cause of the increased mean cell volume (MCV). Long-term use of alcohol may have a direct toxic effect on the bone marrow, causing macrocytosis; in addition, macrocytosis may result from poor nutritional intake in this population.^[22] An increased prevalence of depression and psychosis have been reported in patients with macrocytosis; those psychiatric disorders may share a common etiology with macrocytosis (eg, vitamin B12 deficiency).^[23]

A thorough examination of the patient’s medication regimen is also crucial in the workup of macrocytosis, because a variety of medications may have an effect on the MCV. Recent acute blood loss may signal that reticulocytosis is causing the MCV increase.

Physical Examination

The following physical findings may be noted:

Glossitis suggests that the macrocytosis stems from deficiency of vitamin B12, 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.
Neurologic disorders, such as ataxia, loss of posterior column sensations, loss of deep tendon reflexes (particularly ankle reflex), and confabulation, may suggest thiamine deficiency.

Differential Diagnoses

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Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009 Feb 1. 79(3):203-8. [QxMD MEDLINE Link].
Argento V, Roylance J, Skudlarska B, et al. Anemia prevalence in a home visit geriatric population. J Am Med Dir Assoc. 2008 Jul. 9(6):422-6. [QxMD MEDLINE Link].
McNamee T, Hyland T, Harrington J, Cadogan S, Honari B, Perera K, et al. Haematinic deficiency and macrocytosis in middle-aged and older adults. PLoS One. 2013. 8(11):e77743. [QxMD MEDLINE Link]. [Full Text].
Younes M, Dagher GA, Dulanto JV, Njeim M, Kuriakose P. Unexplained macrocytosis. South Med J. 2013 Feb. 106(2):121-5. [QxMD MEDLINE Link].
Rumsey SE, Hokin B, Magin PJ, Pond D. Macrocytosis--an Australian general practice perspective. Aust Fam Physician. 2007 Jul. 36(7):571-2. [QxMD MEDLINE Link]. [Full Text].
Sternfeld T, Lorenz A, Schmid M, et al. Increased red cell corpuscular volume and hepatic mitochondrial function in NRTI-treated HIV infected patients. Curr HIV Res. 2009 May. 7(3):336-9. [QxMD MEDLINE Link].
Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. Lancet. 1974 May 4. 1(7862):829-31. [QxMD MEDLINE Link].
Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, et al. Macrocytosis, Macrocytic Anemia, and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men. Alcohol Clin Exp Res. 2014 Mar 3. [QxMD MEDLINE Link].
Grgic I, Kaistha BP, Paschen S, Kaistha A, Busch C, Si H, et al. Disruption of the Gardos channel (KCa3.1) in mice causes subtle erythrocyte macrocytosis and progressive splenomegaly. Pflugers Arch. 2009 Jun. 458(2):291-302. [QxMD MEDLINE Link].
Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy. Arthritis Rheum. 1989 Dec. 32(12):1592-6. [QxMD MEDLINE Link].
Schallier D, Trullemans F, Fontaine C, Decoster L, De Greve J. Tyrosine kinase inhibitor-induced macrocytosis. Anticancer Res. 2009 Dec. 29 (12):5225-8. [QxMD MEDLINE Link].
Albai O, Timar B, Paun DL, Sima A, Roman D, Timar R. Metformin Treatment: A Potential Cause of Megaloblastic Anemia in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes. 2020. 13:3873-3878. [QxMD MEDLINE Link]. [Full Text].
Kloth JS, Hamberg P, Mendelaar PA, Dulfer RR, van der Holt B, Eechoute K, et al. Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment. Eur J Cancer. 2016 Mar. 56:101-6. [QxMD MEDLINE Link].
Ng MH, Chen VC, Ting H, Lin TY, Chang SH, Gossop M. Macrocytosis among patients with heroin use disorder. Neuropsychiatr Dis Treat. 2019. 15:2293-2298. [QxMD MEDLINE Link]. [Full Text].
Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar. 18(1):41-3. [QxMD MEDLINE Link].
Hamaguchi Y, Kondoh T, Fukuda M, Yamasaki K, Yoshiura KI, Moriuchi H, et al. Leukopenia, macrocytosis, and thrombocytopenia occur in young adults with Down syndrome. Gene. 2022 Aug 15. 835:146663. [QxMD MEDLINE Link].
Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol. 1980 Dec. 74(6):797-800. [QxMD MEDLINE Link].
Field EA, Speechley JA, Rugman FR, Varga E, Tyldesley WR. Oral signs and symptoms in patients with undiagnosed vitamin B12 deficiency. J Oral Pathol Med. 1995 Nov. 24(10):468-70. [QxMD MEDLINE Link].
Ellaway C, Christodoulou J, Kamath R, Carpenter K, Wilcken B. The association of protein-losing enteropathy with cobalamin C defect. J Inherit Metab Dis. 1998 Feb. 21(1):17-22. [QxMD MEDLINE Link].
Fernando OV, Grimsley EW. Prevalence of folate deficiency and macrocytosis in patients with and without alcohol-related illness. South Med J. 1998 Aug. 91(8):721-5. [QxMD MEDLINE Link].
Ransing RS, Patil S, Pevekar K, Mishra K, Patil B. Unrecognized Prevalence of Macrocytosis among the Patients with First Episode of Psychosis and Depression. Indian J Psychol Med. 2018 Jan-Feb. 40 (1):68-73. [QxMD MEDLINE Link]. [Full Text].
Curtis D, Sparrow R, Brennan L, Van der Weyden MB. Elevated serum homocysteine as a predictor for vitamin B12 or folate deficiency. Eur J Haematol. 1994 Apr. 52(4):227-32. [QxMD MEDLINE Link].
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Phekoo K, Williams Y, Schey SA, Andrews VE, Dudley JM, Hoffbrand AV. Folate assays: serum or red cell?. J R Coll Physicians Lond. 1997 May-Jun. 31(3):291-5. [QxMD MEDLINE Link].
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Veda P. Evaluation of macrocytosis in routine hemograms. Indian J Hematol Blood Transfus. 2013 Mar. 29(1):26-30. [QxMD MEDLINE Link]. [Full Text].
Ganji V, Kafai MR. Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults. Am J Clin Nutr. 2009 Jan. 89(1):363-71. [QxMD MEDLINE Link].

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Author

Vincent E Herrin, MD, FACP Professor of Medicine, Division of Hematology and Medical Oncology, Director, Medicine Residency Program, University of Mississippi School of Medicine

Vincent E Herrin, MD, FACP is a member of the following medical societies: American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Clinical Oncology, Southern Society for Clinical Investigation, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Russell Burgess, MD (Retired) Chief, Division of Hematology/Oncology, Eastern Carolina Internal Medicine, PA

Russell Burgess, MD is a member of the following medical societies: American College of Physicians and American Medical Association

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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