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^[19]
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^[20]
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.^[21] 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).^[22]

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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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. [Medline].
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. [Medline]. [Full Text].
Younes M, Dagher GA, Dulanto JV, Njeim M, Kuriakose P. Unexplained macrocytosis. South Med J. 2013 Feb. 106(2):121-5. [Medline].
Rumsey SE, Hokin B, Magin PJ, Pond D. Macrocytosis--an Australian general practice perspective. Aust Fam Physician. 2007 Jul. 36(7):571-2. [Medline]. [Full Text].
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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. [Medline].
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. [Medline].
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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. [Medline].
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. [Medline]. [Full Text].
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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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