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Macrocytosis

  • Author: Vincent E Herrin, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jul 14, 2016
 

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 increases proportionately with the increase in cell size. Therefore, if the increase in MCV is not related to macrocytic anemia, the mean cell hemoglobin concentration (MCHC) also increases in proportion.

Causes of macrocytosis are many and range from benign to malignant; thus, a complete workup to determine etiology is essential.[1] 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.[2, 3, 4]

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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.[5]

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 deficiency and folic acid 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.

DNA synthesis may also be delayed when certain chemotherapeutic agents are used, including folate antagonists, purine antagonists, pyrimidine antagonists, and even folate antagonist antimicrobials.

Hydroxyurea, an agent now commonly used to decrease the number of vaso-occlusive pain crises in patients with sickle cell disease, interferes with DNA synthesis, causing macrocytosis by which compliance with therapy may be monitored. Patient compliance with zidovudine, an agent used in the treatment of patients with HIV infection, may be monitored in the same way.

Sternfeld et al, in a study using the13 C-methionine breath test to analyze hepatic mitochondrial function in vivo in antiretroviral-treated HIV-infected patients with macrocytosis, found a significantly negative correlation between mean corpuscular erythrocyte volume and the breath test results.[6] They concluded that there is an association between an increase in mean corpuscular erythrocyte volume from treatment with nucleoside reverse transcriptase inhibitors and the hepatic mitochondrial function in vivo.

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 macrocytosis that is secondary to increased deposition of cholesterol or phospholipids on the membranes of circulating red blood cells (RBCs). Similarly, in splenectomized patients, RBC membrane lipids that usually are removed during maturation in the spleen are not effectively removed, and the result is 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 the reticulocyte is released prematurely from the marrow, its volume 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.[7, 8] 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 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.

A murine study found that disruption of the Gardos channel (the erythrocyte Ca2+ -activated K+ channel [KCa3.1]) caused subtle erythrocyte macrocytosis and led to mild but progressive splenomegaly.[9]

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Etiology

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 resulting in macrocytosis. A dietary deficiency of vitamin B-12 is rare and usually only occurs in elderly persons on a "tea-and-toast diet" or in strict vegan vegetarians. However, deficiency can result from the following:

  • Lack of intrinsic factor in patients who have undergone gastrectomy or who have pernicious anemia
  • Malabsorption of vitamin B-12 secondary to small bowel bacterial 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
  • Alcoholism
  • Increased turnover due to conditions such as hemolysis or sickle cell disease, among others

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 (eg, methotrexate [10] )
  • Purine antagonists (eg, 6-mercaptopurine [6-MP])
  • Pyrimidine antagonists (eg, cytosine arabinoside [ara-C])
  • Alkylating agents (eg, cyclophosphamide)
  • Tyrosine kinase inhibitors (eg, sunitinib, and imatinib) [11]
  • Zidovudine (AZT)
  • Trimethoprim
  • Oral contraceptive pills
  • Phenytoin
  • Arsenic

The tyrosine kinase inhibitors sunitinib and imatinib have been shown to induce macrocytosis in patients with a variety of cancers, including renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and breast cancer.[11] In patients with RCC, the development of macrocytosis following the institution of sunitiinib treatment may potentially serve as a positive prognostic factor for overall survival.[12]

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 of the following types may cause macrocytosis:

  • 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.[13]

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 is a manifestation of hormone deficiency. More commonly, hypothyroid patients exhibit a normocytic anemia. Artifactually elevated MCVs must be considered in certain patients. These are observed less frequently with newer counting machines. Hyperglycemia and cold agglutinins may cause artificially elevated MCVs.[14]

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Contributor Information and Disclosures
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

References
  1. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009 Feb 1. 79(3):203-8. [Medline].

  2. 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].

  3. 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].

  4. Younes M, Dagher GA, Dulanto JV, Njeim M, Kuriakose P. Unexplained macrocytosis. South Med J. 2013 Feb. 106(2):121-5. [Medline].

  5. 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].

  6. 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. [Medline].

  7. Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. Lancet. 1974 May 4. 1(7862):829-31. [Medline].

  8. 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].

  9. 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].

  10. 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. [Medline].

  11. Schallier D, Trullemans F, Fontaine C, Decoster L, De Greve J. Tyrosine kinase inhibitor-induced macrocytosis. Anticancer Res. 2009 Dec. 29 (12):5225-8. [Medline].

  12. 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].

  13. Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar. 18(1):41-3. [Medline].

  14. Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol. 1980 Dec. 74(6):797-800. [Medline].

  15. 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. [Medline].

  16. 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. [Medline].

  17. 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. [Medline].

  18. 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. [Medline].

  19. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. 1990 Jun. 34(2):99-107. [Medline].

  20. 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. [Medline].

  21. Veda P. Evaluation of macrocytosis in routine hemograms. Indian J Hematol Blood Transfus. 2013 Mar. 29(1):26-30. [Medline]. [Full Text].

  22. 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. [Medline].

 
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