Macrocytosis

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Practice Essentials

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. Increased MCV is an indication of macrocytic anemia when any of the following is present[1] :

Causes of macrocytosis are many and range from benign to malignant; thus, a complete workup to determine etiology is essential.[2]  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.[3, 4, 5]

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.[6]

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.[7] 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.[8, 9] 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.[10]

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:

Folate also is needed as a cofactor in the synthesis of DNA. Folate deficiency may be caused by any of the following:

Inherited disorders of DNA synthesis include the following:

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:

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.[12] 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.[13]

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:

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.[14]

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.

Artifactual elevation of the MCV must be considered in certain patients, although this occurs less frequently with newer cell-counting machines. Hyperglycemia and cold agglutinins may cause artificially elevated MCVs.[15]

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:

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.[18]  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 B-12 deficiency).[19]

A thorough examination of the patient’s medication regimen is also crucial in the workup of macrocytosis; 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:

Laboratory Studies

A complete blood count (CBC) with platelet count is indicated. The hemoglobin concentration and hematocrit may help guide diagnosis and determine the presence and severity of anemia. White blood cell (WBC) and platelet counts may be decreased in primary marrow disturbances. Mean cell volume (MCV) is a calculated average red blood cell (RBC) volume. An MCV greater than 100 fL is macrocytosis by definition. Because evaluation of RBC size is key to the diagnosis of an anemia, the MCV is considered to be the most important of the RBC indices.

Peripheral blood smear morphology may be helpful. Round macrocytes suggest liver or marrow infiltrative disease, whereas oval macrocytes tend to suggest a megaloblastic disorder. This study provides clues to the etiology of macrocytosis. Hypersegmented neutrophils and macro-ovalocytes strongly suggest megaloblastic anemia. Nucleated RBCs, teardrop cells, decreased or large platelets, and immature WBCs are often present in myelophthisic disease and leukemias.

The reticulocyte count helps determine whether hemolysis is present; it can also indicate malfunctioning bone marrow. Marked reticulocytosis (>4%) is to be expected in hemolytic anemias. A reticulocyte count lower than 1% indicates inadequate marrow production. The reticulocyte count must be corrected for the degree of anemia present.

If the reticulocyte count is elevated, a Coombs test should be performed to aid in identifying the cause of hemolysis. A positive direct Coombs test finding is to be expected in autoimmune hemolytic anemias, hemolytic transfusion reactions, and some drug-induced anemias (eg, those caused by penicillin, methyldopa, some cephalosporins, or sulfonamides).

Lactate dehydrogenase (LDH) levels are elevated in both intravascular and extravascular hemolysis, including the ineffective erythropoiesis that occurs in megaloblastic anemias.

Because the haptoglobin binds free hemoglobin, a low or absent haptoglobin level indicates intravascular hemolysis.

If macro-ovalocytes and hypersegmented neutrophils are noted on peripheral smear, the vitamin B-12 level may be low. If folate deficiency is the cause of the macrocytosis, the RBC folate level likely will be decreased. As in vitamin B-12 deficiency, peripheral smear may reveal hypersegmented neutrophils and macro-ovalocytes.

Serum total homocysteine levels are almost always elevated in patients with folate deficiency because folate is required in the remethylation step that converts homocysteine to methionine.[20] Serum methylmalonic acid and homocysteine levels are increased early in vitamin B-12 deficiency, even before hematologic manifestations or decreases in B-12 levels are noted.[21]

Serum unconjugated bilirubin is expected to be elevated in hemolysis.

If vitamin B-12 deficiency is the cause of the macrocytosis, the serum vitamin B-12 level likely will be decreased. A Schilling test was previously considered the criterion standard for further investigation of a low vitamin B-12 level. However, many institutions no longer offer the Schilling test. Alternative tests to the Schilling test are antibodies to parietal cells and intrinsic factor antibodies.

A serum folate level may be obtained,[22] although an RBC folate level is more reliable because it reflects the level over the lifespan of the RBC.

A study designed to identify the underlying causes of macrocytosis by analyzing hematological features concluded that complete medical histories, analysis of red cell parameters, and peripheral blood smears were simple and inexpensive tools that can be helpful in settings with limited resources.[23]

Bone Marrow Biopsy and Aspiration

Bone marrow biopsy and aspiration are performed to determine whether the marrow is functioning adequately and also may reveal replacement of marrow with tumor, granuloma, or fibrosis. The bone marrow should be obtained before any vitamin B-12 or folate therapy or blood transfusion because megaloblastic changes may reverse rapidly.

The bone marrow in megaloblastic anemias is usually hypercellular, with all cell lines proliferating. Marked erythroid hyperplasia may occur to the point at which the myeloid-erythroid ratio is reversed. Nuclear-chromatin dissociation with a young-appearing nucleus and abundant mature-appearing cytoplasm may occur. Granulocytic hyperplasia with giant metamyelocytes and bands is often noted.

Histologic Findings

On peripheral blood smear, large RBCs are evident. Depending on the etiology of the macrocytosis, peripheral smear may reveal nucleated RBCs, target cells, RBC fragments, hypersegmentation of neutrophils, immature WBCs, large platelets, or pancytopenia.

Depending on the etiology of the macrocytosis, the marrow may reveal hypercellularity, megaloblastic changes, fibrosis, infiltration by tumor or granulomatous disease, leukemic changes, or erythroid hyperplasia.

Approach Considerations

Evaluation usually can be performed on an outpatient basis. Medical treatment depends on the etiology of the macrocytosis, the presence and severity of anemia, and the symptoms and physical findings. Hematologic and oncologic consultation should be obtained as necessary. After the appropriate laboratory studies are obtained, the symptomatic anemic patient may undergo transfusion with packed red blood cells (RBCs).

If a drug is thought to be the cause of the macrocytic anemia, especially if hemolysis is occurring, discontinue administration of the offending drug. If the patient is suspected of abusing alcohol, counsel abstention.

Patients deficient in vitamin B-12 or folate should receive replacement therapy.[24] Folate 1 mg/day may be prescribed in patients with folate deficiency. Intramuscular vitamin B-12 injections (100-1000 mcg/mo), continued indefinitely, may be prescribed.

Treat malignancies, granulomatous diseases, and chronic obstructive pulmonary disease (COPD) according to the standards appropriate for each. Hospitalization may be required to treat some causes of macrocytosis, especially acute leukemias. Outpatient follow-up depends on the cause of the macrocytosis.

Diet

If folate or vitamin B-12 deficiency is the cause of the macrocytosis, modify the diet to include foods rich in these vitamins. Red meat is a good source of vitamin B-12, and green leafy vegetables are excellent sources of folate. Do not provide folate supplementation without vitamin B-12 replacement therapy in any patient with vitamin B-12 deficiency or with suspected vitamin B-12 deficiency; doing so may precipitate subacute combined degeneration of the spinal cord.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Folic acid (Folacin-800)

Clinical Context:  Folic acid is an important cofactor for enzymes used in the production of red blood cells (RBCs).

Vitamin B-12 (CaloMist, Nascobal, Ener-B)

Clinical Context:  Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 is synthesized by microbes but not by humans or plants. Vitamin B-12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.

Multivitamins (M.V.I.-12, Infuvite)

Clinical Context:  Multivitamins are used as dietary supplements.

Class Summary

In macrocytosis associated with vitamin deficiencies, the deficient vitamin is replaced to meet necessary dietary requirements. Used in metabolic pathways, DNA and protein synthesis.

What is macrocytosis?What are the causes of macrocytosis?What is the pathophysiology of macrocytosis?What is the role of hydroxyurea in the pathophysiology of macrocytosis?What is the pathophysiology of macrocytosis in HIV-infected patients?What are nonmegaloblastic macrocytic anemias?What is the role of reticulocytes in the pathogenesis of macrocytosis?What is the role of alcoholism to the development of macrocytosis?What is the role of vitamin B-12 deficiency in the etiology of macrocytosis?What are the causes of folate deficiency leading to macrocytosis?Which inherited disorders of DNA synthesis lead to macrocytosis?Which drugs cause macrocytosis?What is the role of tyrosine kinase inhibitors in the etiology of macrocytosis?What is reticulocytosis?Which refractory anemias may cause macrocytosis?What are possible etiologies of macrocytosis?What are the signs and symptoms of macrocytosis?How does alcohol abuse lead to the development of macrocytosis?Which physical findings are characteristic of macrocytosis?Why is it important to determine the etiology of macrocytosis?What are the differential diagnoses for Macrocytosis?What is the role of lab studies in the workup of macrocytosis?What is the role of bone marrow biopsy in the workup of macrocytosis?Which histologic findings indicate macrocytosis?What are the treatment options for macrocytosis?What dietary modifications are used in the treatment of macrocytosis?What is the goal of drug treatment for macrocytosis?Which medications in the drug class Vitamins are used in the treatment of Macrocytosis?

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

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

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. Moore CA, Adil A. Anemia, Macrocytic. 2017 Jun. [View Abstract]
  2. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009 Feb 1. 79(3):203-8. [View Abstract]
  3. 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. [View Abstract]
  4. 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. [View Abstract]
  5. Younes M, Dagher GA, Dulanto JV, Njeim M, Kuriakose P. Unexplained macrocytosis. South Med J. 2013 Feb. 106(2):121-5. [View Abstract]
  6. Rumsey SE, Hokin B, Magin PJ, Pond D. Macrocytosis--an Australian general practice perspective. Aust Fam Physician. 2007 Jul. 36(7):571-2. [View Abstract]
  7. 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. [View Abstract]
  8. Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. Lancet. 1974 May 4. 1(7862):829-31. [View Abstract]
  9. 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. [View Abstract]
  10. 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. [View Abstract]
  11. 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. [View Abstract]
  12. Schallier D, Trullemans F, Fontaine C, Decoster L, De Greve J. Tyrosine kinase inhibitor-induced macrocytosis. Anticancer Res. 2009 Dec. 29 (12):5225-8. [View Abstract]
  13. 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. [View Abstract]
  14. Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar. 18(1):41-3. [View Abstract]
  15. Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol. 1980 Dec. 74(6):797-800. [View Abstract]
  16. 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. [View Abstract]
  17. 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. [View Abstract]
  18. 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. [View Abstract]
  19. 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. [View Abstract]
  20. 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. [View Abstract]
  21. 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. [View Abstract]
  22. 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. [View Abstract]
  23. Veda P. Evaluation of macrocytosis in routine hemograms. Indian J Hematol Blood Transfus. 2013 Mar. 29(1):26-30. [View Abstract]
  24. 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. [View Abstract]