- Author: Vincent E Herrin, MD, FACP; Chief Editor: Emmanuel C Besa, MD more...
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. 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.
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, 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.
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.
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.
Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician. 2009 Feb 1. 79(3):203-8. [Medline].
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].
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].
Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. Lancet. 1974 May 4. 1(7862):829-31. [Medline].
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].
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].
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].
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].
Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar. 18(1):41-3. [Medline].
Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol. 1980 Dec. 74(6):797-800. [Medline].
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].
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].
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].
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].
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].
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].
Veda P. Evaluation of macrocytosis in routine hemograms. Indian J Hematol Blood Transfus. 2013 Mar. 29(1):26-30. [Medline]. [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. [Medline].