Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin deficiencies (especially B12 deficiency), and liver function tests (SOR: B, inconsistent prospective cohort studies)

Hitchcock, Kristin

Holt, S. Naomi

Oh, Robert C.

University of Missouri: MOspace

CLINICAL INQUIRIES Evidence Based Answers from the Family Physicians Inquiries Network548 VOL 57, NO 8 / AUGUST 2008  THE JOURNAL OF FAMILY PRACTICEFAST TRACK  How do you evaluate macrocytosis without anemia?Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin defi ciencies (especially B12 defi ciency), and liver function tests (SOR: B, inconsistent prospective cohort studies). Thyroid testing may be useful for older patients (SOR: B, prospective study). Reticulocyte count and bone marrow evaluation, although important to rule out hemolysis and myelodysplastic changes, may not be necessary for patients with isolated macrocytosis without anemia (SOR: B, prospective cohort studies). In unexplained macrocytosis, bone marrow evaluation may show early marrow changes, particularly in the elderly (SOR: B, prospective cohort study).Evidence-based answerClinical commentaryWhen the cause isn’t clear, think alcoholMacrocytosis without anemia is not that rare, in my experience, and the cause usually becomes clear with a medication history and a few laboratory tests, such as vitamin B12 studies and thyrotropin. When I see a patient with macrocytosis without an obvious cause, I think of alcohol use.  Sometimes the only hint of a larger underlying problem is overlooked or passed off as a minor laboratory variation amid other normal results. On more than one occasion, I have been able to unmask an occult drinking problem by paying attention to this parameter on the complete blood count. This Clinical Inquiry is a good lesson in understanding the implications of all of the parameters of a CBC, not focusing just on the traditional white blood cell count, hematocrit and hemoglobin, and platelet counts. Grant Hoekzema, MDMercy Family Medicine Residency, St. Louis, Mo❚ Evidence summarySignifi cant macrocytosis is usually defi ned as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.1-4 As many as 60% to 80% of primary care patients may not have anemia.3,4 Because no study has looked spe-cifi cally at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of mac-rocytosis (with and without ane-mia) must help guide evaluation.1,3,5-7 The causes of macrocytosis vary de-pending on the population studied (TABLE). In primary care, alcohol use and vitamin defi ciency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.3Robert C. Oh, MD, MPH, and S. Naomi Holt, MDTripler Army Medical Center, Honolulu, Hawaii Kristin Hitchcock, MSIDepartment of Preventive Medicine, Northwestern University, ChicagoWhen I see a patient with macrocytosis without an obvious cause, I think of alcohol use548_JFP0808   548 7/17/08   2:43:14 PMCopyright® Dowden Health Media  For personal use onlyFor mass reproduction, content licensing and permissions contact Dowden Health Media.FAST TRACK VOL 57, NO 8 /AUGUST 2008 549www.jfponline.comAlthough hypothyroidism rarely causes macrocytosis, it may be more prevalent in the elderlyClues in the history, physical exam, and lab resultsA history focusing specifi cally on alcohol use and medications—especially chemo-therapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocy-tosis. During the physical examination, look for signs consistent with chronic liver disease. Laboratory studies can help iden-tify vitamin defi ciencies, liver disease, and thyroid disease. A normal serum B12 level may not rule out a true B12 defi ciency, but normal levels of the metabolites methyl-malonic acid and homocysteine do essen-tially rule it out.8 In this era of folic acid fortifi cation, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a defi ciency when B12 defi -ciency has been ruled out.7,9 Liver disease—which may be con-founded by alcohol abuse, medications, or cancer—is a common cause of macrocyto-sis.5 Hypothyroidism is rarely a cause, but may be more prevalent in the elderly.10What these 2 tests may, or may not, tell you Although several authorities recommend a peripheral smear and reticulocyte count to help evaluate macrocytic anemia, no specifi c recommendations exist for these tests in the absence of anemia. A pe-ripheral smear can detect megaloblastic changes typical of B12 and folate defi cien-cy and other marrow disorders, especial-ly myelodysplastic changes. Peripheral smear fi ndings and reticulocytosis can also show evidence of hemolysis. How-ever, megaloblastic changes and marrow-related changes on peripheral smear are typically seen with anemia. In 2 prospective studies of primary care patients, 1 reported little diagnostic value for the peripheral smear,1 and the other found that reticulocytosis rarely caused macrocytosis.5 A prospective study of 300 hospitalized patients with macro-cytosis found that 100% of marrow dis-orders and hemolysis that caused macro-cytosis also caused an associated anemia.7 A retrospective chart review of 113 cases of macrocytosis in outpatients found that general practitioners often didn’t order a peripheral smear and reticulocyte count to complete their diagnostic workups.4Bone marrow biopsy may reveal dysplastic changes, but not a DxA prospective study of the utility of bone marrow biopsy in 124 elderly patients with macrocytosis found that as many Have a comment on an article, editorial, illustration, or department? Drop us a line and let us know what you think. You can send a letter 1 of 3 ways.Letters should be addressed to the Editor, The Journal of Family Practice, and be 200 words or less. They may be edited prior to publication.Fax201-391-27782MailThe Journal of Family Practice110 Summit Ave.Montvale, NJ 076453E-mailjfp@fammed.uc.edu 1We want to hear from you!Please take a moment to share your opinion!549_JFP0808   549 7/17/08   2:43:18 PMFAST TRACKCLINICAL INQUIRIES550 VOL 57, NO 8 / AUGUST 2008  THE JOURNAL OF FAMILY PRACTICEas 60% were diagnosed by blood tests alone. All the remaining patients with un-explained macrocytosis underwent bone marrow biopsy, which showed early dys-plastic changes in 39%, but did not pro-vide a diagnosis in nearly 50%. Twelve percent were found to have myelodys-plastic syndrome, but they had a mean hemoglobin of 8.5 g/dL.10RecommendationsWe were unable to fi nd published guide-lines for the evaluation of macrocytosis without anemia by the American Soci-ety of Hematology, the British Commit-tee for Standards in Haematology, or in an authoritative hematology text.11 ■ AcknowledgmentsThe views expressed in this article are those of the au-thors and do not refl ect the offi cial policy or position of the Department of the Army, Department of Defense, or the US Government.References 1.  Breedveld FC, Bieger R, van Wermeskerken RKA. The clinical signifi cance of macrocytosis. Acta Med Scand. 1981;209:319-322.  2.  Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting. J Gen Intern Med. 1990;5:192-197.  3.  Colon-Otero G, Menke D, Hook CC. A practical ap-proach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia. Med Clin North Am.1992;76:581-597.  4.  Seppa K, Heinila K, Sillanaukee P, et al. Evaluation of macrocytosis by general practitioners. J Stud Alcohol. 1996;57:97-100.  5.  Keenan WF. Macrocytosis as an indicator of hu-man disease. J Am Board Fam Pract. 1989;2:25-26.  6.  Davidson RJL, Hamilton PJ. High mean red cell volume: its incidence and signifi cance in routine haematology. J Clin Pathol. 1978;31:493-498. 7.  Savage DG, Ogundipe A, Allen RH, et al. Etiology and diagnostic evaluation of macrocytosis. Am J Med Sci. 2000;319:343-352.  8.  Cravens DD, Nashelsky J, Oh RC. How do we evaluate a marginally low B12 level? J Fam Pract. 2007;56:62-63.  9.  Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med. 2001;110:88-90.  10.  Mahmoud MY, Lugon M, Anderson CC. Unex-plained macrocytosis in elderly patients. Age Age-ing. 1996;25:310-312.  11.  Hoffman R, Benz EJ, Shattil SJ. Hematology: Ba-sic Principles and Practice. 4th ed. Philadelphia: Churchill Livingstone; 2005. As many as 60% of elderly patients with macrocytosis were diagnosed by blood test aloneCauses of macrocytosis: What prospective studies showCAUSE PERCENT OF PATIENTS BY STUDYDAVIDSON6 (N=200)BREEDVELD1 (N=70)KEENAN5(N=80)SAVAGE7(N=300)MAHMOUD10 (N=124)Alcohol 18 27 36 26 14Vitamin deﬁ ciency 13 39 (6% had both defi ciencies)16 6 24B12 8 23 10 5 12Folate 5 10 6 1 12Medications 30 1 —* 37 2Liver disease 16 3 9 6 2Hematologic disease15 19 14 14 20Malignancy/premalignancy15 13 11 6 20Reticulocytosis 0 6 3 8 —†Hypothyroidism —† 3 6 1 12Unexplained 23 9 28 7 19* Excluded patients on cytotoxic and chemotherapeutic medications† Not evaluated.TABLE550_JFP0808   550 7/17/08   2:43:23 PM

How do you evaluate macrocytosis without anemia?

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