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What is causing my patients' macrocytosis?

A 56-year-old man presents for his annual physical. He brings in blood work done for all employees in his workplace (he is an aerospace engineer), and wants to talk about the lab that has an asterisk by it. All his labs are normal, except that his mean corpuscular volume (MCV) is 101. His hematocrit (HCT) is 42. He has no symptoms and a normal physical exam.

What test or tests would most likely be abnormal?

A. Thyroid-stimulating hormone.

B. Vitamin [B.sub.12]/folate.

C. Testosterone.

D. Gamma-glutamyl-transferase (GGT).

The finding of macrocytosis is fairly common in primary care, estimated to be found in 3% of complete blood count results. (1) Most students in medical school quickly learn that vitamin [B.sub.12] and folate deficiency can cause macrocytic anemias. The standard work-ups for patients with macrocytosis began and ended with checking vitamin [B.sub.12] and folate levels, which are usually normal in the vast majority of patients with macrocytosis.

For this patient, the correct answer would be an abnormal GGT, because chronic moderate to heavy alcohol use can raise GGT levels, as well as MCVs.

David Savage, MD, and colleagues evaluated the etiology of macrocytosis in 300 consecutive hospitalized patients with macrocytosis. (2) They found that the most common causes were medications, alcohol, liver disease, and reticulocytosis. The study was done in New York and was published in 2000, so zidovudine (AZT) was a common medication cause of the macrocytosis. This medication is much less commonly used today. Zidovudine causes macrocytosis in more than 80% of patients who take it. They also found in the study that very high MCVs (>120) were most commonly associated with vitamin [B.sub.12] deficiency.

Kaija Seppa, MD, and colleagues looked at all outpatients who had a blood count done over an 8-month period. A total of 9,527 blood counts were ordered, and 287 (3%) had macrocytosis. (1) Further work-up was done for 113 of the patients. The most common cause found for macrocytosis was alcohol abuse, in 74 (65%) of the patients (80% of the men and 36% of the women). No cause of the macrocytosis was found in 24 (21%) of the patients.

A. Wymer, MD, and colleagues looked at 2,800 adult outpatients who had complete blood counts. A total of 138 (3.7%) had macrocytosis, with 128 of these patients having charts that could be reviewed. (3) A total of 73 patients had a work-up for their macrocytosis. Alcohol was the diagnostic cause of the macrocytosis in 47 (64%). Only five of the patients had [B.sub.12] deficiency (7%).

Dr. Seppa and colleagues also reported on hematologic morphologic features in nonanemic patients with macrocytosis due to alcohol abuse or vitamin [B.sub.12] deficiency. (4) They studied 136 patients with alcohol abuse and normal [B.sub.12] levels, and 18 patients with pernicious anemia. The combination of a low red cell count or a high red cell distribution width with a normal platelet count was found in 94.4% of the vitamin-deficient patients but in only 14.6% of the abusers.

Patients with unexplained macrocytosis should be followed for the development of a primary bone marrow disorder. Mohamad Younes, MD, and colleagues followed 43 patients with unexplained macrocytosis, and found that 11.6% developed a primary bone marrow disorder, and 16% developed worsening cytopenia, over 4 years. (5) This is especially important to consider in older patients, among whom myelodysplastic syndromes are more common.

Pearl: Strongly consider alcohol as the cause of the incidental finding of macrocytosis, especially in patients without anemia.


(1.) J Stud Alcohol. 1996Jan;57(1):97-100.

(2.) AmJ Med Sci. 2000 Jun;319(6):343-52.

(3.) J Gen Intern Med. 1990 May-Jun;5(3):192-7.

(4.) Alcohol. 1993 Sep-Oct;10(5):343-7.

(5.) South Med J. 2013 Feb;106(2):121-5.


Caption: Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the university. Contact Dr. Paauw at

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Title Annotation:Pearl of the Month
Author:Paauw, Douglas S.
Publication:Internal Medicine News
Date:Jun 1, 2018
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