A 46-year-old man who lives in Tacoma, Wash., is seen for fatigue. He has a no significant past medical history. He is not taking any medications. His physical exam is unremarkable. His hemoglobin is 12 gm/dL, hematocrit is 37 gm/dL, mean corpuscular volume (MCV) is 103 fL, and thyroid-stimulating hormone level is 1.2 mU/L.
What workup do you recommend?
A) B12, folate testing
B) Alcohol history, B12, folate testing
C) Alcohol history, B12 testing
I would choose doing a careful alcohol history and vitamin B12 testing.
Dr. Seppä and colleagues looked at all outpatients who had a blood count done over an 8-month period.1 A total of 9,527 blood counts were ordered, and 287 (3%) had macrocytosis.1 Further workup 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). In several studies, vitamin B12 deficiency was the cause of macrocytosis in 5%-7% of patients.2,3
In 1978, a study by Davidson and Hamilton looked at 200 consecutive patients with MCVs over 100, and were able to find a cause in 80%.4 Sixteen of these patients had a low B12 level and 10 had a low folate level.
In 1998, the Food and Drug Administration required folic acid fortification of enriched grain products in the United States to help decrease the risk of neural tube defects. Similar fortification efforts were undertaken in Canada. Since 1998, anemia due to folate deficiency has essentially disappeared in individuals who have access to fortified grain products.
Joelson and colleagues looked at data on folate testing from the year prior to fortification of the grain supply (1997) and after (2004).5 They found that, in 1997, 4.8% of tests had a folate level less than 160 ng/mL compared with only 0.6% of tests in 2004.
When a more stringent cutoff for deficiency was used (94 ng/mL) 0.98% of tests were below that level in 1997, and 0.09% in 2004. The mean RBC folate level in 1997 was 420 ng/mL and rose to 697 ng/mL in 2004. Of the patients who did have low folate levels, only a minority had elevated MCVs.
Shojania et al. looked at folate testing in Canada after widespread fortification had started.6 They found that 0.5% of 2,154 serum folate levels were low and 0.7% of 560 red blood cell folate levels were low. Folate deficiency was not the cause of anemia in any of the patients with low folate levels.
Theisen-Toupal and colleagues did a retrospective study looking at folate testing over an 11-year period after fortification.7 The researchers examined the results of 84,187 assessments of folate levels. Forty-seven (0.056%) of the tests found patients with folate deficiency, 166 (0.197%), found patients with low-normal folate levels, 57,411 (68.195%) of tests yielded normal results, and 26,563 (31.552%) of tests found high folate levels. The opinion of the authors was that folate testing should be severely reduced or eliminated. Furthermore, the American Society for Clinical Pathology, as part of the Choosing Wisely campaign, states: “Do not order red blood cell folate levels at all.”8
So what does this all mean? We have been taught to have a reflex response to the evaluation of macrocytosis to test for B12 and folate. Neither of these are particularly common causes of macrocytosis, and in countries where there is grain fortification, folate deficiency is exceedingly uncommon, and should not be tested for early in any diagnostic process.
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 of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at.
1. Seppä K et al. Evaluation of macrocytosis by general practitioners..
2. Seppä K et al. Blood count and hematologic morphology in nonanemic macrocytosis: Differences between alcohol abuse and pernicious anemia..
3. Wymer A, Becker DM. Recognition and evaluation of red blood cell macrocytosis in the primary care setting..
4. Davidson RJ, Hamilton PJ. High mean red cell volume: Its incidence and significance in routine haematology..
5. Joelson DW, Fiebig EW. Diminished need for folate measurements among indigent populations in the post folic acid supplementation era..
6. Shojania AM, von Kuster K. Ordering folate assays is no longer justified for investigation of anemias, in folic acid fortified countries. BMC Res Notes. 2010 Jan 25;3:22..
7. Theisen-Toupal et al. Low yield of outpatient serum folate testing. JAMA Intern Med. 2014 Oct..
8. Choosing Wisely: American Society for Clinical Pathology, Oct. 19, 2017.