Active smoking and macrocytosis in the general population: Two population‐based cohort studies


Importance: Macrocytosis is an elevated mean corpuscular volume (MCV) of erythrocytes, and frequently observed in the general population. Major established causes are vitamin B12 deficiency, folate deficiency, liver disease, myeloid dysplastic syndromes, and alcohol use. Several decades ago, a few papers described an unexpected positive association between smoking and MCV, however failure to comply has resulted in absence of smoking as determinant of macrocytosis nowadays in textbooks and guidelines.

Main Outcome(s) and Measure(s): The association between smoking and MCV and macrocytosis.

Results:In the Lifelines cohort (including 131,886 (age 45±13 years, 40% males) participants), and in the PREVEND cohort (including 6,808 (age 53±12 years, 50% males) participants), current smoking, compared to non-smoking, was strongly associated with MCV (β=0.23, P<.001 and β=0.24, P<.001, respectively), and macrocytosis (OR, 6.25, 95% CI 5.21 to 7.51; P<.001 and OR 8.54, 95% CI 2.57 to 28.37; P<.001, respectively), independent of adjustment for potential confounders, including age, seks, eGFR,        BMI, hs-CRP, alcohol use, gamma-GT, ALAT, FT4, vitamin B12, and folic acid. Similarly,    in sensitivity analyses, 24-hour urinary cotinine excretion, as objective measurement of nicotine exposure, was associated with MCV (β=0.23, P<.001), independent of adjustment for potential confounders.

Background/objectives: In this study, we aimed to investigate the association of smoking with MCV.

Design: Cross-sectional study.

Setting: Population-based cohort studies.

Participants: We used data from two large prospective population-based cohorts, i.e. the Lifelines cohort and the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Smoking behavior was quantified as number of cigarettes smoked per day. In addition, in the PREVEND study 24-hour urinary cotinine excretion levels were measured as objective and quantitative measure of nicotine exposure.

Conclusions: In conclusion, smoking is a prominent determinant of macrocytosis independent of known causes, including alcohol use, vitamin B12 and folate deficiency. Inclusion of smoking as determinant of macrocytosis in current guidelines seems warranted.

year of publication



  • American Journal of Hematology


  • Eisenga, MF
  • Wouters, HJCM
  • Kieneker, LM
  • Klauw van der, M
  • Meer van der, P
  • Wolffenbuttel, BHR
  • et al.

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