Smoking as an independent risk factor for macrocytosis in middle‐aged adults: A population‐based observational study
Authors: Maeve a. O'Reilly, Seán R. Millar, Claire M. Buckley, Janas M. Harrington, Ivan J. Perry, Mary R. Cahill
Journal: American Journal of Hematology (2015)

Mean corpuscular volume (MCV) is a measure of the average volume of red blood cells. The detection of an elevated MCV, termed macrocytosis (with or without anemia), often prompts an extensive and costly work-up for an underlying cause and/or referral to secondary care. Known determinants of macrocytosis listed in textbooks include vitamin B12 and folate deficiency, alcohol use (with or without associated liver disease), hemolysis, hypothyroidism, coeliac disease, drug use, and hematological conditions such as aplastic anemia, myelodysplasia, and myeloma. An association between smoking and elevated MCV has been reported from a number of studies since the 1970s 1-3. However, knowledge of this relationship, causal or otherwise, has not translated into clinical practice or been highlighted in any of the screening models for macrocytosis. In earlier research 4, which focused on the causes of hematinic deficiency in 1,207 Irish adults, we observed an unexpected independent association between smoking and macrocytosis. The current study examined the relationship between smoking and elevated MCV, with particular reference to the independence of this association of known risk factors for macrocytosis. We conducted a cross-sectional study involving a population representative random sample of 2,047 adults aged 46–73 years (49.2% male). Details regarding the study design, sampling procedures, and methods of data collection have been reported previously 5. Data on age, gender, education, and smoking and alcohol behaviors were gathered through a self-completed General Health Questionnaire. Blood samples, which included full blood counts, vitamin B12, folate levels, and gamma-glutamyltransferase (GGT), were analyzed on the day of sampling using automated Sysmex analysers (Sysmex Corporation, Kobe, Japan) in one accredited laboratory. Macrocytosis, was defined as an MCV level ≥99 fl. The threshold of 99 fl was chosen as it was deemed more likely to prompt investigation for an underlying cause or referral to tertiary care. In logistic regression analyses which adjusted for age and gender (Table I), smoking, regular alcohol use, vitamin B12 and folate deficiency, and deranged GGT were significantly associated with having an MCV level ≥99 fl. Chi-square testing also demonstrated an association between current smoking and the frequency of alcohol consumption (P = 0.003) and folate deficiency (P = 0.002). The population attributable fraction (PAF) estimates for current smoking and regular alcohol use as causes of macrocytosis were 57.1% (95% CI: 21.9%–76.4%) and 49.2% (95% CI: 5.6%–72.6%) respectively. In multivariable analysis (Supporting Information) which adjusted for age, gender, alcohol use, and other significant determinants, the relationship between smoking and macrocytosis persisted (Odds ratio: 6.0, 95% CI: 2.3–15.8, P < 0.001). This population-based study consolidates our previous findings and suggests that smoking may be an important causative factor for macrocytosis in middle-aged adults. In our analysis, compared with non-smokers, participants who smoked were six times more likely to have an MCV level ≥99 fl and there was evidence of intermediate effects (albeit non-significant) in former smokers. This strong and significant relationship persisted despite adjustment for other known macrocytosis risk factors. It is estimated that 21% of Irish adults are active smokers. In this population, smoking accounted for over half of the cases of macrocytosis. In current practice, B12 and folate deficiency are considered prominent causes of macrocytosis. However, in contrast to smoking, the prevalence of these deficiencies in our sample was low (2.4% and 1.5% respectively). Therefore, these findings suggest that smoking independently contributes to a greater prevalence of macrocytosis than previously believed. Research has indicated that cigarette smoking elevates MCV with some studies describing a dose–response relationship. However, in some of the previous studies, confounding due to alcohol intake cannot be discounted. McNamee et al. 4 were the first to highlight the importance of smoking relative to the most common causes of elevated MCV in a healthy general population sample. Our analysis in a separate study population of 2,047 middle-aged subjects has confirmed the impact of smoking, after adjustment for vitamin B12 and folate deficiency, liver disease, and alcohol use, as a significant risk factor for macrocytosis. Nevertheless, the pathogenesis of macrocytosis in smokers is currently unknown. Theories include a compensatory response to a reduced oxygen-carrying capacity (secondary to carbon monoxide and hypoxia) 2, the toxic effect of acetaldehyde in tobacco smoke 6, and a cyanide-induced functional vitamin B12 deficiency 3. This cross-sectional study has limitations which will need to be addressed in future work. In particular, it will be important to show in longitudinal analyses the effects of changes in smoking behavior on the occurrence of macrocytosis. Also, it was not possible to adjust for coeliac disease and hypothyroidism, which are recognized causes of macrocytosis. However, both of these conditions are uncommon and are unlikely to confound the association with smoking reported in the current study. As with many population-based studies, there is a concern that self-reported alcohol intake underestimates the true extent of excess in a community setting. Therefore, the possibility of residual confounding due to alcohol intake should be considered. Almost one-fifth of our sample had an elevated GGT, but a much smaller proportion admitted to alcohol use above the weekly recommended limit. Increased body mass index is also associated with abnormalities of GGT. Given that 78% of the participants were classified as either overweight or obese, this may account for the discrepancy. In summary, our research suggests that smoking is a significant risk factor for macrocytosis, independent of other known causes. This study serves to remind physicians of the potential impact of tobacco use on MCV. Smoking should be included in diagnostic algorithms for having an elevated MCV and addressed prior to hospital referral where other causes are excluded. Maeve A. O'Reilly1,2, Seán R. Millar2, Claire M. Buckley2, Janas M. Harrington2, Ivan J. Perry2, Mary R. Cahill1,2* 1Department of Haematology, Cork University Hospital, Cork, Ireland; 2Department of Epidemiology and Public Health, University College Cork, Cork, Ireland; Contract grant sponsor: Irish Health Research Board; Contract grant number: HRC/2007/13. Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.