Macrocytosis: A Metabolic Marker?
Authors: O'Reilly Maeve A , Harrington Janas M , Buckley Claire M , O'Shea Susan , Perry Ivan J , Cahill Mary R 
Published: October 2019

Introduction
The metabolic syndrome (MS) as a disease entity rarely captures the attention of a clinical haematologist. The prevalence of the MS in the Irish population is estimated at 20% (Villegas et al. Prevalence and lifestyle determinants of the metabolic syndrome. Ir Med J. 2004; 97(10): 300-303). While insulin resistance is implicated, the pathogenesis uniting the components of the syndrome remains unclear. In an additional study from our group (O’Reilly et al. Submitted ASH 2013), we demonstrated an independent association between the MS and clinically significant macrocytosis (mean corpuscular volume≥99fl). In this study we estimated the population attributable fraction for macrocytosis associated with the MS at 13.8%. To our knowledge this link has not been reported previously in the literature.

Aims
To study the determinants of clinically significant macrocytosis with particular reference to the independent effects of the MS and its individual components in a cohort of 2,047 Irish patients aged 50-69 years sampled from a primary care centre (Mitchelstown Cohort).

Methods
Details of the methods of the Mitchelstown Cohort study including sampling and recruitment have been described (Kearney et al. Int. J. Epidemiol. (2012) doi: 10.1093/ije/dys131). The study is based in a large primary care centre serving a defined population in Southern Ireland. 66% of eligible patients participated in this study. The metabolic syndrome was defined using the International Diabetes Federation (IDF) 2006 criteria. Systolic and diastolic blood pressures (average of 3 readings), body mass index (BMI) and waist circumferences were measured. A pre-existing diagnosis of hypertension or type II diabetes and use of anti-hypertensive or lipid-lowering agents was recorded. Smoking status and alcohol intake were recorded using a validated questionnaire. Vitamin B12 and folate levels, fasting plasma glucose (FPG), HbA1c and lipid profiles, liver function and full blood counts were measured using standard automated analysers. Statistical analysis was performed using Stata©. Multivariate logistic regression was used to estimate prevalence odds ratios with 95% Confidence Intervals (OR, 95%CI) for macrocytosis and its potential determinants, including the MS and its constituent components.

Results
The prevalence of clinically significant macrocytosis (MCV≥99fl) in this sample of 2,047 patients was 1.6%. The prevalence of the MS was 31%, B12 deficiency 2.4%, folate deficiency, 1.5%, elevated gamma-glutamyltransferase (GGT), 18%, elevated alanine aminotransferase (ALT), 8%, elevated aspartate aminotransferase (AST), 4.7% and current smoking status, 15%. With respect to the IDF criteria, in univariate analyses, hypertension and elevated triglycerides (TG) were significantly associated with an MCV≥99fl (p=0.04, p=0.03 respectively). Central obesity, BMI, elevated FPG and low HDL did not reach significance. Self-reported alcohol intake was also non-significant. In multivariate logistic regression analysis with adjustment for age and gender the following variables were significantly associated with MCV ≥99fl; elevated TG OR 2.3 (95%CI 1.1-4.7), MS OR 3.4 (95% CI 1.6-6.9), vitamin B12 deficiency OR 6.1 (95% CI: 2.0-18.4), folate deficiency OR 8.2 (95% CI 2.3-29.0), elevated GGT OR 2.3 (95% CI 1.0-4.9), elevated AST OR 8.0 (95% CI 3.5-18.5) and current smoking status OR 6.0 (95% CI 2.8-12.5). In further analyses adjusting for age, gender and all other significant variables, the association between the MS and macrocytosis persisted, OR 3.0 (95%CI 1.3-6.9). Isolated elevated TG was no longer significant. The association between macrocytosis and elevated GGT was attenuated following adjustment for the MS.

Conclusions
In this study we observed an independent association between macrocytosis and the MS. Non-alcoholic fatty liver disease (NAFLD), with a clinical spectrum ranging from steatosis to steatohepatitis and cirrhosis, is strongly linked to the MS. However we have demonstrated an association independent of abnormal liver indices. As the obesity epidemic escalates worldwide, haematologists should consider its potential impact on red cell mean corpuscular volume. Additional research is needed to determine the effects of this cluster of metabolic disturbances on erythropoiesis.

Disclosures:
No relevant conflicts of interest to declare.