Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary disease

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Abstract

Background and aims

Patients with chronic obstructive pulmonary disease (COPD) are at increased atherothrombotic risk. Preliminary findings have suggested that COPD patients may have increased plasma total homocysteine (tHcy), a cardiovascular risk factor often caused by a poor B vitamin status, but plasma levels of such vitamins were not measured. The aim of this study was to investigate hyperhomocysteinaemia in COPD and to determine whether it may be secondary to poor plasma concentrations of B vitamins.

Methods and results

We performed a case–control, cross-sectional study of 42 patients with COPD and 29 control subjects. Folate, vitamin B12, vitamin B6, tHcy, renal function, C-reactive protein, blood gases and lipids were measured in patients and controls. COPD patients had higher plasma tHcy (median: 13.9 μmol/l, interquantile range [IQR]: 12.1–18.5 versus 11.5, IQR: 10.1–14, p = 0.002) and lower circulating folate (median: 2.5 ng/ml, IQR: 1.2–3.3 versus 2.8, IQR: 2.1–4 of controls, p = 0.03) than controls had. Compared to the control group, COPD was associated with higher tHcy concentrations also after adjusting for smoking, heart failure, renal function and C-reactive protein with logistic regression analysis (OR 1.36, 95% CI 1.06–1.72, p = 0.01). In the COPD group, low levels of folate (β = −0.27, p = 0.02) and vitamin B12 (β = −0.24, p = 0.04), and hypertriglyceridaemia (β = 0.580, p < 0.0001) were independent predictors of the presence of high tHcy concentrations in a multiple linear regression model (adjusted R2 = 0.522).

Conclusion

COPD patients have a poor B vitamin status and, as a consequence, increased tHcy. These abnormalities may contribute to the COPD-related atherothrombotic risk.

Introduction

Recent studies have clearly established that chronic obstructive pulmonary disease (COPD), the fourth most common cause of death in the Western countries, is an independent risk factor for atherothrombotic disease, the first most common cause of death [1], [2]. Chronic bronchitis, a frequent clinical manifestation of COPD, is associated with a higher risk of myocardial infarction [3] and ischaemic stroke [4]. A low forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio is the spirometric signature of airflow obstruction. In the “Men Born in 1914” Study, subjects in the lowest quintile of FEV1/FVC ratio (≤66.3%) had a 73% higher risk of coronary events than had the persons in the highest FEV1/FVC quintile (≥77.3%) [1]. In a recent meta-analysis, the relative risks of death for coronary events and for all cardiovascular events in subjects with the lowest FEV1 compared to those with the highest FEV1 were 5.65 and 3.36, respectively [2].

In addition to the risk of atherothrombosis that is related to the stable phase, COPD exacerbations may be complicated by venous thromboembolism and represent a strong indication to a treatment with low molecular weight heparin to prevent pulmonary embolism [5].

Systemic inflammation [6], platelet activation and increased blood coagulation [7], commonly observed in COPD, may increase the risk of arterial and venous thrombosis. Systemic inflammation is presumably the most important mechanism of atherothrombosis in COPD and was attributed to the “spilling over” of inflammatory mediators from the lungs into the systemic circulation [6], [7]. In a recent trial, however, the administration of fluticasone, an inhaled corticosteroid, was not able to attenuate systemic inflammation [8]. Therefore, research is currently needed for identifying other potentially treatable mechanisms of atherothrombosis in COPD.

Total homocysteine (tHcy), a sulphur-containing amino acid, is an intermediate product of the metabolism of methionine [9]. Mild-to-moderate hyperhomocysteinaemia (HHcy) is relatively common in the general population, mainly in association with deficiencies of B vitamins, which are essential cofactors in tHcy catabolism. Other main causes of HHcy are renal impairment, aging, hypertension, some drugs (including theophyllines) and a common polymorphism in the methylenetetrahydrofolate-reductase gene [9]. A growing body of evidence suggests that HHcy is associated with an increased cardiovascular risk [10]. Despite this evidence, in some recent randomized controlled trials the rate of cardiovascular events was not reduced by a B vitamin supplementation [11], [12]. These trials were planned when the association between HHcy and cardiovascular events was deemed to be stronger and, thus, they have been criticized for the insufficient statistical power to detect significant changes [13]. In these studies, however, participants with HHcy were confirmed to have higher cardiovascular risk, thus suggesting that HHcy is at least a useful “risk marker” [11], [12].

Increased tHcy levels have been reported in three small COPD groups compared to people without the disease [14], [15], [16]. Indeed, COPD is characterized by complex nutritional abnormalities [17], potentially including lower levels of B vitamins that, in turn, may lead to HHcy. The status of B vitamins in COPD, however, was never investigated [14], [15], [16]. In this study, we measured plasma levels of B vitamins and tHcy in patients with COPD and matched non-COPD subjects to determine whether a poor B vitamin status could lead to HHcy in COPD.

Section snippets

Methods

We enrolled 42 COPD patients and 29 non-COPD subjects. According to previous studies [13], [14], [15], we computed the minimum sample size with respect to a two-tailed one-sample Student's t-test, considering (i) difference in mean tHcy between COPD patients and controls (δ) of 3.0 μmol/l, (ii) standard deviations of 2.5, (iii), type I error probability α = 0.05 and power 1  β = 0.90. This resulted in a minimum sample size of n = 16 for each group.

COPD patients were consecutively recruited in 2002 from

HHcy in COPD

Clinical and laboratory characteristics of COPD and non-COPD subjects are shown in Table 1. Patients with COPD had higher concentrations of tHcy and lower concentrations of folic acid compared to non-COPD subjects (Table 1). In the overall study sample of 71 subjects (42 COPD patients + 29 controls), levels of tHcy were inversely correlated with FEV1% (r = −0.28, p = 0.017) and FEV1/FVC (r = −0.36, p = 0.002).

The prevalence rates of co-morbid diseases and use of respiratory drugs in the two groups are

Discussion

Our study demonstrated for the first time that COPD patients have reduced plasma concentrations of B vitamins, and that this abnormality is the main factor responsible for the COPD-related HHcy [14], [15], [16]. Also, this is the largest study investigating the influence on plasma tHcy concentrations of some important clinical factors – such as B vitamins, renal function, airflow obstruction, CRP, smoking status, arterial oxygen tension, lipids and co-morbid diseases – in a well-defined group

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