**1. Introduction**

20 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

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Homocysteine was first described by Butz and du Vigneaud in 1932 (Butz 1932). An association between elevated homocysteine levels and human disease was first suggested in 1962 by Carson and Neil (Carson 1962). They had found high homocysteine concentrations in the urine of some children with mental retardation.

In 2000, Yi and Melnyk found that plasma total homocysteine is positively associated with parallel increases in plasma S-adenosylhomocysteine and concentrations and lymphocyte DNA hypomethylation. This lead Medina and Urdiales (2001) to speculate on an indirect mechanism for homocysteine pathogenicity secondary to inhibition of DNA methytransferase and that is the disruption of DNA methylation patterns leading to alterations in gene expression which may be of significance in chronic diseases many of which are associated with elevation in homocysteine. Elevated plasma homocysteine has been associated with neural tube defects, cognitive impairment in the elderly, psoriasis and some tumours (Refsum 1998). Hyperhomocysteinaemia has also been associated with cardiovascular disease, atherosclerosis, venous thrombosis, diabetes mellitus and renal failure (Okuyan et al, 2010; Refsum et al, 1998; Givvimani et al, 2011; Kim et al, 2011; Hankey & Eikelboom, 1999; Dominguez et al, 2010; Wile et al, 2010; Austen et al, 2003). Plasma HCY has also been related to clinical outcome in acute respiratory diseases (Tsangaris et al, 2009). This widespread involvement of homocysteine in disease explains the current interest of both basic and clinical biomedical scientists in this amino acid and thus the explosion of articles containing homocysteine as keyword.

There has hitherto not been much interest in homocysteine disorders in respiratory disease. Sanguinetti was one of the first researchers to postulate that there was an imbalance between redox reactions in COPD (Sanguinetti 1993). In an elegant series of experiments, Rahman et al showed that reduced glutathione was depleted by exposure to cigarette smoke in alveolar epithelial cells (Rahman et al 1995). Further work by this group revealed that there is loss of antioxidant capacity in COPD relative to healthy non-smokers (Rahman et al

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Homocysteine is Elevated in COPD 23

Fig. 1. Modified from Tehlivets (2011). The Figure shows the linkage between HCY and

Human plasma contains both free homocysteine (HCY) and its oxidised form, homocystine (HCY-HCY), where two molecules are bound via a disulphide bond. About 99% of

glutathione.

**3. Measurements of homocysteine** 

2000). These results were supported by Andersson who showed that high plasma homocysteine levels were associated with low reduced glutathione levels in 2000 in the plasma of COPD patients (Andersson 2000). Thus establishing an almost inverse relation between the levels of homocysteine and reduced glutathione and giving rise to the hypothesis that homocysteine should be elevated in COPD because of impaired oxidative stress. Taken together this series of studies demonstrate that COPD, the most common chronic respiratory disorder, is linked to hyperhomocysteinaemia.

Chronic obstructive pulmonary disease is a disease mainly of the middle-aged and elderly. It results from an abnormal pro-inflammatory response of the lung to inhaled noxious stimuli that leads to an unrelenting accelerated decline in forced expiratory volume in the first second of exhalation (FEV1) and is characterised by a ratio of FEV1 to forced vital capacity (FVC) of less than 70%. The disease is currently estimated as the fourth leading cause of death world-wide and it is expected to become the third leading cause within the next ten years (GOLD 2010).

In this chapter we will examine the evidence for the association of hyperhomocysteinaemia and COPD and discuss its implications.
