**11. Homocysteine elevation in COPD: Pathogenesis or epiphenomenon?**

Three studies shave shown that HCY is elevated in COPD relative to asymptomatic controls. The Kai et al study showed that COPD patients with a high HCY were likely to have faster

populations and treatment groups and has been shown to be responsive when used for these comparisons (Jones et al, 1991; Jones & Lasserson, 1994). The Symptoms score assesses the degree of distress due to frequency and severity of respiratory symptoms, whilst the

Of the three studies, only the Seemungal et al study assessed quality of life via the St. Georges Respiratory Questionnaire (SGRQ) in the COPD subjects. All of the quality of life indices (total, symptoms, impacts and activities) were related to HCY levels with a minimum correlation of: symptoms score 0.295, impacts score 0.330 and total score 0.289. The activities score was the only component not related to HCY. The HCY scores were higher in patients with worse quality of life scores – consistent with the relationships found between FEV1 and HCY (Seemungal et al 2007). The SGRQ scores have been shown to be an important outcome measures in COPD and predict frequent exacerbations and hospitalisation (Seemungal et al, 1998; Wilkinson et al, 2004). Though few serum parameters have been shown to predict exacerbations apart from CRP (Dahl et al 2007), the relationship between HCY and SGRQ does raise intriguing possibilities. This is the only result so far available for HCY and life style in COPD, HCY has been related to life style determinants in cardiac disease (Nygard et al, 1998). Further the relationship of elevated CRP to ten year mortality in COPD (Dhal et al 2007) and of HCY to mortality in coronary artery disease (Nygard et al, 1997; Ford et al, 2007) raises the issue of whether HCY is also related to

impacts component addresses psychosocial effects (Jones & Booth 1997).

mortality in COPD which would only be revealed by long term studies of COPD.

**10. Effects of diet, renal disease on homocysteine – Other diseases** 

Andersson et al group (Andersson et al, 2007)

would have yielded significant relationships with three B vitamins.

Kai et al did not assess dietary indices. Prior studies have all found that low vitamin B12 and or folic acid are related to hyperhomocysteinaemia (D'Angelo et al, 1997; Clarke et al, 2003; Kluijtmans et al, 2003). Seemungal et al estimated dietary intake of vitamins using the food frequency questionnaire and found no relation to plasma HCY values but Fimognari et al estimated serum vitamin B12and folic acid levels directly. The Fimognari et al study also attempted to determine if there was a role for co-morbidities in the elevation of HCY in COPD. Thus they attempted to control for those factors known to be associated with hyperhomocysteinaemia such as vascular disease, renal disease and diabetes (Dominguez et al, 2010; Austen et al 2003). When they controlled for these factors in a multivariate analysis in the COPD patients only, they found that the best predictors of high HCY were low serum folic acid, vitamin B12 and triglycerides. This has been supported by further work from the

Fimognari et al did not measure vitamin B6 levels. Further these multivariate analysis, did not include the normal subjects therefore did not include COPD as a factor even though a prior analysis of all subjects in the Fimognari et al study had shown a relationship between both presence of COPD as well as FEV1% and HCY. It is therefore not clear whether a repeat analysis using all subjects in the study with COPD and FEV1% as independent variables

**11. Homocysteine elevation in COPD: Pathogenesis or epiphenomenon?** 

Three studies shave shown that HCY is elevated in COPD relative to asymptomatic controls. The Kai et al study showed that COPD patients with a high HCY were likely to have faster decline in FEV1. Seemungal et al showed that HCY was related to COPD severity. Taken together these results suggest that HCY is involved in COPD pathogenesis. In 2001 Andersson et al showed that HCY was elevated in COPD and that patients with high HCY were more likely to have a low reduced GSH and low GSH:GSSG ratio (Andersson et al, 2001; Sibrian-Vazquez et al, 2010). Further there is evidence from a laboratory study that low levels of reduced glutathione are associated with emphysema in the rat (Hamlet et al, 2007). These studies suggest that HCY is involved in redox pathways in COPD and that a high HCY reflects an imbalance in the redox state favouring oxidative stress. However only cohort studies will allow us to determine which comes first the oxidative stress or the elevation in HCY.

#### **12. Implications for management**

The implications for management of COPD are not yet known. However, for now, COPD patients with an elevated HCY should be screened for cardiac disease and more closely monitored for evidence of a faster decline in lung function. Investigations into the role of antioxidants that may effectively lower HCY are ongoing (Zinellu et al 2008).

#### **13. Concluding comments**

Homocysteine is a ubiquitous amino acid, elevation of which is associated with several diseases as diverse as thrombotic disorders and psoriasis. There is a strong link between cardiac disease and homocysteine levels. The cause and effects of HCY elevation in COPD are unknown but preliminary studies suggest that HCY is related to COPD pathogenesis and is likely to be associated with disorders in the redox pathway leading to oxidative stress in COPD. It is unknown whether HCY infiltrates the epithelium of the airway but HCY may well affect the endothelium of the lung.

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**3** 

**Chronic Obstructive Pulmonary Disease: Emphysema Revisited** 

The chronic obstructive pulmonary disease (COPD) encompasses two phenotypically related diseases, chronic bronchitis and emphysema [1-2]. Although the hallmark of COPD is inflammation and inability to maintain efficient gas exchange, emphysema is often characterized by atypical over-distension of the alveoli and permanent destruction of the surrounding supporting structures leading to irreversible damage to gaseous exchange. Statistically, it is rapidly approaching a leading cause of mortality in the United States [3], with a morbidity of 4.9 million [4] and mortality rate at 4.2 per 100,000 [5]. Even with a higher prevalence of COPD related incidences in chronic bronchitis, mortality from emphysema (12,790) had exceeded that of chronic bronchitis (667) in pulmonary-related deaths [5] making early diagnosis and treatment of emphysema an alarming and continued

The pathogenesis of emphysema is embodied by enlargement of alveolar space, progressive destruction of connective tissue and loss of elasticity leading to eventual collapse of the small airways and destruction of pulmonary-alveolar units, all of which combine to limit gas exchange and airflow out of the lungs. These physical manifestations are usually initiated by chronic inflammation and induction of persistent oxidative stress mediated primarily by the neutrophil, a key innate immune cell residing in the conducting airways [6]. The persistent thought for the past four decades was that the tenuous balance between proteases and anti-proteases determined the severity of airway damage and alveolar enlargement, with the main protease-inhibitor, alpha1 anti-trypsin (AAT1) [6] severely lacking to combat the secretagogue elastase, from the chronically activated resident neutrophils [7-8]. Activated neutrophils also promote the secretion of mucus and inhibit the clearance ability of mucocilliary cilia thus adding to the severity of

**1. Introduction** 

cause for concern.

disease.

Corresponding Author

 

**2. Pathogenesis of emphysema** 

Nhue L. Do and Beek Y. Chin *Beth Israel Deaconess Medical Center* 

> *Harvard School of Medicine Center for Life Sciences*

> > *Boston, MA*

*USA* 

