**7. Homocysteine, lung function and lung function decline**

The major manifestation of airflow obstruction in COPD is reduced maximum expiratory flow and slow forced emptying of the lungs (FEV1) and these features do not change

Homocysteine is Elevated in COPD 27

et al, 2006). Rather, the relationship with annual decline in FEV1 would appear to support the conclusion of Seemungal et al that COPD severity is related to a higher HCY (Seemungal

In a subset analysis of the COPD-only group, Kai et al found that those with FEV1 less than 30% (N = 7) had a lower arterial oxygen tension and lower HCY than those with FEV1 greater than 60% (N = 8) – a very small sample in an already small study. However in the entire COPD sample there was no significant correlation between arterial oxygen tension and HCY. Kai et al used this finding to hypothesize that (a) hypoxia could easily occur on exertion in the patients with severe COPD and that (b) there is a possibility that hypoxia played a role in the reduction of the plasma HCY concentration via down regulation of methionine adenosyltransferase gene transcription. The difficulty with this hypothesis is that it is based on a very small subset difference in an already small study (Kai et al, 2006).

Serum C-reactive protein (CRP), is a ubiquitous marker of systemic inflammation, mortality and hospitalisation in COPD (Dahl et al, 2007; Man et al, 2004), cardiac disease in COPD (Sin et al, 2003) and of cardiac disease in the elderly (Zakai et al, 2007). High CRP levels have also

As shown in Table 1, both Seemungal et al and Fimognari et al measured serum CRP in their normal and COPD subjects and though their samples showed significantly different values for mean CRP, they both agreed that CRP was elevated in the COPD subjects compared to asymptomatic controls. The CRP levels in the normal controls in the Seemungal et al study was similar to that in previously published American and Dutch controls (Broekhuisen et al, 2005; Sin & Man 2003) and the greater value of CRP in COPD in the Seemungal et al study is the same as that attributed to COPD by Gan et al in their

The Seemungal et al study found a correlation between CRP and HCY which was not found (rho= 0.377, p = 0.005) in the Fimognari et al study. The clinical implication of this finding from the Seemungal et al study is unclear at present more so because it was not supported by the Fimognari et al study. However, a similar correlation between HCY and CRP (as observed by Seemungal et al) has been reported in psoriatic arthritis (Sattar et al, 2007), in cancer (Schroecksnadel 2007) and in elderly patients with cardiovascular disease and dementia (Ravaglia et al, 2004). Taken together these results suggest that HCY may play a role in immune activation in some chronic diseases (Schroecksnadel et al, 2007) and its relationship to HCY in COPD may be a further indicator of the role of HCY in oxidative

The St. Georges Respiratory Questionnaire (SGRQ) (Jones et al, 1992) assesses quality of life in three domains: symptoms, activities and impacts. Scores in three domains are combined to give weighted average called the total score (Jones et al, 1992). The SGRQ has been shown to be sensitive to different levels of health (Jones 1997). As a standardised questionnaire the SGRQ has the advantage of allowing direct comparison between different patient

**8. Homocysteine and CRP: Evidence for immune activation?** 

been shown to correlate with low 6-min walk test scores (de Torres et al, 2007).

et al, 2007).

metaanalysis (Gan et al, 2004).

stress in COPD (Folchini et al, 2011).

**9. Homocysteine and quality of life** 

markedly over months (GOLD 2010). Most of the lung function impairment is progressive and thus rate of decline in FEV1 is an important outcome measure in COPD. COPD may be accompanied by airway hyperactivity and partial reversibility which when present increases the variance in FEV1 and FVC measurements. To eliminate this all three studies used postbronchodilator lung function measurements (Kai et al 2006; Seemungal et al, 2007; Fimognari et al,2009).

All three studies agree that HCY is higher in COPD patients than in controls (Kai et al, 2006; Seemungal et al, 2007; Fimognari et al, 2009). But only one study found that HCY was higher in the more severe COPD (please see Figure 2) (Seemungal et al, 2007). Kai et al found that HCY was higher in patients with a higher FEV1 – an opposite finding to the Seemungal et al group.

Fig. 2. Homocysteine and COPD severity based on Seemungal et al, 2006.

Kai et al are the only group so far to look at annual decline in FEV1 and HCY. In this study FEV1 decline varied between 0 ml/year and 275 ml /year. However the correlation was positive (r=0.40 and p-value = 0.02), that is, a high HCY was related to a more rapid decline in lung function. The authors have not explained the apparent contradiction between their findings in the cross-sectional analysis (of low HCY related to low lung function) and the paired analysis where FEV1 decline was faster in those with high plasma homocysteine (Kai

markedly over months (GOLD 2010). Most of the lung function impairment is progressive and thus rate of decline in FEV1 is an important outcome measure in COPD. COPD may be accompanied by airway hyperactivity and partial reversibility which when present increases the variance in FEV1 and FVC measurements. To eliminate this all three studies used postbronchodilator lung function measurements (Kai et al 2006; Seemungal et al, 2007;

All three studies agree that HCY is higher in COPD patients than in controls (Kai et al, 2006; Seemungal et al, 2007; Fimognari et al, 2009). But only one study found that HCY was higher in the more severe COPD (please see Figure 2) (Seemungal et al, 2007). Kai et al found that HCY was higher in patients with a higher FEV1 – an opposite finding to the Seemungal et al

Fig. 2. Homocysteine and COPD severity based on Seemungal et al, 2006.

Kai et al are the only group so far to look at annual decline in FEV1 and HCY. In this study FEV1 decline varied between 0 ml/year and 275 ml /year. However the correlation was positive (r=0.40 and p-value = 0.02), that is, a high HCY was related to a more rapid decline in lung function. The authors have not explained the apparent contradiction between their findings in the cross-sectional analysis (of low HCY related to low lung function) and the paired analysis where FEV1 decline was faster in those with high plasma homocysteine (Kai

GOLD Stages 1 &2, FEV1 >= 50% Predicted GOLD Stages 3&4, FEV1 < 50% predicted

Fimognari et al,2009).

HCY (micromol/L)

group.

30.00

5.00

10.00

15.00

20.00

25.00

et al, 2006). Rather, the relationship with annual decline in FEV1 would appear to support the conclusion of Seemungal et al that COPD severity is related to a higher HCY (Seemungal et al, 2007).

In a subset analysis of the COPD-only group, Kai et al found that those with FEV1 less than 30% (N = 7) had a lower arterial oxygen tension and lower HCY than those with FEV1 greater than 60% (N = 8) – a very small sample in an already small study. However in the entire COPD sample there was no significant correlation between arterial oxygen tension and HCY. Kai et al used this finding to hypothesize that (a) hypoxia could easily occur on exertion in the patients with severe COPD and that (b) there is a possibility that hypoxia played a role in the reduction of the plasma HCY concentration via down regulation of methionine adenosyltransferase gene transcription. The difficulty with this hypothesis is that it is based on a very small subset difference in an already small study (Kai et al, 2006).
