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A comparative study of serum homocysteine levels among chronic obstructive pulmonary disease patients with and without acute exacerbation
*Corresponding author: B. S. Swathi, Department of General Medicine, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India. swathisathish1190@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Adarsh LS, Mohan P, Swathi BS, Srinath KM, Manthappa M, Chandana S. A comparative study of serum homocysteine levels among chronic obstructive pulmonary disease patients with and without acute exacerbation. J Pan Afr Thorac Soc. doi: 10.25259/JPATS_26_2024
Abstract
Objectives:
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Acute exacerbations of COPD significantly impact disease progression and patient outcomes. Serum homocysteine, a potential biomarker of systemic inflammation and oxidative stress, may play a role in COPD pathophysiology. This study aims to compare serum homocysteine levels between stable COPD patients and those experiencing acute exacerbations.
Material and Methods:
Serum homocysteine levels were analyzed by enzymatic assay from the stable and acute exacerbation groups and correlated with the severity of COPD, along with erythrocyte sedimentation rate (ESR) and COPD assessment test (CAT) score results.
Results:
The serum homocysteine levels were significantly higher in the acute exacerbation group (18.2 + 7.6) compared to the stable COPD group (15.8 + 5.2). Higher serum homocysteine levels were seen in patients with higher CAT and ESR scores.
Conclusion:
Serum homocysteine is a valuable indicator associated with acute exacerbation of COPD. It also serves as a marker of disease severity in conjunction with ESR and CAT scores.
Keywords
Chronic obstructive pulmonary disease assessment test score
Chronic obstructive pulmonary disease
Erythrocyte sedimentation rate
Oxidative stress
Serum homocysteine
INTRODUCTION
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines chronic obstructive pulmonary disease (COPD) as “A heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production, and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.”[1]
Its subtypes include emphysema, chronic bronchitis, and chronic obstructive asthma.
COPD is the result of long-term cumulative exposure to noxious gases and particles, combined with host factors including genetics, airway hyper-responsiveness, and poor lung growth during childhood.[2-4] The prevalence of COPD is directly related to the prevalence of tobacco smoking, although in many countries, outdoor, occupational, and indoor air pollution are major risk factors.[5,6]
The World Health Organization estimates that COPD will become the 3rd leading cause of death worldwide in 2030.[7] Globally, 212.3 million cases of COPD were documented in 2019.[8] Thirty million people in India are thought to have COPD.[9] In men, the reported prevalence varies from 2% to 22%, whereas in women, it varies from 1.2% to 19%.[10] According to the Global Burden of Disease report, COPD is the 2nd leading cause of death and disability-adjusted life years in India.[11]
Homocysteine elevation in COPD
Elevated serum homocysteine levels in patients with COPD are influenced by several factors mentioned below.
Systemic inflammation and oxidative stress: COPD is characterized by chronic inflammation and increased oxidative stress, which can disrupt homocysteine metabolism, leading to its accumulation in the bloodstream. Chronic hypoxia in COPD patients also activates pathways that increase homocysteine levels.[12]
Nutritional deficiencies: Deficiencies in B vitamins, particularly folate (B9) and cobalamin (B12), which are essential cofactors in homocysteine metabolism, are common in COPD patients. These deficiencies can result in impaired homocysteine breakdown and elevated serum levels.[12]
Smoking: Smoking, a primary risk factor for COPD, is associated with higher homocysteine levels. It can interfere with vitamin absorption and increase oxidative stress, both contributing to elevated homocysteine concentrations.[13]
The present study was undertaken to correlate the serum homocysteine concentrations with the severity of COPD, along with erythrocyte sedimentation rate (ESR) and COPD assessment test (CAT) score results, which will guide us to understand underlying mechanisms linking homocysteine to COPD pathophysiology, and to understand the relationship between homocysteine concentrations and disease severity.
MATERIAL AND METHODS
Study design
This is a cross-sectional, comparative study conducted at the Department of General Medicine, JSS Hospital, a tertiary care hospital in Mysore, from October 1, 2021, to February 28, 2023. Convenience sampling was used to recruit participants who met the inclusion criteria during the study. The sample size was calculated to include 200 participants (100 in each group), based on an expected effect size of 0.5, a power of 80%, and a significance level of 5%. Patients aged ≥18 years with a clinical diagnosis of COPD confirmed by spirometry (forced expiratory volume in one second/forced vital capacity <0.7) and able to provide informed consent were included in the study. Patients with comorbidities such as ischemic heart disease, type 2 diabetes mellitus, pulmonary thromboembolism, obesity, apparent infections such as (lobar and bronchopneumonia), asthma, sepsis, and cancer affecting the lung were excluded. Patients with chronic renal failure, liver disease, or other inflammatory conditions affecting homocysteine metabolism were excluded from the study. Patients on medications that alter homocysteine levels (e.g., methotrexate, anticonvulsants, and Vitamin B12 and folate supplements) were also excluded from the study. A total of 242 patients were initially screened for eligibility. Of these, 42 patients were excluded (20 for comorbid diabetes mellitus, 6 for ischemic heart disease, 4 for asthma, 3 for chronic renal failure, 5 for use of Vitamin B12 or folate supplements, and 4 declined consent). Ultimately, 200 patients were enrolled, all of whom completed the study. Demographic data, smoking status were recorded. The CAT was administered in Kannada to ensure participant comprehension. While the Kannada version of the CAT has not been formally validated, it was used in this study as a practical tool to assess symptom severity. Clinical evaluation was performed by a resident under the supervision of a pulmonologist. Venous blood samples for serum homocysteine measurement were collected on the first day of hospital visit and analyzed using the enzymatic method with Roche Diagnostics kits (Germany, 2021) on a Cobas pure 7 (c-402) automated analyzer. ESR was determined using the Westergren method.
The data were analyzed using the Statistical Package for the Social Sciences software version 29.0.2. Continuous variables were expressed as mean ± standard deviation and compared using Student’s t-test or Mann–Whitney U test, depending on data distribution. Categorical variables were compared using the Chi-square test. A P < 0.05 was considered statistically significant. Correlation between serum homocysteine levels and CAT score and ESR was assessed using Spearman’s rank correlation coefficient, as these variables were not normally distributed.
RESULTS
Patient demographics
Many of the study participants with acute exacerbation or stable COPD were found to be less than 70 years of age. The mean age of the study participants with acute exacerbation and the stable groups was 65.23 + 10.637 and 68.85 + 6.823, respectively. The association was found to be statistically significant between the age and the 2 groups of the study participants. 57% of the study participants in the acute exacerbation group and 100% of them in the stable COPD group were male. There was a significant gender disparity between the stable and exacerbation of COPD groups.
Among the two groups, 142 patients (71%) were current or former smokers, whereas 58 patients (29%) were non-smokers, with most non-smokers being female.
In the stable COPD group, the mean duration of disease was 6.4 ± 2.3 years, while in the acute exacerbation group, it was 7.1 ± 2.8 years. Among patients with exacerbation, the mean duration of hospital stay was 6.2 ± 3.1 days. The difference in the mean number of COPD exacerbations between the stable group (0.8 ± 0.6) and the acute exacerbation group (2.3 ± 1.1) was statistically significant (P < 0.001).
Serum homocysteine levels
The mean serum homocysteine levels of the acute exacerbation and the stable COPD study population group were 18.2 + 7.6 μmol/L and 15.8 + 5.2 μmol/L, respectively, as in Figure 1. The association was found to be statistically significant. The present study indicates that many patients in the acute exacerbation group were more likely to have significantly higher serum homocysteine levels.
- Mean serum homocysteine levels of the study participants. COPD: Chronic obstructive pulmonary disease
CAT scores
The mean CAT scores of the acute exacerbation and the stable COPD study population group were 28.9 ± 3.5 and 20.3 ± 3.1, respectively, as represented in Figure 2. The association was found to be statistically significant.
- Mean COPD assessment test (CAT) scores of the study participants. COPD: Chronic obstructive pulmonary disease
Distribution of homocysteine levels
Patients in the acute exacerbation group were more likely to present with higher cutoff values of serum homocysteine (more than 22 μmol/L) as opposed to stable COPD patients. Mean serum homocysteine levels of the acute exacerbation and the stable study population group were 18.2 + 7.6 and 15.8 + 5.2 μmol/L, respectively. 26.7% of the study population in the acute exacerbation group and 9.3% of the study population in the stable group had high homocysteine levels. This is shown in Table 1. The association was found to be statistically significant between homocysteine levels and the 2 groups of the study participants.
| High homocysteine | Acute exacerbation | Stable | P-value | ||
|---|---|---|---|---|---|
| Count | % | Count | % | ||
| Yes | 27 | 26.7 | 9 | 9.3 | 0.001 |
| No | 74 | 73.3 | 88 | 90.7 | |
P-value was calculated using Chi square test
Distribution of ESR
The ESR of the acute exacerbation and the stable study population group was found to be 30.42 ± 13.51 and 18.11 ± 9.22, respectively, as represented in Figure 3. The association was found to be statistically significant between ESR and the 2 groups of the study participants.
- Distribution of study participants based on erythrocyte sedimentation rate (ESR). COPD: Chronic obstructive pulmonary disease
Correlation between homocysteine levels, CAT scores, and ESR in patients with acute exacerbation of COPD
Correlation between serum homocysteine levels and clinical parameters (CAT score and ESR) was assessed using Spearman’s rank correlation coefficient, as these variables were not normally distributed. Correlation between homocysteine and CAT scores showed a positive correlation of 0.388, and the correlation was found to be statistically significant. Correlation between homocysteine and ESR showed a positive correlation of 0.203, and the correlation was found to be statistically significant. This is illustrated in Figures 4 and 5, which show that higher serum homocysteine levels were observed in patients with higher CAT scores and ESR levels.
- Correlation between homocysteine levels and COPD assessment test (CAT) scores in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD).
- Correlation between homocysteine levels and erythrocyte sedimentation rate in patients with acute exacerbation of chronic obstructive pulmonary disease. ESR: Erythrocyte sedimentation rate.
DISCUSSION
The present study included a total of 200 patients with COPD, among whom 100 patients belonged to the group with acute exacerbation of COPD and another 100 belonged to the group with stable COPD without exacerbation. Most of the study participants with acute exacerbation were <70 years. This could likely be interpreted as the result of immunosenescence in the elderly lessening inflammation as age advances. A significant male predominance was observed, particularly in the stable group, which could be attributed to higher diagnosis rates among males and lower follow-up compliance among females due to socioeconomic and cultural factors. The association was found to be statistically significant between gender and the 2 groups of the study participants. Similarly, in the study by Seemungal et al.,[14] similar age distribution and male predominance were seen in the patient demographics.
Elevated serum homocysteine levels were more common in patients with acute exacerbation than in those with stable COPD, showing a significant association (P < 0.05). This was corroborated in the study by Seemungal et al.,[14] where mean homocysteine levels were significantly higher in the COPD group compared to the control group (10.96 μmol/L vs. 8.22 μmol/L, respectively). The study by Wei et al.,[15] also showed that in acute exacerbation of COPD, patients had significantly higher serum homocysteine levels (14.59 μmol/L) than stable COPD patients (13.14 μmol/L) (P < 0.001). These findings complied with the present study. In a meta-analysis done by Chaudhary et al.,[13] serum homocysteine levels were identified as a risk factor for COPD. However, this correlation was not statistically significant.
The CAT score is an efficient test created to not only evaluate the degree of COPD but also help gauge the impact of COPD symptoms on the patient’s health status and assess the condition of patients at presentation and recovery. A higher CAT score not only helps to grade the patient’s symptoms but is also significantly correlated with the decline in PFT values and is associated with a more severe category on the GOLD classification of COPD.[16] In this study, the mean CAT score in the group with acute exacerbation was significantly higher compared to the group without it (P < 0.05). Consistently, Jones et al.[17] reported lower CAT scores in stable patients compared to those with exacerbations (P < 0.0001), and studies by Ghobadi et al. and Mackay et al.[16,18] showed that patients with more severe COPD had significantly higher CAT scores (P < 0.032). Thus, CAT scores, reflecting the degree of airflow limitation, can serve as a practical surrogate for pulmonary function testing to assess COPD severity and were used in this study to classify patients into acute exacerbation and stable COPD groups. In this study, serum homocysteine levels were positively correlated with CAT scores, indicating that higher homocysteine levels are associated with greater symptom burden during acute exacerbations of COPD. This suggests that homocysteine may serve as a useful biomarker to complement clinical assessment. ESR, which has been demonstrated in previous studies, including Corsonello et al.[19] to be a cost-effective alternative to CRP in systemic inflammatory states, was also significantly elevated in patients experiencing exacerbations and showed a positive correlation with homocysteine levels. The simultaneous elevation and correlation of homocysteine and ESR provide objective evidence of systemic inflammation during exacerbations.
These findings are particularly valuable because they integrate quantitative laboratory markers with a qualitative patient-reported measure of disease severity, the CAT score. By combining these indicators, clinicians can achieve a more comprehensive assessment of COPD exacerbation, capturing both the physiological inflammatory response and the patient’s symptomatic experience. This multi-pronged approach has the potential to improve monitoring, guide treatment decisions, and enhance the overall evaluation of disease severity in patients with COPD.
Limitations of the study
The study design limits the ability to establish causality between elevated homocysteine levels and COPD exacerbations. Convenience sampling may introduce selection bias, affecting the generalizability of the findings to the broader COPD population. Conducting the study at a single tertiary care hospital may limit the external validity of the results. The study does not assess changes in homocysteine levels over time or their predictive value for future exacerbations.
The Vitamin B12 and folate levels have not been assessed in any of the study patients with COPD, which could be a potential confounding factor in patients with vitamin deficiency and hyperhomocysteinemia. Pulmonary function tests could not be included in the quantitative data because patients with severe COPD could not perform the test. These limitations should be considered when interpreting the study results and planning future research.
CONCLUSION
This study highlights the importance of homocysteine as a biomarker for COPD exacerbations, with significantly higher serum homocysteine levels observed in patients with acute exacerbations compared to those with stable COPD. Correlation analyses demonstrated a positive correlation between homocysteine levels and COPD Assessment Test (CAT) scores (r = 0.388, P < 0.05), indicating that higher homocysteine levels are associated with worse symptom burden and reduced quality of life. In addition, ESR, a marker of systemic inflammation, showed a significant positive correlation with homocysteine levels (r = 0.203, P < 0.05), reinforcing the role of systemic inflammation in COPD pathophysiology. These findings suggest that serum homocysteine could serve as a useful biomarker for identifying patients at higher risk of exacerbations and increased symptom severity. Integrating homocysteine measurement with clinical tools such as the CAT score and inflammatory markers such as ESR may improve risk stratification and guide management strategies in COPD patients.
Future longitudinal studies are recommended to explore the prognostic value of homocysteine and the potential benefits of targeted interventions (nutritional therapy and oxygen therapy) to lower homocysteine levels in this population.
Ethical approval:
The research/study was approved by the Institutional Review Board at JSS Medical College, approval number JSS/MC/PG/5156/2021-2022, dated 22nd January 2021.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflict of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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