Arginine, Transsulfuration, and Folic Acid Pathway Metabolomics in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Angelo Zinellu, Arduino A. Mangoni

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)
18 Downloads (Pure)


There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B6, and vitamin B12) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD = −0.50, 95% CI −0.95 to −0.05, p = 0.029) and folic acid (SMD = −0.37, 95% CI −0.65 to −0.09, p = 0.009), and higher homocysteine (SMD = 0.78, 95% CI 0.48 to 1.07, p < 0.001) and cysteine concentrations (SMD = 0.34, 95% CI 0.02 to 0.66, p = 0.038). Additionally, COPD was associated with significantly higher ADMA (SMD = 1.27, 95% CI 0.08 to 2.46, p = 0.037), SDMA (SMD = 3.94, 95% CI 0.79 to 7.08, p = 0.014), and ornithine concentrations (SMD = 0.67, 95% CI 0.13 to 1.22, p = 0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests that the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036.)

Original languageEnglish
Article number2180
Number of pages25
Issue number17
Early online date30 Aug 2023
Publication statusPublished - 1 Sept 2023


  • asymmetric dimethylarginine
  • biomarkers
  • chronic obstructive pulmonary disease
  • folic acid
  • homocysteine
  • nitric oxide
  • ornithine
  • oxidative stress
  • symmetric dimethylarginine
  • transsulfuration


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