A number of metabolites in the sweat of newborns screened positive for cystic fibrosis could provide the basis for complementary diagnostic tests to sweat chloride, according to Canadian research.
As well as potentially improving the diagnosis of cystic fibrosis, the findings also suggest new therapeutic targets for the disease.
Non-targeted metabolite profiling was performed on sweat samples from 50 newborns identified as unaffected carriers of cystic fibrosis and 18 infants confirmed to have cystic fibrosis.
The limbic asked Professor Philip Britz-McKibbin, from the department of chemistry and chemical biology at McMaster University, about the research.
The study identified 64 unique compounds in the sweat of infants who screened positive for cystic fibrosis. Which ones proved to have an association with the disease?
Overall, there were four statistically significant sweat metabolites – glutamine, asparagine, pilocarpic acid and monoethylhexylphthalate (MEHP) – that differentiated affected infants from unaffected screen-positive controls. Pilocarpic acid and MEHP were “unexpected” sweat biomarkers of CF disease status as they are exogenous compounds and unrelated to CFTR mutations or impaired chloride transport. Pilocarpic acid is a metabolite from the pilocarpine used to stimulate sweat response and MEHP is a metabolite of the ubiquitous plasticizer DEHP.
What do these findings reveal about the pathophysiology of cystic fibrosis?
These findings prove that other sweat metabolites beyond chloride can differentiate cystic fibrosis disease status early in life. We surmise that the neutral amino acids (glutamine and asparagine) are most likely reflective of impaired chloride conduction by mutations in CFTR that also impact nutrient transport.
Pilocarpic acid and MEHP were significantly correlated with each other and secreted at lower concentrations in the sweat of CF affected infants. This suggests an underlying deficiency in paraoxonase – an important enzyme that regulates lipid metabolism and inflammation, and has been shown to modulate bacterial biofilm in lungs in CF patients later in life.
In other words, a CF infant’s reduced metabolism towards drug administration (i.e. pilocarpine iontophoresis) and environmental exposures (prenatal exposure to DHEP) indicated a higher risk for intoxication, inflammation and biofilm formation early in life that was unrelated to CFTR, the focus of most drug therapies.
The development of drug-based activators that enhance the activity of paraoxonase may be useful to reduce risk for recurrent infections and prolonged use of antibiotics due to resistant bacteria found in a biofilm environment.
How might your findings improve the early detection of cystic fibrosis or help monitor disease progression?
The screening algorithm implemented in most western countries is quite successful for early detection of cystic fibrosis. We believe that our work can complement sweat chloride testing and improve clinical decision making in two major ways:
- Improve the prognosis in affected infants, especially for ambiguous/borderline sweat chloride results, which is associated with an indeterminate diagnosis for patients and their families. Similarly, cystic fibrosis is a complex disease spectrum that varies significantly between patients, and disease progression for individual patients is not well indicated by sweat chloride or CFTR mutation status information alone.
- Additionally, we anticipate that other sweat metabolites associated with CF disease status may provide a better indicator of treatment responses to therapy, including nutritional supplementation to improve growth and new pharmacological treatments to improve lung function. This is important given the intrinsic variability in CF patients’ responses to therapy.
What are the potential therapeutic implications of this research?
Rigorously validated yet clinical relevant biomarkers can serve as useful tools for charting disease progression in CF, while also validating and customising integrative therapies that aim to improve growth and lung. With early and accurate screening, such therapies can be promptly introduced early in life before symptoms manifest.
This is expected to further increase the median age for survival for CF and improve quality of life by reducing or delaying the need for lung transplantations due to chronic and recurrent lung infections.