The future of Cushing's syndrome diagnosis is here, and it's in your saliva. Professor Brian Keevil, a Consultant Clinical Scientist at Manchester University NHS Foundation Trust, is revolutionizing the way we detect and monitor adrenal disorders, including Cushing's syndrome and adrenal insufficiency. Keevil's groundbreaking work focuses on the power of salivary cortisone testing, a non-invasive method that could transform endocrine medicine.
The Salivary Advantage
Keevil's interest in salivary cortisol and cortisone testing stems from the desire to simplify and patient-friendly alternative to traditional blood-based testing. Saliva collection is easy, convenient, and can be done at home, reducing the burden on patients and healthcare services. Unlike blood sampling, it avoids the discomfort of venepuncture.
From an analytical perspective, saliva contains the free fraction of cortisol, which is the biologically active component. This makes it particularly useful when assessing adrenal function. Keevil's team found that measuring salivary cortisone offered several advantages over salivary cortisol, particularly in terms of sensitivity and correlation with serum cortisol concentrations.
The Rise of Salivary Cortisone
Salivary cortisone has emerged as a valuable biomarker, offering several advantages over salivary cortisol. Keevil explains that free cortisol, which represents only around 5% of circulating cortisol, is what we clinically care about. When free cortisol enters the salivary gland, much of it is converted into cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2.
As a result, salivary cortisone concentrations are around four times higher than salivary cortisol concentrations, making them easier to measure accurately. More importantly, salivary cortisone shows a much more linear relationship with serum cortisol levels, reflecting physiological cortisol exposure and providing a more reliable marker across a wider concentration range.
Cushing's Syndrome: A Complex Diagnosis
Cushing's syndrome remains one of the most challenging endocrine disorders to diagnose because there is no single definitive test. Current investigations include urinary free cortisol measurements, late-night salivary cortisol, and overnight dexamethasone suppression testing. Keevil's studies have shown that late-night salivary cortisone performs extremely well, particularly in patients with pituitary-dependent Cushing's disease.
In one tertiary referral study, late-night salivary cortisone was the single best-performing test, achieving sensitivity of 95% and specificity of 100% using an optimized cutoff value. It outperformed both urinary free cortisol and standard late-night salivary cortisol measurements.
Adrenal Insufficiency: A Life-Threatening Condition
Adrenal insufficiency is a potentially life-threatening condition that is often underdiagnosed because symptoms are nonspecific and existing screening tests can be inconvenient or resource-intensive. Keevil's work has shown that waking salivary cortisone collected at home can act as an effective first-line screening test.
The test is safe, practical, and capable of reducing the number of patients requiring more invasive investigations. Several UK hospitals are now implementing or evaluating this approach, and Manchester University NHS Foundation Trust has already begun routine use of the test.
The Future of Salivary Cortisone Testing
Keevil's research has also explored salivary dexamethasone metabolites, which could become a valuable addition to future saliva-based diagnostic pathways. Measuring salivary 11-dehydrodexamethasone, a metabolite produced through similar enzymatic pathways to cortisone, provides much better correlation with serum dexamethasone concentrations.
This could help identify patients whose suppression tests fail because of altered dexamethasone metabolism or absorption. Keevil believes that salivary cortisone will continue to gain traction as a routine outpatient and home-based test, offering excellent diagnostic performance, convenience, and the potential to reduce healthcare costs while improving access to endocrine testing.
As more centers adopt LC-MS/MS methodologies, Keevil expects saliva-based steroid testing to become an increasingly important part of clinical practice.
