Japan Endocrine Society Proposes Revised Diagnostic Criteria for Adrenal Subclinical Cushing’s Syndrome

The Japan Endocrine Society (JES) has proposed new criteria, including reviewed cutoff values for blood cortisol levels, for the diagnosis of adrenal subclinical Cushing’s syndrome (SCS), a type of Cushing’s syndrome that lacks the clinical signs of the disease.

The research, “New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan Endocrine Society,” appeared in the Endocrine Journal.

Since SCS doesn’t have the clinical signs of CS, it is often detected by examination of adrenal incidentalomas, which are asymptomatic adrenal masses. SCS is often hidden within conditions such as obesity, diabetes mellitus, and hypertension, and has also been linked to cardiovascular disease and bone loss.

In all guidelines, a 1-milligram dexamethasone suppression test (DST) is recommended as the first screening test to diagnose adrenal SCS. However, the recommended cut-off value for cortisol after this test varies. Depending on the guideline used, it is 1.8 micrograms per deciliter or 5 mcg/dL.

Dexamethasone is a synthetic glucocorticoid that inhibits adrenocorticotropic hormone (ACTH) secretion, leading to a decrease in cortisol levels in healthy subjects. However, in Cushing’s syndrome patients, this inhibition does not happen.

In Japan, research showed that a blood cortisol level higher than 1.8 mcg/dL after a 1-mg DST can help confirm SCS, if patients also exhibit base ACTH levels lower than 10 picograms/milliter and a serum cortisol level higher than 5 mcg/dL between 9 and 11 p.m.

Late-night measurement of salivary cortisol is only recommended as a primary screening test by the U.S. Endocrine Society. Adoption of tests confirming subtle cortisol secretion, such as high-dose DST, basal ACTH, or late-night serum or salivary cortisol, has been inconsistent across different guidelines.

These issues related to measuring serum levels of cortisol have put identifying new diagnostic criteria and treatment policy for adrenal SCS at the center of JES’ efforts.

New diagnostic criteria for SCS was based on a study including 530 cases (270 men, mean age 60 years) of SCS, suspected SCS — those with serum cortisol of 3 mcg/dL or higher after a 1-mg DST, but with no other findings relevant for SCS diagnosis — and nonfunctioning adrenal tumors (those that do not secrete hormones).

Researchers found that diagnosis did not change significantly when cut-off values of serum cortisol were 3 mcg/dL or 1.8 mcg/dL after a 1-mg DST. However, they noted that this result must be interpreted with caution, given a reported 10% variance in the measurement of serum cortisol values.

Scientists also found that high blood pressure, impaired glucose tolerance, and high cholesterol did not affect the mean cortisol value after a 1-mg DST among study participants. However, this cortisol value was higher in non-SCS subjects with hypertension than in those with normal blood pressure.

Three cortisol cutoff levels after a 1-mg DST — 1.8, 3 and 5 mcg/dL — are now included in the revised diagnostic criteria for SCS. The 1.8 mcg/dL level was included because patients with higher serum cortisol may not be completely healthy, and may be at risk for complications, the team said. Adopting this value also enables consistency with guidelines outside Japan.

Because the 3 mcg/dL level is used in current criteria, it was included to lower the risk of confusion.

Serum cortisol equal to or higher than 5 mcg/dL was also found sufficient to guarantee autonomous cortisol secretion — by incidentalomas — for the diagnosis of SCS, the team said.

Researchers also observed that a serum cortisol cutoff value of 1.8 mcg/dL after a 1-mg DST, an ACTH value in the early morning lower than 10 pg/mL, and a nocturnal (9 p.m – 12 a.m.) cortisol level of 5 mcg/dL or higher allow for detection of glucose intolerance with high sensitivity, specificity, and accuracy.

“Thus, the criteria are very useful for the diagnosis of SCS and show equivalent diagnostic confidence with that of current criteria,” the investigators wrote.

In cases of serum cortisol levels of 5 mcg/dL or higher after a 1-mg DST, and in suspicious cases of adrenal cancer according to tumor imaging, the team suggests surgery. They further recommend considering the removal of adrenal tumors 3 centimeters or larger and if adrenal cancer cannot be excluded completely.