Cortisol-to-ACTH Ratio May Help Diagnose Cushing’s Disease: Study

CAR ratio may help advance diagnosis, treatment times

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Measuring the ratio of cortisol to adrenocorticotropic hormone (ACTH) could help diagnose Cushing’s disease and other forms of Cushing’s syndrome, according to a recent study.

“We think that it is possible to diagnose and screening [ACTH-independent Cushing’s syndrome] when CAR [cortisol-to-ACTH ratio] is elevated, and screening CD [Cushing’s disease] when CAR is decreased,” the researchers wrote.

The study, “Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing’s syndrome: comparison of CAR with findings in dexamethasone suppression test,” was published in Scientific Reports.

Cushing’s syndrome comprises a group of conditions marked by abnormally high levels of the stress hormone cortisol. Cushing’s disease is a specific form of the syndrome wherein high cortisol levels are driven by a tumor in the brain’s pituitary gland that releases a signaling molecule called ACTH. Other forms of the syndrome are referred to as ACTH-independent Cushing’s syndrome, or AICS.

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Cushing’s Syndrome Treatment Preceded Cushing’s Disease Diagnosis

The 1 mg dexamethasone suppression test (DST) is a diagnostic procedure commonly used to diagnose Cushing’s. It involves patients taking dexamethasone, a steroid medication, at night and then measuring how this affects cortisol levels the following morning. By design, the test takes some time to carry out, which can delay the start of treatment.

Scientists in Japan analyzed whether measuring the ratio of cortisol to ACTH levels — known as the cortisol/ACTH ratio, or CAR — could help identify Cushing’s syndrome.

“If a method for diagnosis of Cushing’s syndrome could be established only with basic endocrine hormone levels without performing 1 mg DST, treatment could be initiated more easily and at an earlier stage,” the researchers wrote. “However, cortisol/ ACTH ratio (CAR) has not been established yet as clear diagnostic criteria for Cushing’ syndrome.”

Diagnosis through ACTH/cortisol ratio

The researchers analyzed data from 327 people who underwent 1 mg DST at Kawasaki School Hospital between January 2010 and March 2021.

“We think that CAR would be promising for many clinicians to easily notice the possibility of Cushing’s syndrome at an earlier point and thus the findings in this study would be very informative and useful from the clinical point view,” they wrote.

Based on the 1 mg DST results and other diagnostic tests, 10 patients were diagnosed with Cushing’s disease and 14 with AICS. Another 44 were diagnosed with subclinical Cushing’s syndrome (SCS), meaning they had elevated cortisol levels, but weren’t having any typical symptoms of Cushing’s. The remaining 248 people analyzed didn’t have Cushing’s.

CAR and 1 mg DST results were significantly correlated with each other among AICS patients, but not in those with Cushing’s disease or SCS, statistical analyses showed. CAR measures also correlated with tumor size in AICS, but not in Cushing’s disease or SCS.

In other statistical tests, researchers evaluated whether various CAR cutoffs could help identify Cushing’s patients. For each cutoff, the team calculated the sensitivity — the percentage of patients who have the condition and are correctly identified as such — as well as the specificity, which refers to the percentage of patients accurately identified as not having the condition.

Results showed, at a CAR cutoff value of 7,006.1 nanomoles per picomoles (nmol/pmol), Cushing’s disease could be diagnosed with a sensitivity of 100% and a specificity of 46.8%.

Based on the high sensitivity, researchers noted “it seems that CAR is useful for screening of [Cushing’s disease]”, though the team also advised caution due to the relatively low specificity.

CAR also showed a good ability to identify AICS — with a sensitivity of 92.3% and a specificity of 83.5% at a cutoff value of 11,849.6 nmol/pmol — but the measure couldn’t identify subclinical disease with significant accuracy.

“Since ACTH and cortisol are usually measured when Cushing’s syndrome or adrenal disease is suspected, the CAR, which can be calculated by a simple formula, may be a useful indicator for estimating the presence of AICS clinically,” the researchers wrote, noting the study was limited by its small size and the fact that it was conducted at a single institution. They said more research was needed to validate and expand their results.