Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing's syndrome: comparison of CAR with findings in dexamethasone suppression test

www.nature.com/scientificreports OPEN Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing’s syndrome: comparison of CAR with findings in dexamethasone suppression test Yuichiro Iwamoto, Fuminori Tatsumi, Takashi Itoh, Taku Sasaki, Shigehito Mori, Toshitomo Sugisaki, Erina Nakao, Mana Ohnishi, Takashi Kusano, Haruka Takenouchi, Hideyuki Iwamoto, Junpei Sanada, Yoshiro Fushimi, Yukino Katakura, Tomohiko Kimura, Masashi Shimoda, Shuhei Nakanishi, Kohei Kaku, Tomoatsu Mune & Hideaki Kaneto* Cushing’s syndrome and subclinical Cushing’s syndrome (SCS) are conditions of increased cortisol secretion from the adrenal glands. Cushing’s syndrome includes adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (Cushing’s disease) and ACTH-independent Cushing’s syndrome (AICS). The purpose of this study was to investigate the diagnostic potential of the cortisol / adrenocorticotropic hormone (ACTH) ratio (CAR) for diagnosis of Cushing’s syndrome or SCS in adult subjects. This was a single-center, retrospective, observational study. This study enrolled 44 subjects with SCS, 14 AICS, 10 CD, and 248 non-Cushing’s syndrome subjects who had undergone a 1 mg dexamethasone suppression test (1 mg DST). Definition of SCS was as follows: no physical signs characteristic of Cushing syndrome and cortisol was ≥ 83 nmol/L in 1 mg DST. The diagnostic potential of CAR for diagnosis of Cushing’s syndrome was evaluated by comparing the correlation between CAR and after-load cortisol level in 1 mg DST. As the results, there was a strong positive correlation between CAR and after-load cortisol level in subjects with AICS (r = 0.800, p < 0.005). CAR was 10,040 ± 4170 nmol/pmol in subjects with NCS, 17,535 ± 10,246 nmol/pmol in SCS, 101,221 ± 18,009 nmol/pmol in AICS, and 4324 ± 2051 nmol/pmol in CD, all of which were significantly higher compared to those with AICS (p < 0.0005). The cutoff values of CAR for screening at our institution were 11,849.6 nmol/pmol for AICS (AUC 0.935, p < 0.005, sensitivity 92.3%, specificity 83.5%) and 7006.1 nmol/pmol for CD (AUC 0.714, p < 0.05, sensitivity 100.0%, specificity 46.8%). There was a positive correlation between CAR and adrenal adenoma diameter in subjects with AICS (r = 0.508, p < 0.05), but there was no correlation between tumor diameter and CAR in subjects with SCS and CD. In conclusion, high CAR indicates increased cortisol secretion from the adrenal glands. Since CAR is a simple indicator that can be easily evaluated by general practitioners as well as endocrinologists, we think CAR would be useful for the early detection of Cushing’s syndrome. Cushing’s syndrome is a chronic excess production of cortisol from the adrenal glands and is broadly classified into adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (so-called adrenocorticotropic Cushing’s syndrome) and ACTH-dependent Cushing’s syndrome (so-called Cushing’s disease)1. Subclinical Cushing’s syndrome (SCS) is not accompanied by the characteristic physical signs of Cushing’s s yndrome2 but shows autonomous cortisol secretion. Subjects with SCS may also be at risk of developing into Cushing’s syndrome. Cushing’s syndrome, including subclinical one, causes hypertension, and glucose intolerance, and cardiovascular events and finally leads to shorter healthy life expectancy and life expectancy3–5. The 1 mg dexamethasone suppression test (1 mg DST) is a test to evaluate cortisol autocrine secretion from the adrenal glands by measuring early morning cortisol levels after taking 1 mg dexamethasone at 23:00 on the Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki 701‑0192, Japan. *email: Scientific Reports | (2022) 12:17680 | https://doi.org/10.1038/s41598-022-22676-1 1 Vol.:(0123456789) www.nature.com/scientificreports/ previous day, and when the after-load cortisol level is 3 μg/dL or higher, cortisol autocrine secretion is considered to be e nhanced6,7. It is very important to confirm cortisol autocrine secretion, because it has been reported that the mortality is increased at after-load cortisol levels of 3 µg/dL or higher in 1 mg DST8. However, it is sometimes difficult to perform 1 mg DST in non-specialized institutions or in ambulatory care settings. 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. Primary aldosteronism is another relatively common adrenal disease and brings about secondary hypertension. For diagnosis of the disease, aldosterone level and renin activity are measured, and aldosterone / renin activity ratio is very often utilized as established diagnostic criteria for primary aldosteronism in clinical practice9,10. Similarly, in diagnosis of Cushing’ syndrome, cortisol and ACTH levels are very often measured. However, cortisol/ ACTH ratio (CAR) has not been established yet as clear diagnostic criteria for Cushing’ syndrome. In this study, we investigated whether CAR would be useful for the diagnosis of Cushing’s syndrome in subjects who underwent 1 mg DST by directly comparing CAR with findings in 1 mg DST. Material and methods Study subjects. Subjects eligible for the present study were patients who visited the endocrinology outpatient clinic in Kawasaki School Hospital between January 1st, 2010 and March 31st, 2021. The study protocol including the opt-out informed consent was approved by Institutional Review Board of Kawasaki Medical School (No. 5531–00). The study was conducted in accordance with the Declaration of Helsinki. Since this study was retrospective, instead of obtaining informed consent from each patient, we provided public information about the study via the hospital homepage. A total of 327 subjects who underwent 1 mg DST between January 1, 2010 and March 31, 2021 were selected as this study participants; subjects younger than 20 years old, pregnant, and taking corticosteroids were excluded from the study (3 cases). Subjects with diseases that could affect ACTH and cortisol secretion were excluded (1 case with Addison’s disease, 1 case with anorexia nervosa, 1 case with hypoproduction of ACTH, 2 cases with growth hormone-secreting tumors, 1 case with congenital adrenocortical enzyme deficiency, and 1 case with ACTH unresponsiveness). Participants included 248 subjects with non-Cushing’s syndrome (NCS), 44 with subclinical Cushing’s syndrome (SCS), 14 with ACTH independent Cushing’s syndrome (AICS), and 10 with Cushing’s disease (CD). Methods. Analysis was performed using age, height, body weight, BMI, systolic and diastolic blood pressure, and blood test results at the time when 1 mg DST was performed. The data were collected from medical records. All cases were diagnosed with SCS, AICS or CD after 1 mg DST was performed. Adrenal adenoma diameter was evaluated by abdominal CT in 35 cases with SCS and 14 cases wi (...truncated)