New diagnostic criteria and the treatment policy for adrenal subclinical Cushing’s syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries.
New diagnostic criteria for adrenal subclinical Cushing’s syndrome (SCS)
1. Presence of an adrenal mass (adrenal incidentaloma)
2. Lack of characteristic features of Cushing’s syndrome (CS)1
3. Laboratory data:
3.1. Normal basal serum cortisol levels2
3.2. Autonomic cortisol secretion confirmed by an overnight 1-mg dexamethasone suppression test (DST)3,4,5
3.3. Low plasma levels of adrenocorticotropic hormone (ACTH) in the early morning6
3.4. No diurnal changes in serum cortisol levels7
3.5. Unilateral uptake on adrenal scintigraphy8
3.6. Low serum levels of dehydroepiandrosterone sulfate (DHEA-S)9
3.7. Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor10
The diagnosis is defined based on the presence of 1, 2, 3.1 (essential) plus the following conditions of (1) or (2) or (3).
(1) Serum cortisol after a 1-mg DST ≥5 μg/dL (3.2)
(2) Serum cortisol after a 1-mg DST ≥3 μg/dL (3.2) plus at least one of 3.3–3.6 or the presence of 3.7
(3) Serum cortisol after a 1-mg DST ≥1.8 μg/dL (3.2) plus 3.3 and 3.4 or the presence of 3.7
Note 1): Hypertension and general obesity (physical status) and glucose intolerance, osteoporosis and dyslipidemia (laboratory examinations) are not regarded as characteristic conditions of CS.
Note 2): Basal serum cortisol levels should be measured in the fasting condition at rest in the early morning, at least twice. Reproducible hypercortisolemia excludes the possibility of SCS. The normal range of serum cortisol is judged according to the reference range of each assay kit.
Note 3): An overnight 1-mg DST should be carried out. Serum cortisol ≥1.8 μg/dL after a 1-mg DST is considered to be not completely normal or to take into account the possibility of a functioning adrenal tumor or that of nonfunctioning adrenal tumor possessing clinical significance.
Note 4): A high dose (4–8 mg) DST is not necessary for the confirmatory diagnosis. However, if it is necessary for the differential diagnosis of pathogenesis, we suggest that it should be done.
Note 5): Low serum levels of cortisol vary by around 10%, so serum cortisol ≈3 μg/dL varies with a difference of around 0.3 μg/dL. Then, we recommend a comprehensive diagnosis by considering the number of positive criteria.
Note 6): If the basal ACTH level in the early morning is <10 pg/mL, then it is desirable to take more than one additional measurement. There can be a poor response of ACTH to the ACTH-stimulating test (less than 1.5-fold of the basal ACTH level). Be aware and cautious that the plasma level of ACTH is not always low when biologically inactive ACTH is secreted.
Note 7): Serum cortisol at 21.00–24.00 is ≥5 μg/dL.
Note 8): Quantitative evaluation using adrenal scintigraphy is desirable because suppressed intake in the contralateral intact adrenal gland is correlated with autonomous cortisol secretion.
Note 9): A DHEA-S level lower than the age- and sex-matched reference level.
Note 10): Preoperatively, sufficient informed consent, including the possibility of a nonfunctioning adenoma, is necessary.
References:
- Yanase T, Oki Y, Katabami T, Otsuki M, Kageyama K, Tanaka T, Kawate H, Tanabe M, Doi M, Akehi Y, Ichijo T. New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan Endocrine Society. Endocr J. 2018 Apr 26;65(4):383-393. [Medline]
- Abe I, Sugimoto K, Miyajima T, Ide T, Minezaki M, Takeshita K, Takahara S, Nakagawa M, Fujimura Y, Kudo T, Miyajima S, Taira H, Ohe K, Ishii T, Yanase T, Kobayashi K. Clinical Investigation of Adrenal Incidentalomas in Japanese Patients of the Fukuoka Region with Updated Diagnostic Criteria for Sub-clinical Cushing’s Syndrome. Intern Med. 2018 Sep 1;57(17):2467-2472. [Medline]
Created Mar 19, 2025.
