Consensus on the Diagnosis of Cushing’s Disease: A Collaborative Statement from the Korean Endocrine Society (KES) and Japan Endocrine Society (JES), 2026Endocrinol...

Journal: Endocrinology and Metabolism, 2026; 41(1):1‑13 DOI: 10.3803/EnM.2025.2707 Task Force: joint expert panel of KES & JES neuroendocrine working groups, Delphi‑based consensus for East‑Asian populationEndocrinol...

Abstract

Cushing’s disease (CD) is a rare ACTH‑secreting pituitary neoplasm causing endogenous hypercortisolaemia, associated with high comorbidity and excess mortality. Diagnostic pathways differ between Korean and Japanese national guidelines, especially biochemical cut‑offs and imaging strategies. This harmonized consensus unifies clinical screening, biochemical work‑up, imaging and differential diagnosis tailored for East‑Asian patients. It provides step‑wise recommendations: clinical suspicion → screening for endogenous Cushing syndrome → confirm ACTH‑dependent aetiology → distinguish pituitary CD from ectopic ACTH‑secreting syndrome → pituitary imaging.

Keywords: Cushing disease; Cushing syndrome; ACTH‑dependent hypercortisolism; diagnosis; pituitary MRI; inferior petrosal sinus sampling (IPSS)Seoul Nati...

1. Clinical suspicion

High‑risk clinical clues for CD (East‑Asian population):

1. Purple‑red striae > 1 cm width; disproportionate central obesity independent of BMI
2. Facial plethora, easy bruising, proximal muscle weakness
3. New‑onset hypertension, diabetes mellitus, dyslipidaemia, hypokalaemia
4. Venous thromboembolism, cognitive impairment, sleep disturbance, osteoporosis with fragility fracture
5. Paediatric: obesity with decelerated linear growth

Note: Hyperpigmentation is non‑specific; differentiate from insulin‑resistance‑related acanthosis nigricans. No single symptom is 100 % sensitive; index of clinical suspicion drives testing.

2. First‑line screening for endogenous hypercortisolism

At least two abnormal screening tests are required before proceeding to further work‑up. No single test is sufficient for diagnosis.

1. Late‑night salivary cortisol (LNSC)
   • Collect at habitual bedtime (not fixed midnight); ≥ 2 separate samples.
   • Mass‑spectrometry assay preferred. Shift‑worker circadian disruption causes false‑positive results.
2. Overnight 1‑mg dexamethasone suppression test (1 mg‑ODST)
   • Morning serum cortisol after overnight 1 mg dexamethasone.
   • Concurrent dexamethasone level measurement improves interpretation, especially with CYP3A4‑interacting medications. Oestrogen elevates CBG and may produce misleading high total cortisol.
3. 24‑hour urinary free cortisol (24‑h‑UFC)
   • Requires complete urine collection; average of 2‑3 collections. Lower sensitivity for mild hypercortisolaemia.

Recommendation: Any two positive tests confirm endogenous hypercortisolism. If results are discordant, repeat or use third screening modalityPMC.

3. Establish ACTH‑dependent hypercortisolism

Measure morning plasma ACTH together with serum cortisol after confirming hypercortisolaemia.

• Inappropriately normal or elevated ACTH → ACTH‑dependent CS (CD or ectopic ACTH syndrome).
• Suppressed ACTH (< 5 pg/mL) → ACTH‑independent (adrenal source, no further pituitary work‑up).

Caveat: Mild CD may show borderline ACTH; must interpret together with cortisol dynamics, cannot rely on ACTH alone for final classificationSemantic S....

4. Differentiate Cushing’s disease versus ectopic ACTH syndrome

4.1 Pituitary gadolinium‑enhanced MRI

• High‑resolution dynamic contrast‑enhanced pituitary MRI is first‑line imaging.
• Pituitary MRI negative does NOT exclude CD: microadenomas (< 6 mm) frequently escape detection in East‑Asian cohorts.
• A visible pituitary lesion ≥ 6 mm in the setting of biochemically confirmed ACTH‑dependent CS supports CD, but cannot fully rule out occult ectopic ACTH.

4.2 Inferior Petrosal Sinus Sampling (IPSS) — gold‑standard differential test

Strong recommendation: perform IPSS when:

1. Pituitary MRI is normal or shows only indeterminate small lesion (< 6 mm);
2. Biochemical picture is ambiguous between CD and ectopic ACTH.

• Basal and CRH‑stimulated IPSS: central‑to‑peripheral ACTH gradient ≥ 2 (basal) or ≥ 3 (post‑CRH) supports Cushing’s disease.
• Negative gradient strongly favours ectopic ACTH syndrome.

IPSS should be performed in high‑volume centres with experienced interventional radiology. False results may occur due to anomalous venous drainage.

4.3 Adjunct dynamic tests

• Desmopressin stimulation test may assist discrimination, but not recommended as stand‑alone test; use only in combination with IPSS/MRI.
• Dex‑CRH test: can help separate non‑neoplastic hypercortisolism (pseudo‑Cushing) from true CS when clinical‑biochemical picture overlaps.

5. Diagnostic algorithm summary (KES‑JES harmonized pathway)

1. Clinical suspicion of Cushing syndrome
2. ≥ 2 positive screening tests (LNSC / 1 mg‑ODST / 24‑h‑UFC) → confirm endogenous hypercortisolism
3. Morning ACTH:
   • Low ACTH → adrenal Cushing; evaluate adrenal glands.
   • Non‑suppressed ACTH → ACTH‑dependent CS
4. Dynamic‑contrast pituitary MRI:
   • Visible adenoma ≥ 6 mm: clinical diagnosis CD; shared decision for surgery.
   • No definite adenoma / lesion < 6 mm → IPSS is indicated to differentiate CD vs ectopic ACTH.
5. If IPSS favours ectopic ACTH: perform chest‑abdomen‑pelvis CT to search neuroendocrine tumour source.

6. Special clinical scenarios

1. Mild / intermittent Cushing’s disease: LNSC is more sensitive than UFC; multiple serial samples are required.
2. Pseudo‑Cushing syndrome (non‑neoplastic hypercortisolism): alcohol excess, severe depression, obesity, OSA. Distinguish by clinical context, Dex‑CRH or desmopressin test; avoid unnecessary pituitary surgery.
3. Paediatric CD: same biochemical principles; MRI false‑negative rate higher, IPSS threshold unchanged.
4. After adrenalectomy for CD (Nelson syndrome surveillance): serial ACTH + pituitary MRI follow‑up.

7. Key pitfalls & safety notes

1. No imaging test alone can diagnose CD; biochemistry always comes first. Do not operate pituitary purely based on incidental pituitary finding without confirmed hypercortisolaemia.
2. Pituitary “incidentaloma” is common in general population; do not misclassify incidental lesion as ACTH‑secreting adenoma.
3. Medications altering CYP3A, oestrogen, anticonvulsants interfere with dexamethasone suppression test.
4. IPSS has procedural risks; only indicated in ambiguous cases, not for every suspected CD.

8. Multidisciplinary requirement

Endocrinology, neurosurgery, interventional radiology, pathology should collaborate before final diagnosis and therapeutic decision‑making.

Disclaimer: This consensus provides evidence‑based expert recommendations for East‑Asian populations, not absolute rules. Clinical judgment is mandatory for individual patient managementSeoul Nati....

Comparison with international Endocrine‑Society guideline

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