What is the most likely cause of Cushingoid features with hypercortisolism and elevated Adrenocorticotropic hormone (ACTH) levels?

Most Likely Diagnosis: Pituitary Adenoma (Cushing's Disease)

The combination of Cushingoid features with elevated cortisol AND elevated ACTH indicates ACTH-dependent Cushing's syndrome, and pituitary adenoma is by far the most common cause, accounting for 75-80% of cases in children and 49-71% in adults. 1

Diagnostic Reasoning

Why Elevated ACTH Matters

• Elevated ACTH levels definitively indicate that the hypercortisolism is ACTH-dependent, meaning the excess cortisol is not originating from the adrenal gland itself 2, 3
• This single finding immediately excludes adrenal adenoma as the cause, since adrenal tumors produce ACTH-independent Cushing's syndrome with low or undetectable ACTH levels 3
• ACTH-dependent Cushing's syndrome has only two main sources: pituitary adenoma (Cushing's disease) or ectopic ACTH production 3

Why Pituitary Adenoma is Most Likely

• Pituitary adenomas represent 75-80% of ACTH-dependent Cushing's syndrome cases, making them the overwhelming favorite statistically 1
• The 4-month duration of symptoms is consistent with pituitary disease, which typically presents with gradual onset 4
• Most pituitary adenomas are microadenomas (≤2 mm in 98% of cases), which explains why they can be challenging to detect on imaging 1

Why NOT the Other Options

Adrenal adenoma is excluded because:

• Adrenal tumors cause ACTH-independent Cushing's syndrome with suppressed ACTH levels 3
• The elevated ACTH in this patient proves the adrenal glands are being stimulated by an external ACTH source, not producing cortisol autonomously 2

Iatrogenic causes are excluded because:

• The question states laboratory investigations show high cortisol, implying endogenous production
• Exogenous glucocorticoid administration would suppress ACTH levels, not elevate them 5

Carcinoid syndrome is not the primary diagnosis because:

• While ectopic ACTH production from neuroendocrine tumors (including thymic carcinoids) can cause Cushing's syndrome, this represents only 2% of cases 2
• Ectopic ACTH syndrome typically presents with more severe biochemical abnormalities, including very high urinary free cortisol and profound hypokalemia 3
• Carcinoid syndrome itself (flushing, diarrhea) occurs in only 2% of thymic carcinoid cases and is distinct from ectopic ACTH production 2

Next Diagnostic Steps

Pituitary MRI should be performed immediately to identify the adenoma 3, 4:

• High-quality 3T MRI with thin slices maximizes detection of small adenomas 3
• If an adenoma ≥10 mm is found, this strongly confirms Cushing's disease 3

If MRI is negative or shows only a lesion <6 mm, bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard to confirm pituitary source 3, 4:

• BIPSS uses a central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation to confirm pituitary origin 3
• This test definitively distinguishes between pituitary and ectopic ACTH sources 3

Common Pitfalls to Avoid

• Do not assume normal MRI excludes pituitary disease: MRI only identifies adenomas in 60-75% of patients, and many are extremely small 4
• Do not pursue adrenal imaging first: The elevated ACTH already tells you the problem is not in the adrenal glands 3
• Do not overlook ectopic sources entirely: While less common, if BIPSS is negative or clinical features suggest ectopic ACTH (very high cortisol, rapid onset, severe hypokalemia), pursue whole-body imaging with CT and consider 68Ga-DOTATATE PET for neuroendocrine tumor localization 2, 3