What is the likely diagnosis and recommended evaluation and management for a patient with markedly elevated ACTH, morbid obesity, and headache?

High ACTH with Morbid Obesity and Headache: Likely Diagnosis and Management

The most likely diagnosis is Cushing's disease (pituitary ACTH-secreting adenoma), which accounts for 75-80% of ACTH-dependent Cushing's syndrome cases and requires immediate biochemical confirmation followed by pituitary imaging. 1

Initial Diagnostic Confirmation

The combination of markedly elevated ACTH with morbid obesity strongly suggests ACTH-dependent Cushing's syndrome, and you must first confirm hypercortisolism before proceeding with localization studies. 1

Confirm hypercortisolism with:

• 24-hour urinary free cortisol (UFC) - elevated levels confirm pathologic cortisol excess 1, 2
• Late-night salivary cortisol (LNSC) - perform 2-3 measurements to demonstrate loss of normal circadian rhythm; this is particularly important in morbidly obese patients where false positives are common 1, 2
• 1-mg overnight dexamethasone suppression test - failure to suppress cortisol to <1.8 μg/dL confirms autonomous cortisol production 1

Critical caveat: Severe obesity alone can cause false-positive screening tests, so multiple confirmatory tests are essential before proceeding with invasive localization procedures. 1, 2

ACTH Level Interpretation

Once hypercortisolism is confirmed, measure morning (08:00-09:00h) plasma ACTH to classify the syndrome. 1

• ACTH >5 ng/L = ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 1
• ACTH >29 ng/L = 70% sensitivity and 100% specificity for Cushing's disease specifically 1
• Low or undetectable ACTH = ACTH-independent (adrenal source) - this would rule out your patient's presentation 1

The patient does NOT need to be fasting for ACTH measurement, but ensure they are not on exogenous steroids which would suppress ACTH. 1

Localization Algorithm for ACTH-Dependent Disease

Step 1: Pituitary MRI with Contrast

Order high-quality pituitary MRI with thin slices (3T preferred over 1.5T) as the next step. 1, 3

Interpretation:

• Adenoma ≥10 mm = proceed directly to transsphenoidal surgery 1
• Adenoma 6-9 mm = consider CRH stimulation test or proceed to BIPSS 1
• No adenoma or <6 mm lesion = proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1

Important limitation: MRI detects only 63% of ACTH-secreting pituitary adenomas because microadenomas are frequently ≤2 mm in diameter. 1, 3 A negative MRI does NOT rule out Cushing's disease.

Step 2: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for distinguishing pituitary from ectopic ACTH sources when MRI is negative or equivocal. 1, 3

Diagnostic criteria:

• Central-to-peripheral ACTH ratio ≥2:1 at baseline = confirms pituitary source 1, 3
• Central-to-peripheral ACTH ratio ≥3:1 after CRH or desmopressin stimulation = confirms pituitary source 1, 3
• Sensitivity 96-100%, specificity approaching 100% when performed correctly 1

Critical technical requirements:

• Must be performed at a specialized center by experienced interventional radiologist 1
• Measure prolactin levels simultaneously from petrosal sinuses to confirm adequate venous sampling 1
• Ensure patient is in active hypercortisolemic phase (especially important if cyclic Cushing's suspected) 1
• Stop all steroidogenesis inhibitors before BIPSS to enable accurate interpretation 1

Step 3: If Ectopic ACTH Suspected

If BIPSS suggests ectopic source OR if clinical features suggest ectopic syndrome (very high UFC, profound hypokalemia, rapid onset, pigmentation without typical Cushingoid features), proceed with: 1, 4

• Neck-to-pelvis thin-slice CT scan to identify occult tumors 1
• 68Ga-DOTATATE PET imaging for neuroendocrine tumors not visible on conventional imaging 1
• Chest CT - small cell lung carcinoma is the most common ectopic source 5, 6

Key distinguishing features of ectopic ACTH syndrome:

• Hypokalemic alkalosis with muscle weakness (present in all ectopic cases vs. only 10% of Cushing's disease) 4
• Hyperpigmentation without full Cushingoid features 4, 6
• Very rapid onset of symptoms 4
• Extremely elevated cortisol and ACTH levels 4, 6

Clinical Features Supporting Cushing's Disease

The headache in your patient may represent mass effect from a pituitary macroadenoma, though microadenomas are more common (98% of cases). 1

Most specific clinical features for Cushing's syndrome:

• Abnormal fat distribution in supraclavicular and temporal fossae 5
• Proximal muscle weakness 2, 5
• Wide purple striae 2, 5
• Central obesity with moon facies 1

Treatment Approach

For Confirmed Cushing's Disease (Pituitary Source):

First-line treatment is transsphenoidal surgical resection of the pituitary adenoma, which cures 80% of microadenomas. 3, 7 Macroadenomas have lower cure rates and represent an unfavorable prognostic indicator. 1

Medical therapy options if surgery fails or is contraindicated:

• Ketoconazole 400-1200 mg/day - most commonly used due to relatively tolerable side effects 3, 5
• Osilodrostat - highest efficacy for UFC normalization based on prospective trials 8
• Metyrapone - effective based on retrospective and prospective data 8
• Pasireotide LAR - prospective data available 8

Monitor ACTH levels during medical therapy with adrenal-targeting agents, as significant elevations may indicate tumor growth requiring MRI reassessment. 8

For Ectopic ACTH Syndrome:

• Surgical removal of ectopic tumor if localized and resectable 3, 5
• Bilateral laparoscopic adrenalectomy if tumor unresectable 3
• Medical management with ketoconazole or other steroidogenesis inhibitors 3

Common Pitfalls to Avoid

• Do not skip confirmatory testing in morbidly obese patients - obesity causes false-positive screening tests 1, 2
• Do not rely on a single screening test - use multiple modalities to confirm hypercortisolism 1, 2
• Do not skip BIPSS based on positive MRI alone if the lesion is <10 mm - incidentalomas occur in 10% of the population 1
• Do not measure ACTH in the afternoon - established diagnostic cutoffs are based on morning measurements only 1
• Do not assume treatment resistance without ensuring adequate dosing - underdosing is commonly misinterpreted as resistance 8