What are the diagnostic and treatment approaches for a patient with suspected Cushing's syndrome, presenting with symptoms such as weight gain, hypertension, glucose intolerance, and osteoporosis?

Cushing's Syndrome: Diagnostic and Treatment Approach

Initial Diagnostic Strategy

Begin screening with 2-3 tests: 24-hour urinary free cortisol (UFC), late-night salivary cortisol, and/or 1 mg overnight dexamethasone suppression test (DST), as recommended by the Endocrine Society. 1, 2 Failure to suppress morning cortisol to <1.8 μg/dL (<50 nmol/L) after 1 mg dexamethasone at bedtime confirms hypercortisolism. 1, 2

Key Screening Considerations

• Measure plasma dexamethasone levels during DST to rule out false positives from malabsorption or drug interactions with CYP3A4 inducers. 2
• Severe obesity, uncontrolled diabetes, alcoholism, and psychiatric disorders can cause false-positive screening results. 2
• Cyclic Cushing's syndrome requires periodic re-evaluation if initial testing is negative but clinical suspicion remains high. 2

Determining Etiology: ACTH-Dependent vs ACTH-Independent

After confirming hypercortisolism, measure morning (8-9 AM) plasma ACTH to distinguish between ACTH-dependent and ACTH-independent causes. 2

ACTH Level Interpretation

• ACTH >5 ng/L indicates ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic ACTH source). 2
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease. 2
• Low or undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal source). 2

Diagnostic Algorithm for ACTH-Dependent Disease

For ACTH-dependent Cushing's, obtain high-quality pituitary MRI (preferably 3T) with thin slices as the next step. 2

MRI-Based Decision Tree

• If pituitary adenoma ≥10 mm: Proceed directly to transsphenoidal surgery without IPSS. 3, 2
• If adenoma 6-9 mm: Perform bilateral inferior petrosal sinus sampling (IPSS) to confirm pituitary source. 3, 2
• If no adenoma or lesion <6 mm: IPSS is mandatory to distinguish Cushing's disease from ectopic ACTH syndrome. 3, 2

IPSS Diagnostic Criteria

IPSS confirms pituitary source with central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation, achieving 96-100% sensitivity and near 100% specificity. 2 IPSS must be performed at specialized centers by experienced interventional radiologists. 2

Ectopic ACTH Evaluation

If ectopic ACTH syndrome is suspected (very high UFC, profound hypokalemia, male patient), obtain neck-to-pelvis thin-slice CT scan. 3 Consider 68Ga-DOTATATE PET imaging for localizing occult neuroendocrine tumors. 2

Diagnostic Algorithm for ACTH-Independent Disease

For ACTH-independent Cushing's, obtain adrenal CT or MRI to identify the adrenal lesion. 2

Treatment Approach

First-Line: Surgical Management

Surgery to remove the cortisol-producing source is the cornerstone of treatment for all etiologies of endogenous Cushing's syndrome. 4, 5, 6

• Cushing's disease: Transsphenoidal resection of pituitary adenoma (75-80% initial success rate). 7
• Adrenal adenoma: Laparoscopic unilateral adrenalectomy. 4
• Ectopic ACTH: Surgical resection of the ectopic tumor when localized. 4
• Postoperative glucocorticoid replacement is mandatory until hypothalamic-pituitary-adrenal axis recovery. 4

Medical Management of Hypertension

Spironolactone or eplerenone is the most appropriate initial antihypertensive agent in Cushing's syndrome because it blocks mineralocorticoid receptors that mediate cortisol-induced hypertension. 1, 4 Conventional antihypertensives (ACE inhibitors, ARBs, calcium channel blockers) may not achieve blood pressure targets alone. 1

Adequate diuretic therapy must be combined with mineralocorticoid receptor antagonists given the prominent role of sodium retention. 4 Aggressive treatment is warranted given the 70-90% prevalence of hypertension and high cardiovascular disease risk. 4

Medical Therapy for Hypercortisolism

Medical therapy is indicated when surgery fails, patients are not surgical candidates, or as a bridge to surgery. 4, 8

Steroidogenesis Inhibitors

Ketoconazole (400-1200 mg/day) is first-line medical therapy due to its relatively tolerable toxicity profile and ability to reduce cortisol production. 4 Metyrapone is an alternative steroidogenesis inhibitor. 1, 7

Pituitary-Targeted Therapy

Pasireotide (somatostatin analog) and cabergoline (dopamine agonist) target ACTH-secreting pituitary tumors but have limited efficacy. 7, 8

Glucocorticoid Receptor Blocker

Mifepristone blocks cortisol action at the receptor level and is used in refractory cases. 7, 8

Management of Metabolic Complications

Address hyperglycemia and dyslipidemia through standard therapies while pursuing definitive treatment of hypercortisolism. 4 Glucose abnormalities, hypertension, and osteoporosis should be managed aggressively given the high cardiovascular disease risk. 3, 4

Thromboprophylaxis

Extended thromboprophylaxis (up to 30 days postoperatively) is recommended given the >10-fold increased risk of venous thromboembolism in Cushing's syndrome. 3 The hypercoagulable state persists for months after cortisol normalization. 3

Special Consideration: Mild Autonomous Cortisol Secretion (MACS)

Younger patients with MACS and progressive metabolic comorbidities (diabetes, hypertension, vertebral fractures) attributable to cortisol excess should be considered for adrenalectomy after shared decision-making. 4 Patients managed conservatively require annual screening for new or worsening metabolic complications. 4

Common Pitfalls

• Never rely solely on LDDST without measuring ACTH levels, as this can lead to misdiagnosis. 2
• Do not perform imaging before biochemical confirmation of hypercortisolism. 3
• Avoid IPSS in patients with lesions ≥10 mm on MRI, as it is unnecessary. 3
• Stop medical therapy for Cushing's disease before IPSS to enable accurate interpretation. 2
• Confirm active hypercortisolism immediately before IPSS in cyclic Cushing's disease. 2
• Recognize that 20-25% of patients experience recurrence within 2-4 years after initially successful surgery, requiring long-term surveillance. 7