What is the appropriate diagnosis and treatment approach for a patient suspected of having Cushing's syndrome?

Cushing Syndrome: Diagnosis and Treatment

What is Cushing Syndrome?

Cushing syndrome is a rare endocrine disorder caused by prolonged exposure to excessive cortisol, either from exogenous glucocorticoid use (most common) or endogenous overproduction (incidence 2-8 per million annually). 1, 2

The condition results from three main endogenous sources:

• Pituitary adenomas (Cushing disease): 60-70% of endogenous cases, caused by ACTH-secreting pituitary tumors 1, 3
• Ectopic ACTH secretion: 15% of cases, from non-pituitary tumors 3
• Adrenal tumors: 15% of cases, producing cortisol independent of ACTH 3

Clinical Presentation

The most specific features for Cushing syndrome include abnormal fat distribution in supraclavicular and temporal fossae, proximal muscle weakness, wide purple striae, and in children, decreased linear growth with continued weight gain. 3

Additional manifestations include:

• Facial plethora, easy bruising, and fragile skin 1, 2
• Hypertension (present in >80% of patients) 4
• Hyperglycemia and metabolic dysfunction 1, 2
• Mood disorders, depression, and neurocognitive changes 1, 2
• Increased risk of infections, thromboembolism, and cardiovascular events 2

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Diagnostic Algorithm

Step 1: Rule Out Exogenous Glucocorticoid Use

Before any biochemical testing, thoroughly review all glucocorticoid use including oral, inhaled, topical, and injected preparations, as iatrogenic Cushing syndrome is the most common cause. 5

Step 2: Screen for Hypercortisolism

For patients with intermediate to high clinical suspicion, perform 2-3 first-line screening tests to confirm hypercortisolism. 6, 5

The three recommended screening tests are:

1. Late-night salivary cortisol (LNSC): Collect 2-3 samples at the patient's usual bedtime on consecutive days (sensitivity 95%, specificity 93-100%) 6, 5

   • Critical contraindication: Do NOT use in night-shift workers or those with disrupted sleep-wake cycles 5
   • Avoid topical hydrocortisone contamination 5

2. 24-hour urinary free cortisol (UFC): Collect 2-3 samples to account for variability (sensitivity 89%, specificity 100%) 6, 5

3. Overnight 1 mg dexamethasone suppression test (DST): Give 1 mg dexamethasone at 11 PM, measure cortisol at 8 AM; normal suppression is <1.8 μg/dL (50 nmol/L) 6, 5

   • Measure dexamethasone levels simultaneously to confirm adequate absorption and rule out false positives 6, 5

If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis. 6, 5

Common causes of false positives include severe obesity, uncontrolled diabetes, depression, alcoholism, pregnancy, and oral estrogen use. 6, 5

Step 3: Determine ACTH Dependency

Once hypercortisolism is confirmed, measure morning (8-9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes. 6, 7, 5

• ACTH >5 ng/L (>1.1 pmol/L): ACTH-dependent Cushing syndrome (pituitary or ectopic source) 7, 5
• ACTH >29 ng/L: 70% sensitivity and 100% specificity for Cushing disease 7
• Low or undetectable ACTH: ACTH-independent Cushing syndrome (adrenal source) 7, 5

Step 4: Localize the Source

For ACTH-Independent Cushing Syndrome (Low ACTH):

Perform adrenal CT or MRI to identify adrenal lesion(s). 7, 5

Treatment options:

• Adrenal adenoma: Laparoscopic adrenalectomy 7
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 7
• Bilateral hyperplasia: Medical management or unilateral adrenalectomy 7

For ACTH-Dependent Cushing Syndrome (Normal/High ACTH):

Perform high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to detect pituitary adenoma. 7, 5

MRI interpretation:

• Adenoma ≥10 mm: Strongly suggests Cushing disease; proceed to surgery 6, 7
• Adenoma 6-9 mm: Consider CRH stimulation test or bilateral inferior petrosal sinus sampling (BIPSS) 6, 7
• No adenoma or <6 mm lesion: Perform BIPSS to distinguish pituitary from ectopic ACTH 6, 7

Note: MRI has only 63% sensitivity for detecting ACTH-secreting pituitary adenomas, as microadenomas are often ≤2 mm in diameter. 7, 5

Step 5: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for differentiating pituitary Cushing disease from ectopic ACTH syndrome when MRI is negative or equivocal. 6, 7

Diagnostic criteria:

• Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH or desmopressin stimulation confirms pituitary source (sensitivity 96-100%, specificity approaching 100%) 6, 7

BIPSS must be performed at a specialized center by an experienced interventional radiologist, with successful bilateral cannulation rate >85%. 7

Measure prolactin levels simultaneously from petrosal sinuses to confirm adequate venous efflux and improve diagnostic accuracy. 7

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Treatment Approach

First-Line Treatment: Surgery

Surgical resection of the tumor causing cortisol excess is the optimal first-line treatment for all forms of Cushing syndrome. 1, 3, 2

• Cushing disease: Transsphenoidal surgery for pituitary adenoma 6
• Ectopic ACTH syndrome: Surgical removal of ectopic tumor when possible 7
• Adrenal adenoma: Laparoscopic adrenalectomy 7

After successful treatment, adrenal function typically recovers within 12 months, with an 80% recovery rate. 6

Second-Line Treatment: Medical Therapy

Medical therapy is indicated for patients awaiting surgery, with persistent disease after surgery, who are not surgical candidates, or who decline surgery. 6, 8

Adrenal Steroidogenesis Inhibitors:

1. Osilodrostat (11β-hydroxylase inhibitor): Achieves urinary free cortisol normalization in 86% of patients with median time to response of 2 months 6

2. Ketoconazole: Response rate approximately 70%; considered the medical treatment of choice in many guidelines 6, 3

3. Metyrapone: Inhibits 11β-hydroxylation in the adrenal cortex, reducing cortisol and corticosterone production 9

For hypertension management in Cushing syndrome, blocking mineralocorticoid actions with spironolactone or eplerenone is a sensible strategy, though the optimal antihypertensive regimen remains inadequately described. 4

Third-Line Treatment: Radiation and Bilateral Adrenalectomy

Radiation therapy can be considered for persistent disease after surgery when medical therapy is inadequate or not tolerated, though cortisol normalization may take months to years. 6

Bilateral adrenalectomy is reserved for ACTH-dependent causes when other treatments have failed. 2

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Critical Pitfalls to Avoid

• Do not perform LNSC in night-shift workers or those with disrupted circadian rhythms 5
• Do not proceed to imaging before biochemical confirmation of hypercortisolism 4
• Do not rely on a single screening test; perform 2-3 tests to confirm diagnosis 6, 5
• Do not forget to measure dexamethasone levels during DST to rule out false positives from malabsorption 6, 5
• Consider cyclic Cushing syndrome if results are inconsistent; perform extended monitoring with multiple sequential measurements 5
• Recognize that up to one-third of diagnostic test results may be discordant; use clinical context to guide management 7

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Special Considerations

In children, lack of height gain with concurrent weight gain is the most common presentation, and children with Cushing syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise. 6

If genetic syndrome is suspected (particularly in young patients or those with family history), genetic counseling and additional investigations are necessary. 6

Given the high morbidity and mortality of untreated Cushing syndrome, aggressive treatment of hypertension and metabolic complications is essential. 4