What is the diagnosis and treatment for a patient with suspected Cushing's syndrome?

Cushing Syndrome: Diagnosis and Treatment

Diagnostic Approach

For patients with suspected Cushing syndrome, first rule out exogenous glucocorticoid use, then perform 2-3 first-line screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight 1 mg dexamethasone suppression test to confirm hypercortisolism. 1, 2

Initial Screening Tests

• Late-night salivary cortisol has 95% sensitivity and 93-100% specificity, making it the easiest test for patient compliance 1, 2
• 24-hour urinary free cortisol demonstrates 89% sensitivity and 100% specificity 1
• Overnight 1 mg dexamethasone suppression test uses a cutoff of <1.8 μg/dL (50 nmol/L) for normal suppression; measuring dexamethasone levels simultaneously is recommended to rule out false positives from malabsorption 1, 2

Important Caveats for Screening

Be aware that false positives occur in several conditions 2:

• Severe obesity
• Uncontrolled diabetes mellitus
• Depression
• Alcoholism
• Pregnancy

If any screening test is abnormal, repeat 1-2 screening tests to confirm the diagnosis before proceeding with further evaluation. 2

Determining the Etiology

ACTH Measurement

Once hypercortisolism is confirmed, measure morning (08:00-09:00h) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes. 1, 3

• ACTH >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent Cushing syndrome 1, 3
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing disease 3
• Low or undetectable ACTH indicates ACTH-independent (adrenal) Cushing syndrome 3

ACTH-Independent Cushing Syndrome (Adrenal Source)

For ACTH-independent disease, perform adrenal CT or MRI to identify adrenal lesions. 1, 3

Treatment options based on imaging findings 4, 1:

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

ACTH-Dependent Cushing Syndrome (Pituitary or Ectopic Source)

For ACTH-dependent disease, obtain high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to detect pituitary adenoma. 1, 2

Interpretation algorithm 1, 2:

• Adenoma ≥10 mm: Presume Cushing disease and proceed to surgery
• Adenoma 6-9 mm: Consider CRH stimulation test for additional confirmation
• No adenoma or <6 mm lesion: Perform bilateral inferior petrosal sinus sampling (BIPSS)

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. 1, 2

Diagnostic criteria 1, 2:

• Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin stimulation confirms pituitary source
• Central-to-peripheral ACTH ratio ≥3:1 after stimulation confirms pituitary source
• Sensitivity approaches 96-100% and specificity approaches 100% when performed correctly

BIPSS must be performed at a specialized center by an experienced interventional radiologist due to potential patient risk. 2

Treatment Strategy

Surgical Management

Surgical resection of the tumor causing cortisol excess is the optimal first-line treatment for all forms of Cushing syndrome. 1, 5, 6

Specific surgical approaches 4, 1:

• Cushing disease (pituitary adenoma): Transsphenoidal surgery
• Ectopic ACTH syndrome: Surgical removal of ectopic tumor when possible
• Adrenal adenoma: Laparoscopic unilateral adrenalectomy
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy

Patients with unilateral cortisol-secreting adrenal masses and clinically apparent Cushing syndrome should undergo unilateral adrenalectomy, with minimally-invasive surgery performed when feasible. 4

Medical Therapy

Medical therapy is indicated for patients awaiting surgery, with persistent disease after surgery, who are not surgical candidates, or who decline surgery. 1, 7

Adrenal Steroidogenesis Inhibitors

Osilodrostat achieves urinary free cortisol normalization in 86% of patients with a median time to response of 2 months 2

Ketoconazole has approximately 70% response rate and is considered the medical treatment of choice by some experts 2, 8. However, the FDA label warns 9:

• Serious hepatotoxicity including fatal cases has occurred
• Baseline liver tests (ALT, AST, alkaline phosphatase, total bilirubin) are required
• Weekly ALT monitoring is mandatory for the duration of treatment
• Doses of 400 mg and higher decrease adrenal corticosteroid secretion
• Can prolong QT interval and is contraindicated with multiple cardiac medications

Metyrapone is an alternative steroidogenesis inhibitor that reduces cortisol production by inhibiting 11-beta-hydroxylation in the adrenal cortex 10

Mild Autonomous Cortisol Secretion (MACS)

Younger patients with MACS who have progressive metabolic comorbidities attributable to cortisol excess can be considered for adrenalectomy after shared decision-making. 4

• Patients not managed surgically should undergo annual clinical screening for new or worsening associated comorbidities 4
• MACS is associated with type 2 diabetes, hypertension, cardiovascular events, vertebral fractures, and mortality 4
• No patients with MACS progress to overt Cushing syndrome 4

Radiation Therapy and Bilateral Adrenalectomy

Radiation therapy and bilateral adrenalectomy are reserved for persistent disease after surgery when medical therapy is inadequate or not tolerated. 1, 2

• Cortisol normalization after radiation may take months to years 2
• After successful treatment, adrenal function typically recovers within 12 months with an 80% recovery rate 2

Post-Treatment Follow-Up

Offer all patients in remission from Cushing disease 6-monthly clinical examination, 24-hour urinary free cortisol, electrolytes, and morning serum cortisol for at least 2 years, followed by lifelong annual clinical assessment. 4

• Recurrence rates vary from 6% to 40% and usually occur within 5 years, though late relapse can occur 4
• Consider long-term monitoring for psychiatric and neurocognitive comorbidities following remission 4
• GH deficiency is the most frequent pituitary deficit after surgical or radiotherapeutic cure 4

Special Populations

In children, lack of height gain with concurrent weight gain is the most common presentation of Cushing syndrome, and referral to multidisciplinary centers with pediatric endocrinology expertise is recommended. 1, 2