What is the diagnostic and treatment approach for Cushing syndrome?

From the Guidelines

The diagnostic approach for Cushing syndrome begins with screening tests to detect hypercortisolism, including 24-hour urinary free cortisol, late-night salivary cortisol, and the overnight dexamethasone suppression test, as recommended by the most recent guidelines 1.

Diagnostic Approach

The initial step in diagnosing Cushing syndrome is to confirm hypercortisolism. This can be achieved through several screening tests:

• 24-hour urinary free cortisol
• Late-night salivary cortisol
• Overnight dexamethasone suppression test Once hypercortisolism is confirmed, the next step is to determine the source of the excess cortisol by measuring ACTH levels.
• High ACTH levels suggest either pituitary adenoma (Cushing's disease) or ectopic ACTH production.
• Low ACTH levels indicate adrenal causes.

Localization and Treatment

Further localization involves imaging studies such as:

• Pituitary MRI for suspected pituitary adenoma
• Adrenal CT for suspected adrenal causes
• Whole-body imaging for ectopic sources Treatment depends on the underlying cause:
• For Cushing's disease, transsphenoidal surgery to remove the pituitary adenoma is first-line therapy.
• For adrenal causes, laparoscopic adrenalectomy is typically performed.
• Medical therapy may be used when surgery is contraindicated or as a bridge to surgery, including steroidogenesis inhibitors like ketoconazole (400-1200 mg/day) or metyrapone (500-6000 mg/day) 1.
• Glucocorticoid receptor antagonists such as mifepristone can also be used.
• For ectopic ACTH syndrome, treatment focuses on the primary tumor.

Monitoring and Management

Patients require careful monitoring for adrenal insufficiency after treatment, and many need temporary glucocorticoid replacement therapy. Prompt diagnosis and treatment are essential as chronic hypercortisolism leads to significant morbidity, including diabetes, hypertension, osteoporosis, and increased cardiovascular risk 1. The most recent and highest quality study 1 provides a comprehensive guideline for the diagnosis and management of Cushing syndrome, emphasizing the importance of a multidisciplinary approach to achieve optimal outcomes.

From the FDA Drug Label

1 INDICATIONS AND USAGE 1.1 Cushing's Disease

SIGNIFOR is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

14 CLINICAL STUDIES 14. 1 Cushing's Syndrome

An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of mifepristone in the treatment of endogenous Cushing's syndrome.

The diagnostic approach for Cushing syndrome is not directly stated in the provided drug labels. However, the treatment approach for Cushing syndrome is mentioned.

• Treatment: The treatment approach includes the use of medications such as pasireotide (IM) 2 and mifepristone (PO) 3 3.
• Medication Dosage: Mifepristone treatment was started at a dose of 300 mg once a day, with the option to increase the dose to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks to a maximum of 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg, based on clinical tolerance and clinical response.
• Key Considerations: The primary efficacy analysis for the diabetes cohort was an analysis of responders, defined as patients who had a ≥ 25% reduction from baseline in glucose AUC.
• Response to Treatment: Fifteen of 25 patients (60%) were treatment responders, with a mean reduction in HbA1c of 1.1% from baseline to the end of the trial. Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations.

From the Research

Diagnostic Approach for Cushing Syndrome

• The diagnosis of Cushing syndrome (CS) is challenging due to its nonspecific presentation 4.
• Diagnostic tests such as 24-h urine free cortisol (UFC) and the overnight 1 mg dexamethasone suppression test (DST) lack sufficient sensitivity and specificity 4.
• Measurement of nocturnal salivary cortisol (NSC) is an accurate and reproducible test with a high sensitivity for CS 4, 5.
• Late-night salivary cortisol (LNSC) measurement is a simple and reliable screening test for spontaneous Cushing's syndrome 5.

Screening Tests for Cushing Syndrome

• The Endocrine Society's Clinical Practice Guidelines recommend a single test with a high diagnostic accuracy, among the 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and 24 h urinary free cortisol (UFC) 6.
• The 1-mg DST explores the normal feedback reaction from the hypothalamic-pituitary-adrenal axis (HPA) 6.
• UFC levels reflect the integrated tissue exposure to free cortisol over 24 h, and thus provide a particular picture of endogenous hypercortisolism 6.
• Salivary cortisone levels, measured by liquid chromatography-tandem mass spectrometry, can be used to investigate hypercortisolism 7.

Interpretation of Results and Further Assessment

• Interpretation of results can be difficult due to individual patient characteristics and requires awareness of test limitations 8.
• Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent or ACTH-independent causes 8.
• Further assessment with different imaging modalities and dynamic biochemical testing, including bilateral inferior petrosal sinus sampling, helps further pinpoint the cause of Cushing's syndrome 8.

Treatment Approach for Cushing Syndrome

• Appropriate surgery is often necessary for the treatment of Cushing syndrome, and histopathology of the tumor is essential for diagnosis 4.
• The treatment approach may vary depending on the underlying cause of Cushing syndrome, such as ACTH-dependent or ACTH-independent causes 8.