What is the definition of Cushing's syndrome?

Definition of Cushing's Syndrome

Cushing's syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology, characterized by specific clinical features and biochemical evidence of hypercortisolism. 1

Etiology and Classification

Cushing's syndrome can be categorized based on the source of excess cortisol:

1. ACTH-dependent causes (70-80% of cases):

   • Cushing's disease (ACTH-secreting pituitary adenoma) - most common form (60-70%)
   • Ectopic ACTH syndrome (non-pituitary tumors in lung, thyroid, pancreas, or bowel)

2. ACTH-independent causes (20-30% of cases):

   • Adrenal adenoma
   • Adrenal carcinoma
   • Bilateral adrenal hyperplasia

3. Exogenous causes (most frequent overall):

   • Iatrogenic (glucocorticoid medication)

Diagnostic Criteria

The diagnosis of Cushing's syndrome requires:

1. Clinical suspicion based on characteristic features
2. Exclusion of exogenous glucocorticoid use
3. At least two positive screening tests 2:
   • 24-hour urinary free cortisol (UFC) - sensitivity >90%
   • Late-night salivary cortisol (LNSC) - sensitivity >90%, specificity 100%
   • 1-mg overnight dexamethasone suppression test (DST) - cutoff <1.8 μg/dL

Clinical Features

The clinical presentation includes:

• Growth pattern changes: In children, weight gain with decreased height velocity is particularly diagnostic 3
• Body composition changes: Central obesity, facial plethora, dorsocervical fat pad ("buffalo hump"), supraclavicular fat pads
• Skin changes: Purple striae, easy bruising, thin skin, hirsutism
• Muscle changes: Proximal muscle weakness
• Metabolic abnormalities: Hyperglycemia, hypertension, dyslipidemia
• Bone changes: Osteoporosis, increased fracture risk
• Neuropsychiatric symptoms: Depression, anxiety, cognitive impairment
• Immunosuppression: Increased susceptibility to infections

Determining the Cause

After confirming hypercortisolism, the diagnostic approach includes:

1. Plasma ACTH measurement to distinguish ACTH-dependent from ACTH-independent causes 2
2. Imaging studies:
   • Pituitary MRI for suspected Cushing's disease
   • Adrenal CT/MRI for adrenal causes
   • Chest/abdomen/pelvis imaging for ectopic sources
3. Specialized testing:
   • Bilateral inferior petrosal sinus sampling to distinguish pituitary from ectopic ACTH sources
   • Adrenal vein sampling in certain cases

Treatment Approach

The first-line treatment for all forms of endogenous Cushing's syndrome is surgical resection of the causative tumor 2, 4:

• Transsphenoidal surgery for Cushing's disease (60-80% remission rate for microadenomas)
• Unilateral adrenalectomy for adrenal adenomas/carcinomas
• Resection of ectopic ACTH-producing tumors when possible

For persistent or recurrent disease, options include:

• Second surgery
• Medical therapy with steroidogenesis inhibitors (osilodrostat, metyrapone, ketoconazole)
• Pituitary radiation therapy
• Bilateral adrenalectomy as a last resort

Monitoring and Complications

Long-term monitoring is essential due to:

• Risk of recurrence
• Persistent comorbidities even after biochemical cure
• Need for hormone replacement in cases of adrenal insufficiency

The most concerning complications include cardiovascular disease, thromboembolic events, infections, and neuropsychiatric disorders, which significantly impact mortality and quality of life 5, 6.

In pediatric patients, special attention must be paid to growth, pubertal progression, and GH deficiency testing 2.

By understanding the definition and diagnostic criteria of Cushing's syndrome, clinicians can identify this condition earlier, potentially reducing the significant morbidity and mortality associated with prolonged hypercortisolism.