What are the causes of Cushing's syndrome, including adrenal carcinoma, chronic use of inhaled corticosteroids (ICS), ethanol (ETOH) abuse, or pituitary microadenoma?

Causes of Cushing's Syndrome

Cushing's syndrome is primarily caused by ACTH-dependent pituitary adenomas (Cushing's disease), followed by adrenal tumors, ectopic ACTH production, and exogenous glucocorticoid use, with pituitary microadenomas being the most common cause in 75-80% of cases. 1

ACTH-Dependent Causes (60-70% of cases)

Pituitary Adenomas (Cushing's Disease)

• Most common cause of endogenous Cushing's syndrome (75-80% of cases) 1, 2
• Typically microadenomas (<10mm), accounting for 98% of cases in children and young people 1
• More common in adult females (79%), but shows male predominance in prepubertal children (71%) 1
• Characterized by elevated ACTH levels and positive dexamethasone suppression testing 1

Ectopic ACTH Syndrome

• Tumors in lung, thyroid, pancreas, or bowel that secrete ACTH 1
• Less common than pituitary source
• Often presents with more severe and rapid-onset symptoms 2

ACTH-Independent Causes (15-20% of cases)

Adrenal Adenomas

• Benign tumors of the adrenal gland 1
• Do not produce ACTH (suppressed ACTH levels) 1
• Treatment is laparoscopic adrenalectomy 1

Adrenal Carcinomas

• Malignant adrenal tumors causing Cushing's syndrome 3
• Should be suspected when:
  • Tumor is larger than 5 cm 1
  • Shows irregular margins or heterogeneous appearance 1
  • Local invasion or metastases are present 1
  • Multiple hormones are being secreted 1
• Poorer prognosis compared to benign causes 3

Bilateral Adrenal Hyperplasia

• Rare cause of ACTH-independent Cushing's syndrome 1
• Treatment depends on cortisol production symmetry between glands 1

Exogenous Causes

Iatrogenic (Medication-Induced)

• Most common overall cause of Cushing's syndrome 2
• Chronic use of exogenous glucocorticoids, including:
  • Oral steroids
  • Injectable steroids
  • Inhaled corticosteroids (ICS) - can cause Cushing's syndrome with prolonged use of high doses, though less common than with systemic steroids 4

Other Factors

• Alcohol (ETOH) - not a direct cause of Cushing's syndrome, but chronic alcohol use can cause pseudo-Cushing's syndrome with similar clinical features 5
• This is a reversible condition that resolves with alcohol cessation

Diagnostic Approach

1. Initial screening tests 4:

   • 24-hour urinary free cortisol (UFC) - sensitivity >90%
   • Late-night salivary cortisol (LNSC) - sensitivity >90%, specificity 100%
   • 1-mg overnight dexamethasone suppression test

2. Determine ACTH dependence 4:

   • Measure plasma ACTH levels
   • Low/suppressed ACTH suggests adrenal cause
   • Normal to high ACTH suggests pituitary or ectopic source

3. Localization studies 4:

   • Pituitary MRI for suspected Cushing's disease
   • Adrenal CT/MRI for suspected adrenal causes
   • Bilateral inferior petrosal sinus sampling to distinguish pituitary from ectopic sources

Clinical Pearls

• Cushing's disease accounts for 75-80% of endogenous Cushing's syndrome cases, with pituitary microadenomas being the most common etiology 1
• Adrenal carcinomas should be suspected in tumors larger than 5 cm with irregular margins or heterogeneous appearance 1
• Inhaled corticosteroids can cause Cushing's syndrome with prolonged use at high doses, but this is less common than with systemic steroids 4
• Alcohol-induced pseudo-Cushing's is a reversible condition that resolves with alcohol cessation 5
• In children, growth failure combined with weight gain is a highly specific indicator of Cushing's syndrome 1
• Pituitary microadenomas in Cushing's disease are often very small (≤2 mm), making detection challenging 1

Remember that early diagnosis and treatment are crucial to limit long-term morbidity and mortality associated with Cushing's syndrome 6.