How can hypercortisolism be considered Adrenocorticotropic Hormone (ACTH)-independent if cortisol production is typically driven by ACTH?

Understanding ACTH-Independent Hypercortisolism

Hypercortisolism can be considered ACTH-independent when cortisol is produced directly by adrenal tumors or hyperplasia without requiring stimulation from pituitary ACTH. 1

Mechanism of ACTH-Independent Cortisol Production

• In normal physiology, cortisol production is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, with ACTH from the pituitary stimulating the adrenal glands to produce cortisol 1
• In ACTH-independent Cushing's syndrome, adrenal tumors (adenomas or carcinomas) or bilateral adrenal hyperplasia produce cortisol autonomously, bypassing the need for ACTH stimulation 1
• This autonomous production leads to suppressed ACTH levels through negative feedback inhibition, as excess cortisol signals the pituitary to reduce ACTH secretion 1

Diagnostic Features of ACTH-Independent Cushing's Syndrome

• Low or undetectable plasma ACTH levels (<5 ng/L or <1.1 pmol/L) in the presence of elevated cortisol levels 1, 2
• Failure of cortisol to suppress with dexamethasone administration 3, 4
• Absence of cortisol circadian rhythm 3
• Elevated 24-hour urinary free cortisol 1
• No response to CRH stimulation test (unlike ACTH-dependent forms) 1

Common Causes of ACTH-Independent Cushing's Syndrome

• Unilateral adrenal adenoma (most common cause) 1
• Adrenal carcinoma (more likely if tumor >5 cm with irregular margins) 1
• Bilateral adrenal adenomas (rare, <40 reported cases) 3, 5
• ACTH-independent macronodular adrenal hyperplasia 5
• Primary pigmented nodular adrenocortical disease 3

Diagnostic Approach

• Confirm hypercortisolism with 24-hour urinary free cortisol, late-night salivary cortisol, or overnight dexamethasone suppression test 1
• Measure plasma ACTH levels - low levels (<5 ng/L) indicate ACTH-independent disease 1, 2
• Perform adrenal imaging (CT or MRI) to identify adrenal tumors 1
• For bilateral adrenal masses, adrenal vein sampling (AVS) helps determine if one or both glands are producing excess cortisol 5, 6

Treatment Options

• Laparoscopic adrenalectomy for unilateral adenomas 1
• For bilateral disease:
  • If cortisol production is asymmetric (determined by AVS), unilateral adrenalectomy of the most active side 1
  • If cortisol production is symmetric, medical management or bilateral adrenalectomy 1, 5
• Medical management with adrenostatic agents (ketoconazole 400-1200 mg/day or mitotane) when surgery is not an option 1
• Postoperative corticosteroid supplementation is required until recovery of the HPA axis 1

Clinical Pitfalls and Caveats

• Bilateral adrenal masses require careful evaluation to determine if one or both are functionally active 5, 6
• Standard cortisol lateralization ratios in AVS may be insufficient; cortisol to metanephrine ratio can improve accuracy in localizing the source 6
• Subclinical Cushing's syndrome with mild autonomous cortisol secretion can be difficult to diagnose with conventional tests 4
• After adrenalectomy for ACTH-independent Cushing's syndrome, patients require glucocorticoid replacement until the contralateral adrenal gland recovers function 1

Understanding the pathophysiology of ACTH-independent Cushing's syndrome explains why it's appropriately named despite cortisol typically being ACTH-driven - these adrenal tumors produce cortisol autonomously without requiring the normal ACTH stimulus.