Differential Diagnosis for High Cortisol and Low ACTH

When cortisol is high and ACTH (Adrenocorticotropic hormone) is low, it suggests that the source of the excess cortisol is not due to stimulation by ACTH from the pituitary gland, pointing more towards an adrenal source or other non-pituitary causes. Here's a differential diagnosis organized into categories:

• Single Most Likely Diagnosis
  • Adrenal Adenoma or Carcinoma: These are tumors of the adrenal gland that can autonomously produce cortisol, leading to Cushing's syndrome. The high cortisol levels feedback inhibit the pituitary gland, reducing ACTH production.
• Other Likely Diagnoses
  • Bilateral Adrenal Hyperplasia: Though less common than unilateral adenomas, this condition can also lead to excessive cortisol production without the need for ACTH stimulation.
  • Familial Cushing's Syndrome: Rare genetic conditions that can lead to adrenal cortisol overproduction.
  • Ectopic ACTH-producing Tumors with Concurrent ACTH Antibody Interference: Though ectopic ACTH-producing tumors typically increase both cortisol and ACTH, rare instances of antibody interference in assays could potentially lead to misleadingly low ACTH levels.
• Do Not Miss Diagnoses
  • Adrenal Crisis due to Exogenous Steroid Use: Patients on long-term corticosteroid therapy can have suppressed ACTH and cortisol levels that do not respond normally to stress, potentially leading to an adrenal crisis if not properly managed.
  • Pheochromocytoma with Incidental Cortisol Elevation: Though primarily associated with catecholamine excess, pheochromocytomas can occasionally co-secrete cortisol or be found in conjunction with other adrenal pathology leading to cortisol elevation.
• Rare Diagnoses
  • McCune-Albright Syndrome: A rare genetic disorder that can lead to Cushing's syndrome among other endocrinopathies, due to adrenal nodular hyperplasia.
  • Primary Pigmented Nodular Adrenal Disease (PPNAD): A rare cause of Cushing's syndrome, often associated with Carney complex, leading to autonomous cortisol production by the adrenal glands.
  • Allgrove Syndrome (Triple A Syndrome): A rare autosomal recessive disorder that can include adrenal insufficiency but in some cases might present with cortisol imbalance due to its impact on adrenal function.

Each of these diagnoses has a different set of implications for patient management and prognosis, highlighting the importance of a thorough diagnostic workup to determine the underlying cause of high cortisol and low ACTH levels.