Cushing syndrome

Epidemiology

---

Etiology

Hypercortisolism can be categorized as either ACTH-dependent or ACTH-independent.

• ACTH-Dependent Causes:

  • Cushing’s Disease: This is the most common endogenous cause, resulting from an ACTH-secreting pituitary adenoma.
  • Ectopic ACTH Syndrome: Non-pituitary tumors, most commonly small-cell lung cancer, can secrete ACTH.

• ACTH-Independent Causes:

  • Iatrogenic (Exogenous): This is the most common overall cause, resulting from long-term administration of glucocorticoid medications.
  • Adrenal Tumors: Adrenal adenomas or carcinomas can autonomously produce excess cortisol.

---

Pathophysiology

---

Clinical features

Mnemonic

诱发三高和溃疡，伤口感染不好长，骨松眼青人发狂 三高 is related to Permissive action of corticosteroids

• ↑ Hematocrit
  • Steroids, particularly anabolic steroids, stimulate the production of erythropoietin

---

Diagnostics

1. Confirm Hypercortisolism: Initial screening tests are used to confirm the presence of excess cortisol. These include:

   • 24-hour urinary free cortisol (UFC)
   • Late-night salivary cortisol
   • Low-dose dexamethasone suppression test
     • Screening test only
     • In a healthy person, giving a low dose of dexamethasone (a potent steroid) will suppress the pituitary’s ACTH production, causing morning cortisol levels to be low.
     • In a patient with Cushing’s syndrome, the source of cortisol is autonomous and will not be suppressed by a low dose. Their morning cortisol will remain high.

2. Determine Etiology: Once hypercortisolism is confirmed, plasma ACTH levels are measured to differentiate between ACTH-dependent and ACTH-independent causes.

   • Low ACTH: Suggests an adrenal source (adenoma or carcinoma).
   • Normal or High ACTH: Indicates an ACTH-dependent cause (pituitary or ectopic).

3. Localize the Source:

   • If ACTH is low, a CT or MRI of the adrenal glands is performed.
   • If ACTH is high, a high-dose dexamethasone suppression test and/or a CRH stimulation test can help distinguish between a pituitary source (Cushing’s disease) and an ectopic source. An MRI of the pituitary is the next step for suspected Cushing’s disease.
     • Most pituitary adenomas retain partial sensitivity to feedback inhibition in response to high doses of glucocorticoids, while ectopic tumors are resistant even to high doses.

---

Treatment

Bilateral adrenalectomy

• Indications
  • Primary hypercortisolism caused by bilateral adrenal disease (recommended curative treatment)
  • Emergency treatment in severe ACTH-dependent hypercortisolism that cannot be controlled pharmacologically
  • Symptomatic treatment for metastatic or occult ectopic tumors
• Complication: Nelson syndrome (post adrenalectomy syndrome)
  • Etiology: bilateral adrenalectomy in patients with a previously undetected pituitary adenoma
  • Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on the hypothalamus → ↑ CRH production → uncontrolled enlargement of preexisting but undetected ACTH-secreting pituitary adenoma → ↑ secretion of ACTH and MSH → manifestation of symptoms due to pituitary adenoma and ↑ MSH
  • Clinical features: headache, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation
  • Diagnostics
    • High levels of β-MSH and ACTH
    • Pituitary adenoma on MRI confirms the diagnosis.
  • Treatment: surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g., if the tumor cannot be fully resected)

---