Doctors Revision

Endocrine & Metabolic System

Cushing's Syndrome

A disorder resulting from prolonged exposure to inappropriately high levels of cortisol (a glucocorticoid hormone). Most commonly caused by exogenous administration of steroids (iatrogenic), less commonly by endogenous overproduction.

Also known as: Hypercortisolism

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Referral and warning signs

When to refer

Refer to specialist (Endocrinologist/Physician) for: Diagnosis confirmation (hormonal testing) if endogenous cause suspected. Management of non-iatrogenic Cushing's syndrome. Guidance on complex steroid tapering. Management of significant complications (severe HTN/diabetes/osteoporosis/psychosis). Consideration for medical therapy to lower cortisol or surgery.

Red flags

  • Rapid onset of Cushingoid features
  • Signs of virilization (suggests adrenal carcinoma)
  • Severe hypokalemia/hypertension (suggests ectopic ACTH)
  • Visual field defects (suggests large pituitary adenoma)
  • Pathological fractures

Signs and symptoms

  • Central (truncal) obesity
  • Moon face (facial rounding)
  • Buffalo hump (fat pad on upper back/neck)
  • Thin skin, easy bruising
  • Purple striae (stretch marks, esp. abdomen, thighs, breasts)
  • Proximal muscle weakness and atrophy (difficulty rising from chair/climbing stairs)
  • Poor wound healing
  • Hirsutism (excess hair growth) and acne (especially in females)
  • Menstrual irregularities
  • Hypertension
  • Hyperglycaemia / Steroid-induced diabetes
  • Osteoporosis / Fractures
  • Mood changes (depression, anxiety, irritability, psychosis)
  • Increased susceptibility to infections
  • Peripheral oedema

Risk factors

  • Chronic use of exogenous glucocorticoids (oral, inhaled, topical, injected) - Iatrogenic Cushing's Syndrome.
  • Endogenous Causes:
  • - Cushing's Disease: Pituitary adenoma secreting excess ACTH.
  • - Ectopic ACTH Syndrome: Non-pituitary tumour (e.g., small cell lung cancer) secreting ACTH.
  • - Adrenal Adenoma or Carcinoma: Adrenal tumour secreting excess cortisol.

Diagnosis

Clinical assessment

Suspected based on characteristic physical features. Crucial to obtain detailed medication history (steroid use in any form). Differentiate from simple obesity, metabolic syndrome, Polycystic Ovary Syndrome (PCOS), depression, alcoholism (pseudo-Cushing's).

Investigations

  • Confirm Hypercortisolism (Specialist level):
  • - 24-hour Urinary Free Cortisol (UFC) - requires accurate collection.
  • - Late-Night Salivary Cortisol.
  • - Low-Dose Dexamethasone Suppression Test (LDDST - e.g., 1mg overnight test): Failure of cortisol to suppress suggests Cushing's syndrome.
  • Determine Cause (If hypercortisolism confirmed and not iatrogenic):
  • - Plasma ACTH level: Suppressed (<5 pg/mL) suggests adrenal cause (adenoma/carcinoma). Normal/High suggests ACTH-dependent cause (pituitary or ectopic).
  • - High-Dose Dexamethasone Suppression Test (HDDST): Suppression suggests pituitary cause (Cushing's disease). Failure to suppress suggests ectopic ACTH or adrenal cause.
  • - Imaging: Pituitary MRI (for Cushing's disease), Adrenal CT/MRI (for adrenal tumours), Chest/Abdomen CT (search for ectopic source).
  • Other tests: Blood glucose, Electrolytes, BP measurement.

Diagnostic criteria

Clinical features + Biochemical confirmation of hypercortisolism + Further tests to determine etiology (pituitary, adrenal, ectopic, iatrogenic).

Management

Non-pharmacological management

  • Treat Underlying Cause:
  • - Iatrogenic: Gradual withdrawal/tapering of exogenous steroids. This is the primary management. Dose reduction needs to be slow (e.g., by 2.5-5mg prednisolone equivalent every 1-2 weeks or slower) to allow suppressed adrenal axis to recover, avoiding adrenal insufficiency.
  • - Cushing's Disease: Transsphenoidal pituitary surgery (first-line).
  • - Ectopic ACTH: Resection of primary tumour if possible.
  • - Adrenal Tumour: Adrenalectomy.
  • Manage complications: Control hypertension, diabetes, dyslipidemia; treat osteoporosis; manage mood disorders.

Pharmacological treatment

  • Medications to lower cortisol (Used if surgery not possible/failed, or pre-operatively - specialist use): Ketoconazole, Metyrapone, Etomidate, Mitotane, Mifepristone.

Monitoring

Monitor clinical features, weight, BP, glucose. Monitor cortisol levels/suppression tests during steroid taper or after surgery/medication. Monitor for adrenal insufficiency during/after steroid withdrawal.

Complications

  • Cardiovascular disease (Hypertension, MI, Stroke, VTE)
  • Diabetes mellitus
  • Osteoporosis / Pathological fractures
  • Increased susceptibility to infections
  • Psychiatric disorders
  • Muscle weakness / Myopathy
  • Poor wound healing
  • Adrenal suppression/insufficiency after withdrawal of exogenous steroids or treatment of endogenous Cushing's.

Prevention

  • Use lowest effective dose of glucocorticoids for shortest possible duration.
  • Use alternative non-steroidal therapies where possible.
  • Educate patients on risks of long-term steroid use.
  • Ensure gradual tapering when stopping long-term steroids.

Patient education

  • Explain Cushing's syndrome and the cause (exogenous steroids vs endogenous).
  • If iatrogenic: Explain the need for slow, supervised tapering of steroids, risks of abrupt cessation (adrenal crisis).
  • Lifestyle measures (diet, exercise).
  • Monitoring for and managing complications (BP, glucose, bone health).
  • Information on specific treatments if endogenous cause (surgery, medication).

Uganda-specific notes

Iatrogenic Cushing's due to widespread availability and use/misuse of oral/depot steroids is very common. Recognizing this and managing steroid withdrawal appropriately is crucial. Diagnosis and management of endogenous causes require specialist referral and resources often unavailable outside major centres.

References

  • Uganda Clinical Guidelines (UCG) 2023

    Chapter 8, Section 8.1.2

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