Cushing’s syndrome

Cushing’s Syndrome

1. Introduction and Overview

Definition:

Cushing’s syndrome is a clinical condition resulting from prolonged exposure to excess glucocorticoids, either endogenous (from increased cortisol production) or exogenous (from corticosteroid therapy).

Epidemiology:

  • Prevalence:

    • Rare: 10–15 cases per million people annually.

    • More common in females (3–5 times more than males), particularly in ACTH-dependent cases.

  • Age: Most prevalent in adults aged 20–50 years.

  • Etiology-Based Distribution:

    • ACTH-dependent (e.g., pituitary adenomas) accounts for ~70%.

    • ACTH-independent (e.g., adrenal adenomas) accounts for ~15–20%.

Relevance:

If untreated, Cushing’s syndrome significantly increases morbidity and mortality due to complications like cardiovascular disease, infections, and metabolic dysfunctions.

2. Etiology

Primary Causes:

  1. ACTH-Dependent Causes:

    • Cushing’s Disease: Pituitary adenoma producing ACTH (most common endogenous cause).

    • Ectopic ACTH Syndrome: ACTH secretion by non-pituitary tumors (e.g., small-cell lung cancer, neuroendocrine tumors).

  2. ACTH-Independent Causes:

    • Adrenal adenomas or carcinomas.

    • Adrenal hyperplasia.

Secondary Causes:

  • Exogenous Glucocorticoids: Most common overall cause, due to prolonged corticosteroid therapy.

Risk Factors:

  • Prolonged corticosteroid use.

  • History of neoplasms (e.g., pituitary or adrenal tumors).

  • Genetic predisposition (e.g., MEN-1 syndrome).

3. Pathophysiology

Normal Physiology:

  • Cortisol is secreted by the adrenal cortex under ACTH stimulation from the anterior pituitary.

  • ACTH release is regulated by CRH from the hypothalamus in a diurnal rhythm and via a negative feedback loop.

Mechanisms of Disease:

  1. Endogenous Causes:

    • Pituitary or ectopic overproduction of ACTH leads to excessive cortisol secretion.

    • ACTH-independent causes directly increase cortisol synthesis.

  2. Exogenous Causes:

    • Chronic glucocorticoid use suppresses the hypothalamic-pituitary-adrenal (HPA) axis, leading to adrenal atrophy.

Key Pathways:

  • Excess cortisol affects glucose metabolism, protein catabolism, fat distribution, immune function, and electrolyte balance.

4. Clinical Features

Symptoms:

  1. General: Fatigue, weakness, weight gain.

  2. Metabolic: Hyperglycemia, central obesity, easy bruising.

  3. Musculoskeletal: Muscle weakness, osteoporosis, fractures.

  4. Reproductive: Menstrual irregularities, reduced libido.

  5. Neuropsychiatric: Depression, insomnia, cognitive dysfunction.

Signs:

  1. Physical Examination Findings:

    • Central Obesity: Truncal fat deposition with thin extremities.

    • Moon Face: Rounded facial appearance.

    • Buffalo Hump: Fat pad over the upper back.

  2. Skin Changes:

    • Purple striae (abdomen, thighs).

    • Fragile skin with easy bruising.

  3. Other Findings:

    • Hypertension, proximal myopathy, hirsutism, acne.

Stages and Progression:

  • Mild Disease: Subtle signs like weight gain and fatigue.

  • Severe Disease: Multi-system involvement, increased risk of infections and fractures.

Differentiating Features:

  • Compare with metabolic syndrome: absence of striae and ACTH elevation in metabolic syndrome.

5. Diagnostic Approach

Clinical Diagnosis:

  • Detailed history and physical exam focusing on symptoms of hypercortisolism and glucocorticoid exposure.

Laboratory Investigations:

  1. Initial Screening Tests:

    • 24-Hour Urinary Free Cortisol: Elevated levels confirm hypercortisolism.

    • Late-Night Salivary Cortisol: Loss of diurnal variation indicates Cushing’s syndrome.

    • Low-Dose Dexamethasone Suppression Test (LDDST): Failure to suppress cortisol suggests Cushing’s.

  2. Confirmatory Tests:

    • ACTH levels:

      • Elevated in ACTH-dependent causes.

      • Suppressed in ACTH-independent causes.

Imaging Studies:

  1. MRI of the Pituitary: To detect pituitary adenomas in ACTH-dependent cases.

  2. CT/MRI of the Adrenals: For adrenal tumors or hyperplasia.

  3. PET-CT: To localize ectopic ACTH-producing tumors.

Functional Testing:

  • High-Dose Dexamethasone Suppression Test: Differentiates Cushing’s disease from ectopic ACTH syndrome.

Diagnostic Criteria:

  • Elevated cortisol on two of three screening tests and an identifiable source (e.g., imaging or biochemical).

6. Management

Medical Management:

  1. ACTH-Dependent Cases:

    • Pituitary Adenomas:

      • First-line therapy: Transsphenoidal surgery.

      • Adjunctive medications:

        • Ketoconazole or Metyrapone: Cortisol synthesis inhibitors.

        • Pasireotide: Somatostatin analog.

        • Cabergoline: Dopamine agonist.

  2. Ectopic ACTH Production:

    • Treat underlying tumor with surgery, chemotherapy, or radiation.

  3. ACTH-Independent Cases:

    • Adrenalectomy for adrenal adenomas or carcinomas.

    • Medical therapy in inoperable cases.

  4. Exogenous Causes:

    • Gradual tapering of corticosteroids to allow HPA axis recovery.

Surgical Management:

  • Transsphenoidal Surgery: For pituitary adenomas.

  • Adrenalectomy: For adrenal tumors.

  • Resection of Ectopic Tumors: Depending on location.

Emergency Management:

  • Acute Adrenal Insufficiency (post-surgery):

    • Immediate glucocorticoid replacement with IV hydrocortisone.

7. Prognosis

Natural History:

  • Untreated Cushing’s syndrome has a high mortality rate due to cardiovascular and metabolic complications.

Outcomes with Treatment:

  • Surgery has a high success rate for pituitary adenomas (~80–90%).

  • Medical therapy can control hypercortisolism but may not cure the underlying cause.

Long-Term Impacts:

  • Risk of recurrence or persistent adrenal insufficiency.

8. Complications

Primary Disease Complications:

  1. Cardiovascular: Hypertension, atherosclerosis.

  2. Metabolic: Diabetes mellitus, dyslipidemia.

  3. Musculoskeletal: Osteoporosis, fractures.

  4. Immunosuppression: Increased susceptibility to infections.

Therapeutic Complications:

  • Adrenal insufficiency following surgery or medical therapy.

  • Side effects of medications (e.g., hepatotoxicity with ketoconazole).

9. Prevention

Primary Prevention:

  • Avoid unnecessary or prolonged use of glucocorticoids.

Secondary Prevention:

  • Early detection and management of hypercortisolism.

Tertiary Prevention:

  • Regular monitoring for recurrence or complications in treated patients.

10. Patient Education

Disease Understanding:

  • Explain the effects of excess cortisol and the importance of treatment.

Self-Monitoring:

  • Recognize signs of hypercortisolism and adrenal insufficiency.

Lifestyle Advice:

  • Maintain a balanced diet with adequate calcium and vitamin D.

  • Engage in weight-bearing exercises to prevent osteoporosis.

When to Seek Help:

  • Worsening symptoms or new signs like severe weakness or infections.

11. Recent Research and Advances

  • Novel Medications: Investigations into selective glucocorticoid receptor antagonists.

  • Improved Surgical Techniques: Advances in minimally invasive pituitary and adrenal surgeries.

  • Genetic Insights: Identification of genetic mutations associated with familial Cushing’s.

12. Case Studies

Example:

A 40-year-old woman presents with weight gain, hypertension, and purple striae. Biochemical tests confirm hypercortisolism, and MRI reveals a pituitary adenoma. She undergoes transsphenoidal surgery with successful resolution of symptoms.

13. References

  1. Nieman LK, et al. "Cushing’s Syndrome." Lancet, 2015.

  2. Endocrine Society Clinical Practice Guidelines for Cushing’s Syndrome (2021).

  3. Harrison’s Principles of Internal Medicine, 21st Edition.

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