Makindo Medical Notes

Related Subjects: |Adrenal Physiology |Addisons Disease |Phaeochromocytoma |Adrenal Adenomas |Adrenal Cancer |Cushing's Syndrome |Cushing's Disease |Cushing's Syndrome due to Ectopic ACTH |Congenital Adrenal hyperplasia |Primary hyperaldosteronism (Conn's syndrome) |ACTH |McCune Albright syndrome

Hypokalemia is more likely when there is a malignant source of adrenocorticotropic hormone (ACTH). Importantly, a normal CT or MRI scan of the sella turcica does not exclude Cushing's disease; up to 50% of patients, especially children, may have normal imaging. In such cases, inferior petrosal sinus sampling is particularly useful for diagnosis.

About

• Cushing's Syndrome is a clinical condition resulting from chronic exposure to excessive cortisol levels.
• This leads to disruption of the normal hypothalamic-pituitary-adrenal (HPA) axis feedback mechanisms.
• There is also a loss of the normal circadian rhythm of cortisol secretion.
• Cushing's Disease refers specifically to Cushing's syndrome caused by excessive secretion of ACTH from a pituitary adenoma.

Aetiology

• Excessive cortisol can result from various causes:
  • ACTH-dependent causes:
    • Excessive production of ACTH by a pituitary adenoma (Cushing's disease).
    • Ectopic ACTH production from non-pituitary tumors.
  • ACTH-independent causes:
    • Autonomous cortisol secretion by adrenal adenomas or carcinomas.
    • Exogenous administration of glucocorticoids (e.g., oral prednisolone).
• The leading cause of Cushing's syndrome is the chronic use of exogenous steroids.

Causes

• Pituitary Adenoma (Cushing's Disease):
  • Accounts for approximately 70% of endogenous Cushing's syndrome cases.
  • Microadenomas secrete excess ACTH, leading to bilateral adrenal hyperplasia and increased cortisol production.
  • Features:
    • Cortisol levels not suppressed by low-dose dexamethasone but partially suppressed by high-dose dexamethasone.
    • Elevated ACTH and cortisol levels, which may increase further with corticotropin-releasing hormone (CRH) stimulation.
• Adrenal Tumors:
  • Includes adrenal adenomas (benign) and carcinomas (malignant).
  • Secrete cortisol autonomously, leading to suppressed ACTH levels.
  • Features:
    • Lack of cortisol suppression with both low- and high-dose dexamethasone tests.
    • Undetectable or decreased ACTH levels due to negative feedback.
• Ectopic ACTH Production:
  • Non-pituitary tumors produce ACTH, leading to adrenal hyperplasia and cortisol excess.
  • Common sources:
    • Small cell carcinoma of the lung.
    • Bronchial carcinoid tumors.
    • Pancreatic neuroendocrine tumors.
  • Features:
    • ACTH levels are elevated.
    • No suppression of cortisol with high-dose dexamethasone.
    • More profound hypokalemia due to mineralocorticoid effects.
• Iatrogenic Cushing's Syndrome:
  • Due to prolonged or intermittent use of exogenous glucocorticoids.
  • Common in patients treated for:
    • Asthma.
    • Rheumatoid arthritis.
    • Polymyalgia rheumatica (PMR).
    • Ulcerative colitis.
    • Post-transplant immunosuppression.
• Pseudo-Cushing's States:
  • Conditions that mimic Cushing's syndrome but are reversible.
  • Causes include chronic alcoholism, depression, and severe obesity.
• Functional Hypercortisolism during Pregnancy:
  • Increased cortisol-binding globulin leads to elevated total cortisol levels.
  • Rarely causes clinical Cushing's syndrome.

Clinical Features

• Appearance:
  • Centripetal (truncal) obesity.
  • Moon face—rounded facial appearance.
  • Facial plethora (redness) and acne.
  • Dorsocervical fat pad ("buffalo hump").
  • Thin extremities due to muscle wasting.
  • Purple striae on the abdomen, thighs, and breasts.
• Skin Changes:
  • Thin, fragile skin that bruises easily.
  • Delayed wound healing.
  • Hirsutism (excess hair growth) in women.
  • Hyperpigmentation (in ACTH-dependent causes).
• Musculoskeletal:
  • Proximal muscle weakness (difficulty climbing stairs or rising from a chair).
  • Osteoporosis leading to back pain and increased fracture risk.
  • Avascular necrosis of the femoral head.
• Metabolic:
  • Glucose intolerance or diabetes mellitus.
  • Hyperlipidemia.
  • Hypertension.
  • Hypokalemia and metabolic alkalosis.
• Neuropsychiatric:
  • Mood swings, irritability, depression, or psychosis.
  • Cognitive impairments.
• Reproductive:
  • Menstrual irregularities or amenorrhea in women.
  • Decreased libido and impotence in men.
• Growth:
  • Impaired growth in children due to cortisol's catabolic effects.
• Immune System:
  • Increased susceptibility to infections.
  • Possible reactivation of latent infections like tuberculosis.
  • Poor wound healing.

Investigations

• Biochemical Tests:
  • Demonstrate Cortisol Excess:
    • Overnight Dexamethasone Suppression Test:
      • Administer 1 mg dexamethasone orally at 11 pm.
      • Measure serum cortisol at 8 am the next morning.
      • A cortisol level <50 nmol/L (<1.8 µg/dL) effectively excludes Cushing's syndrome.
      • Failure to suppress suggests cortisol excess.
    • 24-Hour Urinary Free Cortisol:
      • Collect two separate 24-hour urine samples.
      • Elevated cortisol levels (usually >250 nmol/day) indicate cortisol excess.
    • Late-Night Salivary Cortisol:
      • Measures cortisol at the time it should be lowest.
      • Elevated levels suggest loss of diurnal variation.
  • Determine ACTH Dependence:
    • Measure plasma ACTH levels:
      • Low or undetectable ACTH: Suggests ACTH-independent causes (adrenal tumors or exogenous steroids).
      • Normal or elevated ACTH: Suggests ACTH-dependent causes (pituitary adenoma or ectopic ACTH production).
• High-Dose Dexamethasone Suppression Test:
  • Helps differentiate between pituitary and ectopic ACTH production.
  • Administer 8 mg dexamethasone at 11 pm and measure cortisol at 8 am.
  • Suppression of cortisol (>50% reduction): Suggests pituitary source (Cushing's disease).
  • No suppression: Suggests ectopic ACTH production.
• CRH Stimulation Test:
  • Measures response of ACTH and cortisol to CRH administration.
  • Enhanced response suggests pituitary source.
  • Lack of response suggests ectopic ACTH production or adrenal tumor.
• Imaging Studies:
  • MRI of the Pituitary:
    • Detects pituitary adenomas, but up to 50% may have normal imaging.
  • CT or MRI of the Adrenals:
    • Identifies adrenal adenomas or carcinomas.
  • Chest and Abdominal Imaging:
    • CT scans to locate ectopic ACTH-producing tumors (e.g., lung, pancreas).
• Inferior Petrosal Sinus Sampling:
  • Measures ACTH levels in blood draining from the pituitary.
  • Helps distinguish between pituitary and ectopic sources when imaging is inconclusive.
• Additional Tests:
  • Electrolytes: Hypokalemia is more common in ectopic ACTH production due to mineralocorticoid effects.
  • Metabolic alkalosis: Elevated bicarbonate levels.
  • Radiolabeled octreotide scans may help localize ectopic ACTH-producing tumors.

Management

• Pituitary Adenoma (Cushing's Disease):
  • First-line Treatment: Transsphenoidal surgical resection of the pituitary adenoma.
  • Radiotherapy: Considered if surgery is unsuccessful or not feasible.
  • Medical Therapy: May be used preoperatively or if surgery and radiotherapy fail.
    • Medications to suppress ACTH secretion (e.g., pasireotide).
• Adrenal Tumors:
  • Surgical Resection: Adrenalectomy is the treatment of choice.
  • Adjuvant Therapy: Mitotane for adrenal carcinomas.
• Ectopic ACTH Production:
  • Treatment of Primary Tumor: Surgical removal if possible.
  • Medical Management: Medications to control cortisol levels if the tumor is inoperable.
• Iatrogenic Cushing's Syndrome:
  • Gradual Tapering of Steroids: To allow recovery of the HPA axis.
  • Alternative Therapies: Use steroid-sparing agents when possible.

Medical Management

• For patients who are not surgical candidates or awaiting surgery, medications to inhibit cortisol synthesis can be used:
  • Metyrapone: Inhibits 11β-hydroxylase.
  • Ketoconazole: Antifungal that inhibits multiple steps in steroidogenesis.
  • Aminoglutethimide: Inhibits conversion of cholesterol to pregnenolone.
  • Mitotane: Adrenolytic agent used mainly in adrenal carcinoma.
  • Etomidate: Used intravenously in acute situations to rapidly lower cortisol levels.
• Monitoring and Supportive Care:
  • Treat hypertension, diabetes, and infections.
  • Bone protection with bisphosphonates or vitamin D and calcium supplementation.
  • Psychiatric support as needed.

Key Points

• Early recognition and diagnosis of Cushing's syndrome are crucial to prevent long-term complications.
• A systematic approach to diagnosis helps differentiate between various causes.
• Treatment is directed at the underlying cause and may involve surgery, radiotherapy, and/or medical therapy.
• Long-term follow-up is necessary to monitor for recurrence and manage comorbidities.