Makindo Medical Notes.com

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

Hypokalaemia is more likely when there is a malignant source of ACTH. A normal CT or MRI of the sella does not exclude Cushing's disease. 50% have normal imaging, especially children, and in these cases, Petrosal sinus sampling is particularly useful.

About

• Cushing's syndrome is a clinical state caused by chronic excess cortisol.
• Loss of the normal feedback mechanisms hypothalamopituitaryadrenal axis
• Loss of circadian rhythm of cortisol secretion
• Cushing's disease is Cushing's syndrome due to excess Pituitary ACTH.

Aetiology

• Primary excess of ACTH (pituitary or from elsewhere) stimulating the adrenals
• Primary excess of Cortisol either produced by the adrenals or exogenous e.g. Oral prednisolone.

The leading cause of Cushing syndrome is the chronic use of oral steroids

Causes

• 80% of intrinsic causes are due to Pituitary tumour microadenoma releases ACTH (Cushing disease) leads to adrenal hyperplasia: which is normal or increased It's cortisol level is not suppressed by low dose Dexamethasone test but partially suppressed by high dose Dexamethasone and there is an Increased ACTH and cortisol when stimulated with CRH
• Adrenal Tumour: Cushing's (adenoma 60% , carcinoma 40% ) : Secretes Cortisol, ACTH undetectable or decreased. There is a lack of cortisol suppression with high dose test
• Tumour releasing Ectopic ACTH: (malignancy related) releases ACTH which is normal or increased and there is a lack of cortisol suppression on testing and a more profound hypokalaemia. Seen with Malignancy
  • Small cell carcinoma of lung
  • Bronchial carcinoid
  • Pancreatic tumour with a high ACTH
• Iatrogenic Cushing's : Exogenous Steroids used long term or intermittently for Asthma, Rheumatoid arthritis, PMR, Ulcerative colitis, Transplant and where immunosuppression required
• Pseudo-Cushing states as described previously with depression, alcoholism
• Functional hypercortisolism during pregnancy

Clinical

• Obesity - centripetal truncal and livid purple striae
• Hypertension and headache, Moon face and Facial plethora and acne, Osteopenia and back pain and proximal myopathy
• Thin fragile skin and bruising
• Avascular necrosis of femoral head
• Diabetes and Impaired glucose tolerance
• Psychosis and neuropsychiatric disorders
• Menstrual disorders and impotence
• Dorsocervical fat pad "Buffalo hump"
• Impaired growth in children
• Septicaemia, Immunosuppression, TB reactivation

Cushing's

Cushing's

Cushing's

Investigations

• U&E - Hypokalaemia is more likely when there is a malignant source of ACTH
• Metabolic alkalosis - raised [HCO₃]
• CXR/CT/Bronchoscopy - look for lung neoplasia
• Radiolabelled octreotide may help localise ectopic ACTH producing sites
• The steps in diagnosis of Cushing syndrome
  • 1. Demonstrate cortisol excess
  • 2. Determine if the ACTH is high or low.
• Overnight dexamethasone suppression test is a useful screening test to demonstrate cortisol excess that fails to be suppressed
  • Dexamethasone 1 mg PO given at 11 pm and measure Plasma cortisol level 9 hr later (8-9 am)
  • Plasma cortisol level <5 mcg/100 ml (50 nmol/l) excludes Cushing syndrome
  • 24-hour urine collection measuring free cortisol in the urine.
  • Random cortisol or 9 am cortisol provides no diagnostic information whatsoever.
  • Chest x-ray and adrenal computerised tomography (CT) are useful in investigating the possible cause of Cushing's syndrome.
• Cortisol Excess Suspected
  • If Cortisol excess suspected then consider Overnight Dexamethasone suppression tests or diurnal salivary cortisol studies
  • Dexamethasone 1 mg is given at night orally between 11 and 12 midnight
  • Serum cortisol is tested at 9 am and a value < 50 nmol/L is highly sensitive and specific to exclude Cushing's disease
  • If elevated then check ACTH to see if the excess is adrenal or pituitary origin
• Measure urinary free cortisol excretion
  • Also commonly used as a first-line screening test
  • Collect 2 x 24 hour urinary cortisol secretion along with creatinine.
  • An elevated cortisol (usually above 250 nmol/day) suggests Cushing's syndrome.
  • Once proven then to determine aetiology do high dose dexamethasone (8 mg) suppression test with RIA measurement of ACTH and cortisol
  • ACTH undetectable or decreased and lack of suppression indicates adrenal aetiology of Cushing syndrome.
  • ACTH normal or increased and lack of cortisol suppression indicate ectopic ACTH production.
  • ACTH normal or increased and partial suppression of cortisol suggest pituitary excess (Cushing's disease)
  • CT/MRI adrenals and MRI pituitary may be required. There is a worry that scanning adrenals prior to biochemical results can lead to the finding of abnormalities later compounded by the result then of normal biochemistry - so called incidentalomas which leads to difficult questions of what to do with them?

Management

• Pituitary adenoma - surgical resection usually transsphenoidal and Radiotherapy in selected cases
• Adrenal tumour - surgical resection
• Ectopic ACTH - Treatment of the primary malignancy or other cause
• Iatrogenic - Switch to a steroid sparing agent

Medical

• Blockage of Cortisol production can be used in all those unsuitable for surgery.
• Drugs used are metyrapone, Ketoconazole and aminoglutethimide.