7- Cushing syndrome

• Cortisol

  Stress hormone/anti-insulin + some aldosterone-like effect
• Cortisol levels are highest in early morning
• Increased cortisol

  Hyperglycemia, hyperlipidemia, hypokalemia, metabolic acidosis, leukocytosis
• Decreased cortisol

  Hypoglycemia, weight loss, anorexia, nausea & vomiting, abdominal pain, lethargy, confusion, psychosis
• Other effects of cortisol

  • Impaired collagen production
  • Enhanced protein catabolism
  • Impaired immunity (inhibitory effect on PMNs & T-cells)
  • Enhance catecholamine activity (HTN)
• Cushing syndrome

  Excessive levels of glucocorticoids (cortisol is the principal glucocorticoid) due to any cause
• Cushing disease

  Pituitary overproduction of ACTH (pituitary adenoma) - 70% of hypercortisolism
• Causes of Cushing syndrome

  • Iatrogenic (prescribed prednisone or other steroids)
  • ACTH-secreting adenoma of the pituitary (Cushing disease)
  • Adrenal adenomas and carcinomas
  • Ectopic ACTH production (Small cell carcinomas of the lung/Bronchial carcinoid/Thymoma)
• Clinical features of Cushing syndrome

  • Fat redistribution: Moon face, buffalo hump, central obesity, thin extremities
  • Skin: hirsutism, purple striae on abdomen, acne, easy bruising, decreased wound healing & thinning of skin
  • HTN (due to increased Na reabsorption & increased vascular reactivity)
  • Diabetes (cortisol is a gluconeogenic hormone) & polyuria (from hyperglycemia & increased water clearance)
  • Menstrual irregularity, erectile dysfunction & infertility
  • Masculinization in females (in ACTH-dependent forms)
  • Proximal muscle wasting and weakness
  • Osteoporosis (aseptic necrosis of femoral head may occur)
  • Cognitive disturbances: from decreased concentration to psychosis
• Diagnosis

  1. Confirm cortisol excess

  2. Establishing the cause/location of high cortisol
• Screening tests to confirm cortisol excess

  • 24-hour urine cortisol
  • 1 mg overnight dexamethasone suppression test
  • Midnight salivary cortisol
• If screening tests are negative, it is not Cushing's
• ACTH level

  Low - Cushing syndrome (adrenal source)

  High - source could be from pituitary or ectopic, proceed to high dose dexamethasone
• High dose dexamethasone suppression test

  Suppressed - Pituitary (Cushing disease), low ACTH, +ve CRH stimulation

  Not suppressed - Ectopic ACTH producing tumor, -ve CRH stimulation
• Other laboratory findings

  • Hyperglycemia
  • Hyperlipidemia
  • Hypokalemia
  • Metabolic alkalosis
  • Leukocytosis
• Imaging: Pituitary MRI and chest x-ray
• Treatment

  Iatrogenic Cushing syndrome: tapering of glucocorticoid

  Surgically remove the source: transsphenoidal surgery for pituitary & laparoscopic removal for adrenal sources

  Medical treatment: If surgery not successful OR cannot be done, use somatostatin analogs (inhibits cortisol receptors)
• Lab values in different conditions

  • Conn's (1o Hyperaldo): High Na, Low K, High Aldo, N Cortisol, High Glucose, Metabolic Alkalosis
  • Cushing: High Na, Low K, N Aldo, High Cortisol, High Glucose, Metabolic Alkalosis
  • Addison (1o adrenal insufficiency): Low Na, High K, Low Aldo, Low Cortisol, Low Glucose, Metabolic Acidosis
• Differentiate 1o vs 2o adrenal insufficiency by ACTH and renin levels: 1o - high renin, high ACTH; 2o - normal renin, low ACTH, low aldo, normal Na & K
• Glucocorticoids are involved in metabolism, immune function, stress response, blood pressure regulation, electrolyte balance, and bone health.
• The hypothalamus secretes CRH (corticotropin releasing hormone) which stimulates the anterior pituitary to secrete ACTH (adreno corticotropic hormone)
• Cortisol is the main glucocorticoid hormone, produced by the adrenal cortex
• Androgens play a role in male sexual development and maintenance of secondary sex characteristics.
• Mineralcorticoids regulate sodium and potassium homeostasis through their effects on the kidneys.
• Adrenal glands produce mineralocorticoids such as aldosterone that regulate sodium and potassium balance
• Estrogen is responsible for female sexual development and menstruation.
• Aldosterone is the primary mineralocorticoid hormone, also produced by the adrenal cortex
• ACTH has two peaks per day, one at midnight and another around 6 am
• Aldosterone is produced from cholesterol through several steps involving enzymes like cytochrome p450c11b and 3β hydroxysteroid dehydrogenase
• CRH secretion is controlled by circadian rhythm and stress
• Mineralocorticoids regulate salt and water balance through sodium retention and potassium excretion.
• Aldosterone is the primary mineralocorticoid hormone, secreted by the adrenal glands in response to changes in blood volume or salt intake.
• Aldosterone acts on the distal tubule and collecting duct of the nephron to increase reabsorption of Na+ and excretion of K+
• The hypothalamus secretes CRF (Corticotropin Releasing Factor) which stimulates ACTH release from the anterior pituitary