Diagnosis

Cushing syndrome

Etiology

Cause [eo9][s87]

1. Exogenic: Iatrogenic Cushing syndrome (the most common cause) [eo9]

2. Endogenic:

   • ACTH dependent:

     • Pituitary tumor secreting ACTH (Cushings disease): common endogenic cause

     • Ectopic ACTH secretion by tumor (small cell lung cancer)

   • ACTH independent:

     • Functional adrenal adenoma secretes cortisol

     • Functional adrenal carcinoma

     • Adrenal hyperplasia

3. Pseudo-Cushing syndrome: Other causes for elevated plasma cortisol:

   • Psychiatry: Chronic stress, depression, anorexia nervosa, OCD, panic disorder

   • Excessive exercise

   • Drugs: Chronic alcoholism, alcohol and nicotine withdrawal

   • Metabolic: Diabetes mellitus, central obesity, hyperthyroidism, premenstrual tension syndrome, pregnancy

Pathophysiology [eo9]

1. The hypothalamic-pituitary-adrenal axis:

   1. Hypothalamus: Corticotrophin Releasing Hormone (CRH

   2. Adenohypophysis (pituitary gland): AdrenoCorTicotropic Hormone (ACTH)

   3. Adrenal cortex:

      • Zona glomerulosa: aldosterone

      • Zona fasciculata: Baseline cortisol production + Secretory responses to stimuli

      • Zona reticularis: adrenal androgens

      • Cortisol inhibit pituitary ACTH and hypothalamic CRH (negative feedback)

2. Derangement of the hypothalamic-pituitary-adrenal axis:

   • Fatigue, muscle weakness, osteoporosis, hypertension, hyperglycemia/diabetes, facial plethora, proximal myopathy, pigmented palpable striae, cutaneous bruising, central weight gain, headaches, dizziness, visual blurring, polyuria, polydipsia, polyphagia, anorexia, oligomenorrhea, amenorrhea, infertility, reduced libido, erectile dysfunction, arrested growth, sleep deprivation, mood decline, depression, psychotic episodes, hirsutism, acne, moon face, facial flushing, malar telangiectasia, enlarged dorsocervical pad (buffalo hump), supraclavicular fat pad, scalp hair loss, hyperpigmentation

Complications [eo9]

• Obesity

• Coronary artery disease,

• Cerebrovascular disease

• Diabetes mellitus

• Dyslipidemia

• Growth retardation in children

• Hypertension

• Atherosclerosis

• Osteoporosis

• Hypercoagulability: deep venous thrombosis and embolism

• Immune suppression

• Neuropsychiatric disturbances

• Infertility

• Gastro-esophageal reflux disease

• Nephrolithiasis

• Cataracts / glaucoma

• Psychosis, depression, bipolar state, dysthymia, chronic anxiety

• Cognitive decline: progressive memory loss

Epidemiology

Incidence per 100.000

Approach

• Blood test: ACTH, cortisol (morning and midnight)

• Urinary cortisol (24-hour)

• Salivary cortisol (midnight)

• Dexamethasone test

• CT abdomen

• MR caput

• Petrosal sinus sampling

Treatment

1. Medical treatment: [zft]

   • Iatrogenic: gradual withdrawal of the causative drug

   • Inhibitors of ACTH: Pasireotide (somatostatin receptor ligand)

   • Adrenal inhibition: Ketoconazole, Metyrapone, Mitotane and Etomidate

   • Glucocorticoid receptor blockade: Mifepristone

   • Treatment of comorbidities (hypertension, diabetes, obesity, dyslipidemia)

2. Surgical resection of the causative tumor [zft]

   • Pituitary surgery

   • Adrenalectomy (bilateral if pituitary therapy fail or ectopic ACTH-producing tumors are difficult to locate/resect)

   • Ectopic ACTH --> resection of metastatic adrenal carcinoma

3. Pituitary radiation therapy

Differential diagnoses

Alcoholism, Cancer origo incerta, Cushings disease, Depression, Lipodystrophy Syndromes, Obesity, Primary Generalized Glucocorticoid Resistance Syndrome