Cushing's syndrome

Question 1

What is cushing’s syndrome?

Answer 1

Syndrome associated with chronic inappropriate elevations of free circulating cortisol

Question 2

What can cause cushing’s syndrome?

Answer 2

It can be divided into ACTH Dependent (80%) and ACTH Independent (20%)
1. ACTH Dependent:
o Excess ACTH from a pituitary adenoma (Cushing’s disease) – 2nd commonest cause
Adenoma causes bilateral adrenal hyperplasia
o Ectopic ACTH (e.g. small cell lung cancer, pulmonary carcinoid tumours)
Would cause weight loss, pigmentation (ACTH), hypokalaemic metabolic alkalosis, hyperglycaemia
o Rare: ectopic CRF production – some thyroid medullary and prostate cancers
2. ACTH Independent
o Benign adrenal adenoma
o Adrenal carcinoma
o Adrenal nodular hyperplasia
o Oral steroids – chief cause
o Rare: Carney complex, McCune-Albright syndrome

Question 3

Summarise the epidemiology of Cushing’s syndrome

Answer 3

● Incidence: 2-4/1,000,000 per year
● Peak incidence 20-40 yrs

Question 4

What are the presenting symptoms of cushing’s syndrome?

Answer 4

● Increasing weight
● Fatigue
● Muscle weakness – proximal myopathy
● Myalgia
● Thin skin
● Easy bruising
● Poor wound healing
● Fractures
● Gonadal dysfunction – Hirsuitism, irregular menses, erectile dysfunction
● Acne
● Frontal balding
● Recurrent Achilles tendon rupture
● Depression or psychosis

Question 5

What signs of cushing’s syndrome can be found on physical examination?

Answer 5

● Moon face
● Facial plethora
● Interscapular fat pad – buffalo neck hump
● Supraclavicular fat distribution
● Proximal muscle weakness - myopathy
● Thin skin
● Bruises
● Central obesity
● Pink/purple striae on abdomen/breast/thighs
● Kyphosis (due to vertebral fracture)
● Poorly healing wounds
● Hirsuitism, acne, frontal balding
● Hypertension
● Ankle oedema (due to salt and water retention from the mineralocorticoid effect of excess cortisol)
● Pigmentation in ACTH dependent cases
● Osteoporosis

Question 6

What investigations are used to diagnose/ manage cushing’s syndrome?

Answer 6

1. Low Dose (1mg) overnight dexamethasone suppression test → most sensitive and 1st line test. Morning cortisol >50 nanomol/L. Patient is given 1 mg of dexamethasone (binds to the same receptor as cortisol) at 11 p.m., and a plasma cortisol level is measured the following morning at 8am. Patients with Cushing’s syndrome do not have their morning cortisol spike suppressed.
2. High Dose dexamethasone suppression test → can be done next to distinguish between Cushing’s disease and ectopic ACTH production
   - Cushing’s Disease (Pituitary Adenoma) ⇒ will suppress cortisol. As excess ACTH production from the pituitaries can be inhibited by high doses of dexamethasone, however autonomous cortisol production from the adrenals will not be affected.
3. 24-hour urinary free cortisol or Late-night salivary cortisol → elevated
4. Bloods → Hyperglycaemia, Hypokalaemia, Hypernatremia, Metabolic Alkalosis (due to increased H+ excretion and bicarbonate reabsorption)
5. Ectopic ACTH production (ie. due to small cell lung cancer) is associated with very low potassium levels.

Question 7

How is cushing’s syndrome managed?

Answer 7

1. If Iatrogenic → discontinue steroids or use lower dose
2. Medical → metyrapone or ketoconazole (inhibit cortisol synthesis)
3. Surgical → transsphenoidal pituitary adenectomy (if pituitary tumour), adrenalectomy (if adrenal adenoma or carcinoma)

Question 8

What complications may arise from cushing’s syndrome?

Answer 8

1. Diabetes
2. Osteoporosis
3. Hypertension
4. Pre-disposition to infections
5. Complications of surgery:
   o CSF leakage
   o Meningitis
   o Sphenoid sinusitis
   o Hypopituitarism
6. Complications of radiotherapy:
   o Hypopituitarism
   o Radionecrosis
   o Increased risk of second intracranial tumours and stroke
7. Bilateral adrenalectomy may be complicated by the development of Nelson’s syndrome (locally aggressive pituitary tumour causing skin pigmentation due to ACTH secretion)

Question 9

Summarise the prognosis for patients with Cushing’s syndrome

Answer 9

● Untreated - 5 yr survival = 50%