Cushing’s syndrome

Question 1

Define Cushing’s syndrome

Answer 1

Syndrome associated with chronic inappropriate elevation of free circulating cortisol

Question 2

Explain the aetiology/risk factors for Cushing’s syndrome

Answer 2

It can be divided into ACTH Dependent (80%)
and ACTH Independent (20%)

ACTH Dependent
Excess ACTH from a pituitary adenoma (Cushing’s disease). Ectopic ACTH (e.g. lung cancer, pulmonary carcinoid tumours)

ACTH Independent
Benign adrenal adenoma
Adrenal carcinoma

Question 3

Summarise the epidemiology of Cushing’s syndrome

Answer 3

Incidence: 2-4/1,000,000 per year

Peak incidence 20-40 yr

Question 4

Recognise the presenting symptoms of Cushing’s syndrome

Answer 4

Increasing weight
Fatigue
Muscle weakness
Myalgia
Thin skin
Easy bruising
Poor wound healing
Fractures
Hirsuitism
Acne
Frontal balding
Oligomenorrhoea/amenorrhoea
Depression or psychosis

Question 5

Recognise the signs of Cushing’s syndrome on physical examination

Answer 5

Moon face
Facial plethora
Interscapular fat pad
Proximal muscle weakness
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 (salt and water retention due to cortisol)
Pigmentation in ACTH dependent cases

Question 6

Identify appropriate investigations for Cushing’s syndrome

Answer 6

Must be performed on patients with a high pre-test probability

Bloods
U&Es-hypokalaemia due to mineralocorticoid effect
BM-high glucose

Initial High-Sensitivity Tests
Urinary free cortisol
Late-night salivary cortisol
Overnight dexamethasone suppression test

Low dose dexamethasone suppression test (LDDST)
Give 0.5 mg dexamethasone orally ever 6 hrs for 48 hrs
In Cushing’s syndrome, serum cort isol measured 48 hrs after the first dose of dexamethasone fails to suppress below 50 nmol/

Question 7

Tests to determine the underlying cause

Answer 7

ACTH-independent (adrenal adenoma/carcinoma)
Low plasma ACTH
CT or MRI of adrenals
o
ACTH-dependent (pituitary adenoma)
High plasma ACTH
Pituitary MRI
High-dose dexamethasone suppression test (Cushing's disease suppressed, Ectopic not)

Inferior petrosal sinus sampling (SUPERIOR to high-dose dexamethasone suppression test) Central: peripheral ratio of venous ACTH > 2:1 (or > 3:1 after CRH administration) in Cushing’s disease

ACTH-dependent (ectopic)
If lung cancer suspected: CXR, sputum cytology, bronchoscopy, CT scan

Radiolabelled octreotide scans can detect carcinoid tumours because they express somatostatin receptor

Question 8

Generate a management plan for Cushing’s syndrome

Answer 8

If iatrogenic - discontinue steroids, use lower dose or use a steroid-sparing agent

Medical
Used pre-operatively or if unfit for surgery
Inhibit cortisol synthesis with metyrapone or ketoconazole (hepatotoxic)

Treat osteoporosis
Physiotherapy for muscle weakness

Surgical
Pituitary Adenomas- trans-sphenoidal resection
Adrenal adenoma/carcinoma- surgical removal of tumour
Ectopic ACTH- treatment directed at the tumour

Radiotherapy
Performed in those who are not cured and have persistent high cortisol after trans-sphenoidal resection of the tumour

Bilateral adrenalectomy may be performed in refractory Cushing’s disease

Question 9

Identify possible complications of Cushing’s syndrome

Answer 9

Diabetes
Osteoporosis
Hypertension
Pre-disposition to infections

Complications of surgery:
CSF leakage
Meningitis
Sphenoid sinusitis
Hypopituitarism

Complications of radiotherapy:
Hypopituitarism
Radionecrosis

Increased risk of second intracranial tumours and stroke

Bilateral adrenalectomy may be complicated by the development of Nelson’s syndrome (locally aggressive pituitary tumour causing skin pigmentation due to ACTH
secretion)

Question 10

Summarise the prognosis for patients with Cushing’s syndrome

Answer 10

Untreated- 5 yr survival = 50%

Depression persists for many years following treatment