MRCEM Notes

Cushing's syndrome

Physiology · Endocrine physiology
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Background

Cushing's syndrome refers to the clinical syndrome caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids.

The severity of symptoms can vary significantly depending on the level of steroid exposure.

Classification

Causes of Cushing's syndrome can be divided into two groups:
  • Adrenocorticotropic hormone (ACTH)-dependent disease: excessive ACTH from the pituitary gland or ACTH secreting tumours stimulate excessive cortisol production
  • Non-ACTH-dependent disease: excess glucocorticoid independent of ACTH stimulation.

Illustration of Hypothalamic-pituitary-adrenal axis and feedback between CRH, ACTH and cortisol. Click on image to enlarge

Causes

ACTH dependentACTH independent
ACTH from the pituitary gland (Cushing's disease)
ACTH secreting tumours
Excess exogenous ATCH administration		Adrenal adenomas
Adrenal carcinomas
Excess glucocorticoid administration

Cushing syndrome causes
Exogenous steroid use is the most common cause of Cushing syndrome

Pituitary adenoma is the second most common cause of Cushing syndrome & the most common endogenous cause.

Cushing disease versus Cushing syndrome

Cushing disease refers to Cushing syndrome that is caused by an ACTH-producing pituitary tumour

Clinical features


Illustration of Cushing syndrome symptoms. Click on image to enlarge

  • Truncal obesity
  • Supraclavicular fat pads, buffalo hump
  • Weight gain.
  • Moon facies
  • Proximal muscle wasting and weakness.
  • Diabetes or impaired glucose tolerance.
  • Gonadal dysfunction, reduced libido.
  • Hypertension.
  • Nephrolithiasis.
  • Skin changes (skin atrophy, striae, easy bruising, hirsutism, acne & hyper-pigmentation in ACTH-dependent causes).
  • Depression & emotional lability.
  • Osteopenia or osteoporosis.
  • Oedema.
  • Iirregular menses or amenorrhoea
  • Polydipsia & polyuria.
  • Poor wound healing.
  • Signs related to tumour if that is underlying cause e.g. headaches & visual problems

Investigations

The recommended diagnostic tests for Cushing's syndrome are:
  • 24-hour urinary free cortisol
  • 1 mg overnight dexamethasone suppression test
  • Late-night salivary cortisol

Other investigations are aimed at assessing metabolic disturbance and identifying underlying cause. They include:
  • Plasma ACTH
  • FBC: raised white cell count
  • U&E's and VBG: hypokalaemia & metabolic alkalosis can occur
  • CT or MRI of abdomen, chest and/or pituitary may be required to assess suspected adrenal tumours, ectopic ACTH secreting tumours and pituitary tumours

Imaging may be guided by the ACTH result:
  • Undetectable ACTH with elevated serum cortisol level is diagnostic of ACTH-independent Cushing's syndrome. Imaging of adrenals is indicated.
  • Raised ACTH suggests an ACTH secreting tumour and imaging of the pituitary +/- chest/abdo (to detect ectopic ACTH secreting tumours).

Summary of causes
ACTH dependent causes
  • Cushing's disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia
  • ectopic ACTH production (5-10%): e.g. small cell lung cancer

ACTH independent causes
  • iatrogenic: steroids
  • adrenal adenoma (5-10%)
  • adrenal carcinoma (rare)
  • Carney complex: syndrome including cardiac myxoma
  • micronodular adrenal dysplasia (very rare)

Pseudo-Cushing's
  • mimics Cushing's
  • often due to alcohol excess or severe depression
  • causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
  • insulin stress test may be used to differentiate
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