Cushing’s Syndrome

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Overview

Cushing’s syndrome describes a set of signs and symptoms due to prolonged exposure to elevated glucocorticoids, which may be endogenous (from within the body) or exogenous (from outside the body).

This is not to be confused with Cushing’s disease, which describes a pituitary tumour secreting excess adrenocorticotropic hormone (ACTH) leading to the increased release of cortisol. Cushing’s disease can lead to Cushing’s syndrome.

To help make sense of this chapter, it may be helpful to refer to Endocrine and Metabolic Physiology.

Epidemiology

  • The most common cause of Cushing’s syndrome is exogenous glucocorticoids
  • ACTH-secreting pituitary adenomas are the most common endogenous cause of Cushing’s syndrome

Causes

Overview

The most common cause of Cushing’s syndrome is the use of exogenous glucocorticoids (e.g. a patient unnecessarily taking corticosteroids for too long). The causes of endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent causes.

ACTH-dependent

These are endogenous causes that lead to inappropriately raised ACTH levels resulting in excess glucocorticoid production. They may be:

  • Cushing’s disease – ACTH-secreting pituitary adenoma
  • Ectopic ACTH-secreting tumours (e.g. small cell lung cancer)

ACTH-independent

These are endogenous causes that lead to excess glucocorticoid production despite having low or normal ACTH levels. They may be:

  • Exogenous glucocorticoids
  • A unilateral adrenal adenoma 
  • An adrenal carcinoma

Presentation

The presentation of Cushing’s disease can vary significantly, as many of its signs and symptoms are non-specific. Features may be:

  • Facial plethora – redness of the face
  • Facial fullness – ‘moon face’
  • Truncal obesity, ‘buffalo hump’ (dorsocervical fat pads), and supraclavicular fat deposits
  • Purple striae – ‘stretch marks’
  • Glucose intolerance
  • Osteoporosis
  • Acne
  • Depression
  • Decreased libido
  • Easy bruising
  • Muscle weakness – typically proximal muscles
  • Irregular periods or amenorrhoea
  • Hirsutism
  • Pituitary tumours may cause bitemporal hemianopia if large enough

Differential Diagnoses

Pseudo-Cushing’s syndrome

  • Often due to alcohol excess, severe depression/anxiety, obesity, or poorly-controlled diabetes mellitus
  • Avoidance of alcohol results in normal cortisol levels after a few days

Investigations

Overview

  • Overnight dexamethasone suppression tests (see below):
    • Often used first-line as it has a higher sensitivity than collecting 24-hour urine samples and can help localise where the problem is
    • Dexamethasone is given at night, then cortisol levels are measured in the morning. See below for interpretation.
  • 24-hour urinary free cortisol:
    • An alternative to the dexamethasone suppression tests, but does not help localise where the problem is

Other investigations

Other findings patients with Cushing’s disease may have can be:

  • FBC:
  • U&Es, ABGs/VBGs:
  • Blood glucose:
    • May be raised, suggesting impairment
  • Urine pregnancy test:
    • Should be considered in people of childbearing age – usually negative
  • Pituitary MRI:
    • Used if a pituitary adenoma is suspected

Dexamethasone suppression tests

Administering dexamethasone should lead to decreased cortisol secretion due to negative feedback on the hypothalamus and pituitary gland. This negative feedback should lead to reduced cortisol-releasing hormone (CRH) from the hypothalamus and ACTH from the pituitary, leading to low cortisol levels.

The dexamethasone suppression tests are based on this principle and help to localise where the problem is. There are two tests used:

  • Low-dose dexamethasone suppression test – done first to screen for Cushing’s syndrome:
    • Cortisol suppressed (low) – normal
    • Cortisol not suppressed (high/normal) – Cushing’s syndrome
  • High-dose dexamethasone suppression test:
    • This is done if the low-dose test shows Cushing’s syndrome may be present
    • Cortisol suppressed and ACTH suppressed – Cushing’s disease
    • Cortisol not suppressed but ACTH suppressed – adrenal adenoma
    • Cortisol not suppressed and ACTH not suppressed – ectopic ACTH

Management

  • 1st-line: manage underlying cause, examples are:
    • Cushing’s disease: transsphenoidal pituitary adenomectomy
    • Ectopic ACTH: manage cause (e.g. chemotherapy/radiotherapy/surgery for cancer)

Complications

  • Diabetes mellitus
  • Metabolic syndrome
  • Hypertension
  • Obesity
  • Hyperlipidaemia
  • Thrombophilia

Prognosis

  • Without treatment, median survival is around 5 years. With treatment, the mortality rate is similar to the general population. 
  • Mortality is mainly due to cardiovascular disease.

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