Cushing syndrome

Cushing syndrome is due to the effects of excessive glucocorticoids which may be exogenous or endogenous.

Terminology

Cushing disease refers to glucocorticoid excess solely due to an adrenocorticotropic hormone-secreting pituitary adenoma, while Cushing syndrome encompasses all aetiologies of glucocorticoid excess ⁶.

Clinical presentation

Typically, patients have the following clinical features ⁶:

• rounded face, sometimes described as 'moon-shaped' 
• progressive centripetal obesity and weight gain
• prominent supraclavicular and dorsocervical fat pad,pads (the latter is sometimes known as a 'buffalo hump')
• purple skin striae
• easy skin bruising
• acanthosis nigricans
• proximal myopathy
• depression and other mood disorders
• osteoporosis
• hypertension
• hyperglycaemia and development of overt diabetes mellitus
• immunosuppression and recurrent infections

Female patients with Cushing syndrome may also have signs of androgen excess (e.g. hirsutism, acne, changes in libido, virilisation) and menstrual changes ⁶. Features of androgen excess are not present in men as the adrenal glands are not a major source of androgens in men ⁶.

Furthermore, certain patient groups may demonstrate additional or atypical clinical features depending on the aetiology of Cushing syndrome ⁶:

• patients with Cushing disease:
  • hyperpigmentation, because melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) share the same precursor molecule, proopiomelanocortin (POMC)
  • clinical features as a result of an intracranial mass (see: pituitary adenoma)
• patients with ectopic ACTH secretion (e.g. secondary to small cell lung cancer):
  • cachexia
  • hyperpigmentation, because ACTH has an alpha MSH sub-unit as part of its structure
• patients with an adrenal carcinoma:
  • cachexia

Pathology

In modern Western populations, iatrogenic steroid administration for treatment of inflammatory condition is the most common cause, e.g. asthma, rheumatoid arthritis.

Endogenous sources of excess cortisol production include:

• adrenal adenoma: 20%
• primary pigmented nodular adrenal dysplasia (PPNAD): rare ²
• ACTH-secreting tumour: 80%
  • pituitary adenoma: 85% (i.e. Cushing disease)
  • ectopic production: 15% ⁵
    • lung cancer: small cell lung cancer, bronchial carcinoid
    • small cell cancers of the thymus
    • pancreatic neuroendocrine tumour
    • pheochromocytoma
    • benign ovarian tumours
• adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH): rare cause of ACTH-independent Cushing syndrome ⁴
• corticotropin-releasing hormone-secreting tumour: very rare
  • hypothalamic tumours
  • ectopic production

The workup of Cushing syndrome requires measurement both of cortisol as well as ACTH. Measuring cortisol typically needs to be over a 24 hour period because release is intermittent. 

Radiographic features

Imaging of the suspected region is then required:

• CT or MRI for adrenal glands
• MRI (or CT) for pituitary gland

If ACTH is elevated but no microadenoma can be identified, and no ectopic source can be found, then inferior petrosal sinus sampling can be undertaken. Bilateral adrenal hyperplasia is one of the most common findings on abdominal CT.

ACTH-secreting pituitary microadenomas may be unapparent on imaging in 40-50% of cases.

Treatment and prognosis

Management depends on the specific aetiology ⁶.

Complications

• bilateral adrenalectomy in a patient with Cushing disease can lead to the development of Nelson syndrome

History and etymology

It is named after Harvey Williams Cushing (1869-1939), a pioneering American neurosurgeon, who first described a patient with hypercorticism ⁷.