Cushing Syndrome

Definitions

Cushing syndrome: excess adrenal steroids from iatrogenic sources such as drugs

Cushing disease: pituitary tumour causing ACTH overproduction.  Adrenal adenomas and ectopic ACTH production can occur due to causes such as neuroendocrine tumours, but these are very rare.

Cushing’s disease is a rare entity, with Cushing syndrome being more common.

Pathophysiology

The adrenal gland secretes cortisol via the hypothalamic-pituitary axis (HPA).  There is a negative feedback loop with cortisol-releasing hormone (CRH) and adrenocortical hormone (ACTH) stimulating the adrenal gland to secrete cortisol, which then feeds back to suppress further ACTH and CRH release, as shown in Figure 1.  This pathway exhibits a circadian rhythm.  Cortisol then binds to intracellular glucocorticoid and mineralocorticoid receptors.

Cushing syndrome occurs after the HPA axis is affected.  Various factors can result in excess cortisol and adrenal steroids.  They can be defined as ACTH-dependent or independent depending on which part of the above pathway it affects.

ACTH-Independent Cushing’s Disease

ACTH Independent Cushings Disease is where the adrenal adenoma is not reliant on ACTH to secrete cortisol, but it still exerts a negative feedback on ACTH and CRH secretion. It can take a long time for the body to recover.

ACTH-Dependent Cushing’s Disease

ACTH-dependent Cushing’s disease is when there is an alternative source of ACTH secretion which is not influenced by the negative feedback loop, leading to excess cortisol secretion. This exerts a negative feedback to the body’s own pituitary gland and hypothalamus, so production of ACTH and CRH is reduced.

Risk Factors

These include particular patient groups such as:

• Severe asthmatics who are often on high doses of inhaled corticosteroids for prolonged periods, and sometimes oral steroids.
• Any patient who has been on steroids for a prolonged period of time; in children, > 2 weeks is the defined period.
• A family history of endocrine tumours, such as MEN-1, as well as rare inherited adrenal tumours.

Clinical Features

From history:

• Past medical history or family history of endocrine tumours
• History of weight gain
• Change in facial appearance
• Hirsuitism
• Skin rashes
• Drug history
• Fatigue
• Diabetes symptoms
• Mood disturbance

From examination:

• Obesity (particularly truncal)
• Hypertension
• Easy bruising
• Decreased growth rate with rapid weight gain
• Decreased skeletal maturity
• Hirsutism
• Acne in a prepubertal child is always abnormal
• Striae (purple stretch marks on the skin)
• Myopathy (positive Gower’s sign)
• Freckling (rare but associated with Carney’s disease).
• Examine the abdomen to rule out an adrenal mass on palpation.

Differential Diagnosis

• MEN type 1: Multiple endocrine tumours such as parathyroid, pituitary, and endocrine tumours of the gastro-entero-pancreatic tract. Tumours present simultaneously rather than as isolated tumours and tend to be young adults/teenagers.
• Cancer predisposition: Li-Fraumeni Syndrome, P53 mutations, Beckwith-Wiedemann, Carneys, McCune Albrights.
• Exogenous steroids
• ACTH-secreting adenocarcinomas
• Obesity

Investigations

Laboratory tests are used to identify Cushing syndrome and a cause.

• 24-hour urinary cortisol: Patient needs to have 2 x 24hr colllections, as a one-off measurement is hard to interpret due to the diurnal nature of cortisol secretion.
• Midnight cortisol: The normal circadian pattern should see a level < 50 nmol/l.
• Dexamethasone suppression testing: Exogenous administration of dexamethasone, with 6-hour testing to demonstrate cortisol suppression. Cortisol levels should normally suppress and can be a screening test to exclude Cushing syndrome.  A dose of dexamethasone is given, and cortisol and ACTH are checked at 9 am the next morning.  If cortisol is not suppressed, then further tests are needed to identify ACTH-dependent Cushing’s. Two tests are currently available, with the low-dose dexamethasone suppression test (LDDST) being more common. The LDDST will typically be followed by the high-dose dexamethasone suppression test (HDDST) to distinguish between ACTH-dependent and independent causes of Cushing’s. Adrenal tumours and ectopic ACTH will not suppress, but there will be some suppression if there is a pituitary tumour.
• Corticotrophin-releasing hormone (CRH) test: Exogenous CRH is given, with samples taken for ACTH and cortisol.  If there is a pituitary tumour, there will be an increase in ACTH and cortisol. In ectopic ACTH production, there is no response. The CRH test directly stimulates the hypothalamus and sometimes helps in the diagnosis of Cushing’s disease.
• CRH testing with inferior petrosal sinus sampling: This is selective sampling of the venous system that supplies the pituitary, measuring ACTH and cortisol. In an established diagnosis of Cushing’s disease, it helps with lateralisation of an ACTH-secreting tumour in the pituitary and helps with neurosurgical outcomes in treating the disease.

Imaging or invasive tests

• Pituitary MRI or CT adrenal: Identify pituitary/adrenal adenomas, their precise location and help in treatment decisions.
• Adrenal MRI: Helpful in identifying an adrenal source.
• Chest/abdominal CT: Indicated when a diagnosis of ectopic ACTH secretion is suspected, to identify the presence of an elusive ACTH-secreting tumour.

Management

• Surgical resection for adrenal adenomas
• Transsphenoidal surgery for pituitary tumours
• Pituitary irradiation if transsphenoidal surgery has failed
• Adrenalectomy in very resistant Cushing’s disease
• Etomidate: used in emergencies; infusions can be used to control Cushing’s disease that is life-threatening.
• Cushing’s syndrome: Graded reduction of the exogenous steroid +/- intermittent Synacthen testing to exclude steroid-induced suppression of adrenal steroidogenesis.

Complications

• SIADH
• Hypothyroidism
• Diabetes Insipidus
• Hypopituitarism +/- hormone replacement therapy.
• Adrenal insufficiency until the HPA axis recovers

References and further reading