Cushing's Syndrome

Pituitary cause = Cushing's Disease
Cushing's disease = everything

Cushing's syndrome is caused by prolonged exposure to elevated levels of

• Endogenous glucocorticoids
• Exogenous glucocorticoids

 The degree of cortisol is very variable. When presentation is florid, diagnosis is usually straightforward. May be subtle however and combination of nonspecific clinical manifestations and variable cyclical biochemical parameters often make diagnosis difficult.
Early diagnosis and prompt treatment are essential.


Causes

• Adrenocorticotropic hormone dependent causes
• Excessive ACTH from the pituitary (Cushing's disease)
• Ectopic ACTH producing tumours
• Excess ACTH administration
• Non-ACTH dependent causes
• Adrenal adenomas
• Adrenal carcinomas
• Excess glucocorticoid administration

Epidemiology

•  Incidence of Cushing's is 10 to 15 people per million increases with
• Diabetes
• Obesity
• Hypertension
• Osteoporosis

Risk factors

• Cushing's syndrome due to an adrenal or pituitary tumour is more common in females (5:1)
• Peak incidence 25-40 years
• Ectopic ACTH production is due to lung cancer

Common causes

•  The most common cause of Cushing's syndrome is the use of exogenous glucocorticoids. Endogenous Cushing's syndrome is divided into corticotropin-dependent and corticotropin-independent causes:
• Corticotropin-dependent causes account for about 80-85% of cases
• Pituitary adenomas (Cushing's disease)
• Small cell carcinoma and other endocrine tumour
• Corticotropin-independent Cushing's syndrome
• Adrenal adenoma and adrenal carcinoma
• McCune-Albright syndrome (polycystic fibrous dysplasia and cafe au lait spot pigmentation with autonomous endocrine hyperfunction) and primary pigmented nodular adrenal disease and macronodular adrenal hyperplasia

Presentation

• Truncal obesity, supraclavicular fat pads, buffalo hump, weight gain
• Facial fullness, moon facies, facial plethora
• Proximal muscle wasting and weakness
• Diabetes or impaired glucose tolerance
• Gonadal dysfunction, reduced libido
• Hypertension
• Nephrolithiasis
• Skin: skin atrophy, purple striae, easy bruising, hirsuitism, acne: pigmentation occurs with ACTH dependent causes
• Psychological problems: depression, cognitive dysfunction, and emotional lability
• Osteopenia and osteoporosis
• Oedema
• Woman may complain of irregular menses
• Thirst, polydipsia, polyuria
• Impaired immune function: increased infections, difficulty with wound healing
• Child: growth restriction
• Patients with an ACTH producing pituitary tumour may develop headaches, visual problems and galactorrhoea
• Destruction of the anterior pituitary may cause hypothyroidism and amenorrhoea

Differential diagnosis

• Pseudo-Cushing's syndrome: all or some of the clinical features of Cushing's syndrome combined with biochemical evidence of hypercortisolism (but not caused by pituitary adrenal axis problems)
• Chronic severe anxiety and/or depression
• Prolonged excess alcohol consumption, which can cause a cushingoid appearance
• Obesity
• Poorly controlled diabetes
• HIV infection

Investigations

• During referral
• Not when there is intercurrent illness

Confirm presence of disease

• 24 hour urinary free cortisol
• 1mg overnight dexamethasone suppression test
• late-night salivary cortisol
• Midnight cortisol levels
• CRH test

Identify cause

• Plasma ACTH
• High-dose dexamethasone suppression test
• Inferior petrosal sinus sampling (IPS)
• MRI of pituitary
• Chest and abdominal CT scans
• Plasma CRH

Treatment

• Drugs
• Metyrapone
• Ketaconazole
• Mitotane
• Surgery
• Trans-sphenoidal microsurgery
• Radiotherapy
• For tumour in pituitary

Complications

• Metabolic syndrome
• Hypertension
• Impaired glucose tolerance and diabetes
• Obesity
• Hyperlipidaemia: raised LDL, cholesterol and triglycerides
• Coagulopathy: thrombophilia
• Osteoporosis
• Perforated viscera
• Impaired immunity, including opportunistic fungal infections
• Nelson's syndrome, which may follow bilateral adrenalectomy for Cushing's disease
• A primary pituitary tumour, which may cause panhypopituitarism and visual loss

Prognosis

• 5x more mortality
• Vascular disease and diabetes (with complications of diabetes including infections) killing them
• Usual course is chronic, with cyclic exacerbations and rare remissions
• Better prognosis with surgery
• Adrenocortical carcinomas have 5 year survival rate of 30% or less