cushing's syndrome

Cushing's syndromeBY HAZEM SAMY HUSSEINASSISTANT LECTURER OF INTERNAL MEDICINE

Definition

an illness resulting from excess cortisol secretion, which has a high mortality if left untreated.

Epidemiology of Cushing’s disease

Rare; annual incidence approximately 2/million. Commoner in ♀ (♀:♂, 3–15:1). Age—most commonly, 20–40 years.

Causes of Cushing’s syndrome

Pseudo-Cushing’s syndrome:• Alcoholism <1%.• Severe depression 1%. ACTH-dependent:• Pituitary adenoma 68% (Cushing’s disease).• Ectopic ACTH syndrome 12%.• Ectopic CRH secretion <1%. ACTH-independent:• Adrenal adenoma 10%.• Adrenal carcinoma 8%.• Nodular (macro- or micro-) hyperplasia 1%. Exogenous steroids, including skin creams, e.g. clobetasol.

Clinical features

progressive and may be present for several years prior to diagnosis.

A particular difficulty may occur in a patient with cyclical Cushing’s where the features and biochemical manifestations appear and disappear with a variable periodicity.

Features may not always be florid, and clinical suspicion should be high.

Clinical features• Most patients don’t have all these

signs/symptoms• Many doctors may have only seen 1

case of Cushing’s and textbooks may show only severe cases.

Clinical features Facial appearance—round plethoric complexion, acne and hirsutism, thinning of

scalp hair. Weight gain—truncal obesity, buffalo hump, supraclavicular fat pads. Skin—thin and fragile due to loss of SC tissue, purple striae on abdomen, breasts,

thighs, axillae, easy bruising, tinea versicolor, occasionally pigmentation due to ACTH.

Proximal muscle weakness. Mood disturbance—labile, depression, insomnia, psychosis. Menstrual disturbance. Low libido and impotence. There is a high incidence of venous thromboembolism (careful during surgery). Overall mortality greater than of general population (by a factor of 6). Growth arrest in children.

Striae rubra

Associated features

Hypertension (>50%) due to mineralocorticoid effects of cortisol (cortisol overwhelms the renal 11B-hydroxysteroid dehydrogenase enzyme protecting the mineralocorticoid receptor from cortisol). Cortisol may also increase angiotensinogen levels.

Impaired glucose tolerance/diabetes mellitus (30%). Osteopenia and osteoporosis (leading to fractures of spine and

ribs). Vascular disease due to metabolic syndrome. Susceptibility to infections.

Investigations

Does the patient have Cushing’s syndrome? What is the underlying cause?

Does the patient have Cushing’s syndrome?

Outpatient tests:1. 24h urinary free cortisol: 2–3x false –ve rate of 5–10% means that it should not be used alone

(reduced GFR <30mL/min) . false +ves(Fenofibrate, carbamazepine, and digoxin) depending

on assay. Mild elevation occurs in pseudo-Cushing’s and normal pregnancy.


2. Overnight dexamethasone suppression test Administration of 1mg dexamethasone at midnight is followed by

a serum cortisol measurement at 9 a.m. Cortisol <50nmol/L(1.8 mcg/dl.) makes Cushing’s unlikely. False +ves with poor dexamethasone absorption or hepatic

enzyme induction. The false –ve value is 2% of normal individuals but rises to <20%

in obese or hospitalized patients.


If both the above tests are normal, Cushing’s syndrome is unlikely.


Inpatient tests:1. Midnight cortisol: Loss of circadian rhythm of cortisol secretion is seen in Cushing’s

syndrome, and this is demonstrated by measuring a serum cortisol at midnight (patient must be asleep for this test to be valid and ideally after 48h as an inpatient).

In normal subjects, the cortisol at this time is at a nadir (<50nmol/L), but in patients with Cushing’s syndrome, it is elevated.


2. Low-dose dexamethasone suppression test: Administration of 0.5mg dexamethasone 6-hourly (30

micrograms/kg/day) for 48h at 9 a.m., 3 p.m., 9 p.m., and 3 a.m. should lead to complete suppression of cortisol to <50nmol/L in normal subjects (30 micrograms/kg/day).

Serum cortisol is measured at time 0 and 48h (day 2).


3. Diurnal Salivary Cortisol Test:• Salivary cortisol levels reflect plasma cortisol

levels.• Midnight plasma cortisol measurement

requires blood-drawing and may be difficult to obtain in an outpatient setting.

• uses a "Salivette" in which the patient chews on a cotton tube for 2-3 minutes. The samples are stable for a week at room temperature and salivary cortisol is independent of the rate of saliva production.

Pseudo-Cushing’s

Patients with pseudo-Cushing’s syndrome will also show loss of diurnal rhythm and lack of low-dose suppressibility.

However, alcoholics return to normal cortisol secretory dynamics after a few days’ abstinence in hospital. Severe depression can be more difficult to differentiate, particularly since this may be a feature of Cushing’s syndrome itself.

Typically, patients with pseudo-Cushing’s show a normal cortisol rise with hypoglycaemia (tested using ITT) whereas patients with true Cushing’s syndrome show a blunted rise. However, this is not 100% reliable, as up to 20% of patients with Cushing’s syndrome (especially those with cyclical disease) show a normal cortisol rise with hypoglycaemia.

Pseudo-Cushing’s

The combined dexamethasone suppression test–CRH test (0.5mg dexamethasone 6-hourly for 48h, starting at 12 p.m., followed by ovine CRH 1 microgram/kg IV at 8 a.m.) (2h after last dose of dexamethasone) may be helpful, as patients with pseudo-Cushing’s are thought to be under chronic CRH stimulation, thus showing a blunted response to CRH after dexamethasone suppression (cortisol 15min after CRH >38nmol/L in Cushing’s and <38nmol/L in pseudo-Cushing’s).

No screening tests are fully capable of distinguishing all cases of Cushing’s syndrome from normal individuals/pseudo-Cushing’s

Cyclical Cushing’s

A small group of patients with Cushing’s syndrome have alternating normal and abnormal cortisol levels on an irregular basis.

All causes of Cushing’s syndrome may be associated with cyclical secretion of cortisol.

Clearly, the results of dynamic testing can only be interpreted when the disease is shown to be active (elevated urinary cortisol secretion and loss of normal circadian rhythm and suppressibility on dexamethasone).

What is the underlying cause?

ACTH Serum potassium. High-dose dexamethasone suppression test. Corticotrophin-releasing hormone test. Inferior petrosal sinus sampling


1. ACTH: serum basal ACTH should be measured to differentiate between ACTH-

dependent and ACTH-independent aetiologies . ACTH may not be fully suppressed in some adrenal causes of Cushing’s;

however, ACTH >4pmol/L is suggestive of an ACTH-dependent aetiology. The basal ACTH is of very little value in differentiating between pituitary-

dependent Cushing’s syndrome and ectopic Cushing’s syndrome, as there is considerable overlap between the two groups, although patients with ectopic disease tend to have higher ACTH levels


2. Serum potassium: useful discriminatory test, as hypokalaemia <3.2mmol/L is found

in almost 100% of patients with ectopic secretion of ACTH but in <10% of patients with pituitary-dependent disease.


3. High-dose dexamethasone suppression test: performed in an identical way to the low-dose test but with 2mg

doses of dexamethasone (120 micrograms/kg/day). In Cushing’s disease, the cortisol falls by >50% of the basal

value. In ectopic disease, there is no suppression. However, approximately 10% of cases of ectopic disease,

particularly those due to carcinoid tumours, show >50% suppression, and 10% of patients with Cushing’s disease do not suppress.


4. Corticotrophin-releasing hormone test: administration of 100 micrograms of CRH IV leads to an

exaggerated rise in cortisol (14–20%) and ACTH (35–50%) in 95% of patients with pituitary-dependent Cushing’s syndrome.

There are occasional reports of patients with ectopic disease who show a similar response.

Side effects: transient flushing; very rarely, apoplexy reported.


5. Inferior petrosal sinus sampling: Bilateral simultaneous inferior petrosal sinus sampling with measurement of

ACTH centrally and in the periphery in the basal state and following stimulation with IV CRH (100 micrograms) allows differentiation between pituitary-dependent and ectopic disease.

A central to peripheral ratio of >2 prior to CRH is very suggestive of pituitary-dependent disease, and >3 following CRH gives a diagnostic accuracy approaching 90–95% for pituitary-dependent disease.


5. Inferior petrosal sinus sampling (cont.): The test should be performed when cortisol levels are elevated. The accurate lateralization of a tumour using the results from

inferior petrosal sinus sampling (IPSS) is difficult, as differences in blood flow and catheter placement, etc. will affect the results.

Brainstem vascular events and deep vein thrombosis are rare complications.

Investigation of ACTH-dependent Cushing’s syndrome

Pituitary imaging

MRI, following gadolinium enhancement which significantly increases

the pickup rate, localizes corticotroph adenomas in up to 80% of cases. However, it should be remembered that at least 10% of the

normal population harbour microadenomas and, therefore, the biochemical investigation of these patients is essential, as a patient with an ectopic source toCushing’s syndrome may have a pituitary ‘incidentaloma’.

Adrenal Imaging• Patients with severe pituitary Cushing’s can

have adrenal enlargement.• not helpful for the diagnosis of

hypercortisolism • Helpful for determining the type of

Cushing’s syndrome .

FIG. 1. Algorithm for testing patients suspected of having Cushing's syndrome (CS)`

Treatment of Cushing’s disease

1. Transsphenoidal surgery:

First-line option in most cases. Selective adenomectomy gives the greatest chance of cure, with a

reported remission rate of up to 90%. However, strict criteria of a post-operative cortisol of <50nmol/L

lead to lower cure rates but much lower recurrence rates (<10% compared with up to 50% in those with detectable post-operative cortisol).

Delayed normalization (1–2 months) of cortisol after surgery can occur.

Risk of relapse lasts for at least 10 years and is higher in Cushing’s disease than for other secreting adenomas (13% at 5 years).

2. Pituitary radiotherapy

usually as second-line treatment, following unsuccessful transsphenoidal surgery.

As control of cortisol levels may take months to years, medical treatment to control cortisol levels, while waiting for cortisol levels to fall, is essential.

A more rapid response to radiotherapy is seen in childhood.

3. Adrenalectomy This used to be the favoured form of treatment. It successfully controls

cortisol hypersecretion in the majority of patients. Occasionally, a remnant is left and leads to recurrent hypercortisolaemia. Bilateral adrenalectomy may still be indicated when pituitary surgery,radiotherapy, and medical treatment have failed to control the disease. It is also helpful in Cushing’s syndrome due to ectopic disease whenthe ectopic source remains elusive or inoperable. Laparoscopic surgery minimalizes morbidity and complications.

4. Medical treatment

indicated during the preoperative preparation of patients or while awaiting radiotherapy to be effective or if surgery or radiotherapy are contraindicated.

Inhibitors of steroidogenesis:1. metyrapone : usually used first-line.2.Ketoconazole: used as first-line in children, as it is unassociated with increased

adrenal metabolites. There is also a suggestion that ketoconazole may have a direct

action on the corticotroph as well as lowering cortisol secretion.

4. Medical treatment (cont.)

Disadvantage of these agents inhibiting steroidogenesis is the need to increase the dose to maintain control, as ACTH secretion will increase as cortisol concentrations decrease.

Steroidogenesis inhibitors may be used with glucocorticoid replacement regimen to completely inhibit cortisol or with an aim for partial inhibition of cortisol production.

aiming for a mean cortisol of 150–300nmol/L, as this approximates the normal production rate.

Follow-up of Cushing’s disease

Successful treatment for Cushing’s disease leads to a cortisol that is undetectable (<50nmol/L) following surgery. (This is due to the total suppression of cortisol production from the normal corticotrophs in Cushing’s disease.)

An undetectable post-operative cortisol leads to a significantly higher chance of long-term cure compared to the patients who have post-operative cortisol between 50–300nmol/L.

• The aim of follow-up is: To detect recurrent Cushing’s.

When cortisol is detectable following surgery, recurrent disease must be excluded (low-dose dexamethasone suppression). If recurrence is excluded, it is then important to document the adequacy of the stress response once weaned off glucocorticoid replacement (ITT).

Thank you

cushing's syndrome

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