Case Hx 25 years old female Weight gain – 6 months DM – 1 month BP 130/90 mm Hg Round plethoric face Central obesity Pinkish striae on abdominal wall Proximal myopathy

Case Hx 24 hour urine cortisol – more than 3 fold rise LDDST 683 nmol/l 526 nmol/l ACTH – 81.2 pg/ml MRI Pituitary Two microadenomas, one on left and one on right side

Case Hx TSS performed Not fully cured 9 am Cortisol was 340 nmol/l (3 days after surgery) Marked improvement in glycemic control Plan - Assessment after two months with 24 hour urinary cortisol and LDDST (if needed)

Cushing’s=hypercortisolism Cushing's Syndrome- Clinical effects of increased glucocorticoid hormone - all causes of excess cortisol Cushing's Disease- ACTH producing pituitary adenoma

Clinical Features of Excess Cortisol Truncal obesity Moon face Fat deposits supraclavicular fossa and posterior neck- buffalo hump HTN Hirsutism Amenorrhea Depression Thin skin Easy bruising Purplish abdominal striae Proximal muscle weakness Osteoporosis Diabetes Mellitus Avascular necrosis Wound healing impaired Pysch symptoms Hyperpigmentation Hypokalemic alkalosis

Ectopic ACTH All the previous clinical features but….. Ectopic dominated by : – Hypokalemic alkalosis (dominant feature) – Fluid retention – HTN – Glucose intolerance – Steroid psychosis Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.

Causes of Cushing Syndrome Iatrogenic ACTH secreting pituitary microadenoma (Cushing’s disease) – 48% cases of Cushing’s syndrome – 3 x more women than men – 15% of pituitary tumors (usu 3 rd or 4 th decade of life)

Causes of Cushing Syndrome Adrenal tumors- - 32%, usually unilateral - Small tumour – benign - mostly cortisol - large- carcinoma - cortisol and androgens Ectopic ACTH secretion- 10% - most common small cell lung CA 15%- cause not identified

Ectopic ACTH SCLC >50% Thymic carcinoid 15% Islet cell tumors 10% Bronchial carcinoid 10% Other carcinoids 5% Pheochromocytomas 2%

Investigation of Cushing’s Syndrome

SCREENING TESTS

24 hour Urine Free Cortisol Useful for outpatient screening 3 times normal false –ve rate of 5–10% means that it should not be used alone. Fenofibrate, carbamazepine, and digoxin may lead to false +ves Reduced GFR <30mL/min may lead to false –ves. Mild elevation occurs in pseudo-Cushing’s and normal pregnancy.

Overnight DST Administration of 1mg dexamethasone at 11 pm is followed by a serum cortisol measurement at 9 a.m. Cortisol < 50nmol/L makes Cushing’s unlikely. False +ves (poor dexamethasone absorption or hepatic enzyme induction). The false –ve value is 2% of normal individuals but rises to upto 20% in obese or hospitalized patients.

Midnight Cortisol Loss of circadian rhythm of cortisol secretion is seen in Cushing’s syndrome 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.

Salivary Cortisol A late evening salivary cortisol concentration can be used to establish the diagnosis of Cushing's syndrome. Saliva is easily collected and cortisol is stable in saliva even at room temperature for several days. It is especially useful for patients suspected of having cyclical or intermittent Cushing's syndrome, who can collect many samples over an extended period of time and return the accumulated samples to the lab at one time.

False Positives Severe depression Severe stress Phenytoin/phenobarbital/rifampin (accelerated metabolism of dexamethasone) Estrogen (pregnancy or OCP) Morbid obesity

CONFIRMATORY TESTS

LDDST 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).

LDDST Interfering conditions should be considered with all dexamethasone testing ↓ dexamethasone absorption hepatic enzyme inducers (e.g. phenytoin, carbamazepine, and rifampicin) ↑ CBG.

Pseudo-Cushings 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.

Pseudo-Cushings 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-Cushings The combined DST–CRH test 0.5mg dexamethasone 6-hourly for 48h followed by ovine CRH 1 microgram/kg IV 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 IV desmopressin 10 micrograms increases ACTH in 80–90% with Cushing’s but rarely in patients with pseudo-Cushing’s.

Underlying Cause

Serum ACTH Once the presence of Cushing’s syndrome has been confirmed, a 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.

Serum ACTH The basal ACTH is, however, 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

Serum Potassium A rapidly spun potassium is a 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.

HDDST The high-dose dexamethasone suppression test is performed in an identical way to the low-dose test but with 2mg doses of dexamethasone 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.

CRH Test The 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. No response in ectopic ACTH disease There are occasional reports of patients with ectopic disease who show a similar response.

IPSS 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 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.

Pituitary Imaging MRI (gadolinium enhanced) localizes corticotroph adenomas in up to 80% of cases. 10% of the normal population harbour microadenomas and, therefore, the biochemical investigation of these patients is essential, as a patient with an ectopic source to Cushing’s syndrome may have a pituitary ‘incidentaloma’.

Treatment Cushing’s Disease: Transphenoidal resection of pituitary adenoma Adrenal neoplasms: resection Ectopic ACTH: resection if possible Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

‘Medical’ Adrenalectomy Medications that inhibit steroidogenesis Ketoconazole (600 to 1200 mg/day) Metyrapone (exacerbates female virilization, 2- 3 g/day) Mitotane(2-3 G/day)- slow onset Aminoglutethimide (1g/day) Ocreotide can work in 1/3 of patients. Major side affect is adrenal insufficiency, therefore start at lowest dose and titrate

Follow up and Monitoring Successful treatment for Cushing’s disease leads to a cortisol that is undetectable (<50nmol/L) following surgery. 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.

Follow up and Monitoring After successful surgery, the adrenals are suppressed. Patients need to have regular assessment of cortisol production off glucocorticoid replacement. When cortisol is detectable following surgery, recurrent disease must be excluded (low-dose dexamethasone suppression). If recurrence is excluded, adequacy of ACTH reserve should be assessed with ITT after patient is weaned off glucocorticoids.

Follow up and Monitoring Adequacy of glucorticoid replacement is assessed by - Clinical examination and lying/standing BP monitoring - Hydrocortisone day curve - 24 hour urine cortisol

Prognosis Benign adrenal adenoma- 95% 5 year survival, 90% 10 year Cushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years. Ectopic ACTH survival depends on malignancy Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival Adrenal carcinoma- median survival 7 months