Cushing’s Syndrome

Armed Forces Academy of Medical Sciences

Outline

• Define Cushing’s Disease and Syndrome• Review normal cortisol regulation• Discuss the clinical manifestations of Cushing’s• How to diagnose Cushing’s Syndrome• Treatment options for Cushing’s Syndrome

Normal Cortisol Synthesis and Regulation

• Hypothalmus secretes Corticotropin Releasing Hormone (CRH) in response to– Low Serum Cortisol– Low Blood Sugar– Stress

• CRH stimulates anterior pituitary to release Corticotropin (ACTH)

• ACTH stimulates adrenal gland to produce cortisol

ACTH Secretion

• ACTH secretion is pulsatile• Pulse frequency remains constant throughout

the day– Amplitude of each pulse varies in circadian fashion– Highest at time of awakening– Lowest in late evening and very early morning

hours• Variation makes measuring ACTH to diagnose

Cushing’s syndrome or disease inaccurate

Cortisol Metabolism

• Cortisol secretion reflects ACTH secretion and is therefore also pulsatile

• Cortisol exists in two forms– Free cortisol in serum– Bound to corticosteroid-binding globulin

(majority)• Free cortisol– Enters tissue for action and metabolism– Filtered into urine or saliva for excretion

Normal Cortisol Synthesis and Regulation

• Cortisol provides negative feedback inhibition at multiple levels– Anterior Pituitary– Hypothalmus

Definitions• Cushing’s Syndrome: chronic exposure to

excessive levels of glucocorticoids

• Cushing’s Disease: specifically refers to pituitary hypersecretion of ACTH leading to Cushing’s syndrome

• Dr. Harvey Cushing– Neurosurgeon

Cushing’s Syndrome Etiology

ACTH-dependent• Pituitary hypersecretion

(Cushing’s Disease) – 65-70%

• Ectopic secretion of ACTH by non-pituitary tumors – 10-15%

• Ectopic secretion of CRH by nonhypothalamic tumor– 1%

ACTH-independent• Exogenous administration of

glucocorticoids– Probably the most common

• Adrenocortical adenomas and carcinomas– 18-20%

• Bilateral adrenal micronodular hyperplasia– 1%

Cushing’s Syndrome Epidemiology

• Relatively even distribution between men and women– Men more common ACTH secreting lung tumors– Women more commonly have Cushing’s Disease

• Age at presentation varies depending on etiology– Ectopic ACTH secretion: Age > 50– Cushing’s Disease: 25-45 years old– Adrenal Tumors: 40-50 years old

Clinical Manifestations of Cushing’s Syndrome

• Centripetal obesity• Facial plethora• Glucose intolerance• Proximal muscle weakness• Hypertension• Abdominal striae• Hirsutism

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Symptoms of Cushing’s Syndrome: Progressive Obesity

• Most common feature• Involves face, neck, abdomen– Moon Facies (cheeks)– Buffalo Hump (dorsocervical fat pad)

• Spares extremities• Children with Cushing’s syndromehave generalized obesity• Degree of fat accumulation variable

Buffalo Hump

Moon Facies

Symptoms of Cushing’s Syndrome: Skin Manifestations

• Rarely seen in other clinical scenarios– Can be very specific for Cushing’s Syndrome

• Skin atrophy• Easy bruisability• Striae• Frequent fungal infections• Hyperpigmentation– Caused by increased ACTH not cortisol

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Symptoms of Cushing’s Syndrome: Neuropsychological Effects

• 50% of all cases of Cushing’s Syndrome• Most common symptoms– Emotional liability– Agitated depression– Irritability– Anxiety and Paranoia

• After correction of hypercortisolism, resolution of psychiatric symptoms is variable

Diagnosis of Cushing’s Syndrome

• Possible presence of Cushing’s syndrome suggested by clinical signs and symptoms– No symptom pathognomonic– All non-specific

• Diagnosis must be confirmed by biochemical tests

• Many causes of Cushing’s syndrome, pulsatile nature of ACTH and cortisol secretion make biochemical testing complex– No test with ideal sensitivity or specificity

Diagnosis of Cushing’s Syndrome

• History must exclude exogenous glucocorticoid intake– Ingestion of prednisone (oral, injected, topical or

inhaled formulations)• Exclude physiologic hypercortisolism– States where elevated cortisol is NOT Cushing's– Physically stressed (infection)– Severe obesity– Psychologically stressed– Chronic Alcoholism

Diagnostic Strategy

• First line tests– Late night salivary cortisol (done at least twice)– Urinary cortisol (at least 3x normal)– Dexamethasone suppression test

• Need 2/3 tests to be positive to establish diagnosis of Cushing’s Syndrome

• Further testing indicated for patients with slightly abnormal or discordant results

2008 Endocrine Society Clinical Guidelines

Urinary Cortisol

• Should be first screening test• 24-hour urine collection• Measures serum free cortisol concentration• Physiologic elevations of cortisol are always <

3x ULN– Re-evaluated several weeks later– Subjected to another screening test

Low Dose Dexamethasone Suppression Test

• Exogenous dexamethasone substitutes for endogenous cortisol suppressing ACTH

• In normal subjects dexamethasone should suppress pituitary secretion of ACTH and cortisol secretion by adrenal glands– Low salivary and urinary cortisol– Cortisol assays do not measure dexamethasone

• Two types of low dose suppression tests– 1 mg overnight– 2 mg two day test

Low Dose Dexamethasone Suppression Test

• Overnight 1 mg test– Administration of 1 mg dexamethasone at 11 pm– Measure serum cortisol at 0800 next morning– Normal value < 1.8 mcg/dL

• Two-day 2 mg test– 0.5 mg dexamethasone every six hours for 8 doses– Measure serum cortisol at 2 and 6 hours after LAST

dexamethasone dose– Normal value < 1.8 mcg/dL

Low Dose vs. High Dose Dexamethasone Suppression

• Low dose– Utilized to establish diagnosis of Cushing’s

Syndrome

• High Dose– Utilized to differentiate Cushing’s Disease from

patients with ectopic ACTH syndrome

Late Evening Salivary Cortisol

• Morning serum or salivary cortisol concentrations have no diagnostic value

• Normal evening cortisol nadir preserved in obese and depressed patients– Nadir not present in patients with Cushing’s

• Benefits– Easy: can be done at home– Non-invasive– Cortisol stable in saliva for days permitting testing days

after collection• Normal ranges vary depending on commercial assay

Late Evening Serum Cortisol

• Normal evening nadir of serum cortisol in obese and depressed patients,

but not in patients with Cushing’s Syndrome• Midnight blood draw• Normal valve < 2 mcg/dL• Very high sensitivity, marginal specificity• Intermediate values rechecked weeks later

Cushing’s Disease• Pituitary adenoma– 95% microadenoma, not visible on MRI

• ACTH secretion– Remains pulsatile– Amplitude and duration of pulse increased– Frequency of pulses not altered– Lose normal circadian rhythm– Results in bilateral adrenocortical hyperplasia– Hypersecretion of cortisol

• Increased cortisol secretion reflected by increased urinary excretion of cortisol

Ectopic ACTH Syndrome

• Non-pituitary tumor secretion of ACTH results in bilateral adrenocortical hyperplasia– Hypersecretion of cortisol

• Suppresses pituitary ACTH release• Tumor secretion of ACTH not suppressed• Salivary cortisol concentrations accurately

reflect serum free cortisol levels• Tumors of lung, pancreas, and thymus

frequently secretion ACTH

Ectopic CRH Syndrome

• Tumor secreting CRH– Very rare

• Results in hyperplasia and hypersecretion of pituitary corticotrophs– Increased ACTH secretion– Cortisol hypersecretion– Bilateral adrenal Hyperplasia

Iatrogenic of Factitious Cushing’s Syndrome

• Administration of excessive amounts of synthetic glucocorticoid

• Inhibit CRH and ACTH secretion• Bilateral adrenocortical atrophy• Plasma ACTH, serum and salivary cortisol, and

urinary cortisol levels all low

Primary Adrenocortical Hyperfunction

• Includes adrenocortical tumor, micronodular dysplasia, ACT-independent macronodular hyperplasia

• Elevated levels of cortisol which suppresses– CRH– ACTH– Cortisol steroid precursors (DHEA-S)

Treatment of Cushing’s Syndrome

• Should be directed at primary cause of hypercortisolemia– Pituitary Tumor producing ACTH– Ectopic ACTH secretion– Cortisol Secretion by an adrenal tumor

• Exogenous Cushing’s Syndrome: Stop the glucocorticoid

Treatment of Cushing’s Disease• Transsphenoidal Surgery– Initial therapy of choice– 75-90% cure rate for microadenomas– Greater the resection, greater risk of loss of pituitary function (loss of fertility)

• Pituitary Irradiation– Choice of discrete microadenoma cannot be localized and

fertility is a concern– 3-12 months for maximum benefit– 45% cure rate for adults

• Adrenalectomy– Bilateral total adrenalectomy with lifelong daily

glucocorticoid and mineralcorticoid replacement is final definitive therapy

Treatment of Ectopic ACTH or CRH Tumors

• Optimal therapy is surgical resection of tumor• High recurrence rate• Tumor with metastases to liver can be resected

with cyroablation to liver mets• Nonresectable tumors– Hypercortisolism can be medially controlled with

adrenal enzyme inhibitors• Ketoconazole• Etomidate• Metyrapone

Treatment of Ectopic ACTH or CRH Tumors

• Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralcorticoid replacement is final definitive therapy

• Prognosis dictated by– Nature of tumor– Severity of hypercortisolism

• Most patients with metastatic disease die within 1 year– Small cell lung cancer, medullary thyroid cancer and

gastrinomas have particularly poor prognosis

Primary Adrenal Disease• Adrenal Tumors– Ademonas cured with

unilateral resection– Carcinomas with high

rate of recurrence

• Bilateral Adrenal Hyperplasia– Bilateral adrenalectomy

• Goal is to Remove the tumor– Unilateral adrenalectomy– Bilateral adrenalectomy

Patient Course After Therapy

• Physical symptoms and signs resolve gradually over 12 months

• Hypertension and hyperglycemia will improve, but may not completely resolve

• Osteoporosis improves after 6 months

Conclusion

• Cushing Syndrome is difficult to diagnose• Cushing Syndrome encompasses many

different diseases that lead to elevated serum cortisol levels

• Diagnosis requires multiple biochemical tests• Cushing’s syndrome is 100% fatal if untreated• Specific treatment depends on etiology of

Cushing’s syndrome