Cushing's syndrome resident survival guide

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

This section provides a short and straight to the point overview of the disease or symptom. The first sentence of the overview must contain the name of the disease.

Causes

Life Threatening Causes

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

• Does not include any known cause.

Common Causes

• Iatrogenic or factitious Cushing's syndrome due to administration of exogenous glucocorticoids.
• Cushing's disease (due to excess secretion of Adrenocorticotropic hormone from anterior pituitary).
• Paraneoplastic: due to ectopic secretion of ACTH (includes, small cell lung cancer, benign carcinoid tumors, Ewing's sarcoma).
• Ectopic secretion of Corticotropin-releasing hormone (CRH).
• Adenoma and carcinoma in the adrenal cortex
• Primary pigmented nodular adrenocortical disease (PPNAD)
• Bilateral macronodular adrenal hyperplasia (BMAH)

Diagnosis

Shown below is an algorithm summarizing the diagnosis of Cushing's syndrome according to the Endocrine Society clinical guidelines.

Symptoms suggestive of Cushing’s syndrome: Osteoporosis unusual for the age Refractory hypertension Facial edema resulting in Moon-like face Central obesity Proximal muscle weakness Abdominal striae Easy bruising Menstrual abnormalities: oligomenorrhea Mood disorders, depression Hirtuism

Take a detailed history of the patient including medication history. Rule out the use of any exogenous topical, oral, parenteral, or inhaled glucocorticoid and synthetic progesterone.

Perform any two of the following three laboratory investigations: Measure late-night levels of salivary cortisol (twice) Measure 24 hours urinary free cortisol (UFC) excretion (twice) Perform low-dose (1mg) overnight dexamethasone suppression test (DST)

Two of the following abnormal results: Elevated levels of late-night salivary cortisol 24 hours UFC threefold greater than the upper reference range. Early morning (8 am) sample having serum cortisol 1.8 mcg/dL or higher after overnight DST

Any one abnormal result

High suspicion for Cushing's syndrome

Low suspicion for Cushing's syndrome

Measure late night plasma ACTH levels

Refer to endocrinologist

Low value plasma ACTH <5 pg/mL

Indeterminate values of plasma ACTH between 5 to 20 pg/mL

High value plasma ACTH >20 pg/mL

CRH or desmopressin stimulation test

No ACTH response

+ ACTH response

ACTH independent Cushing's syndrome

ACTH dependent Cushing's syndrome

CT scan/ MRI of adrenal glands to look for adrenal tumors or hyperplasia.

Perform both tests: CRH or desmopressin stimulation test High dose (8mg) overnight DST

Adequate suppresion of early morning serum cortisol (with levels less than 5 mcg/dL) and stimulation with CRH

Negative or equivocal response

MRI of the pituitary

Tumor >6mm

Tumor <6mm or no mass lesion

Cushing's disease

Perform Inferior petrosal sinus sampling.

Central step-up

No Central step-up

Ectopic ACTH production

Treatment

Shown below is an algorithm summarizing the treatment of Cushing's syndrome according the the Endocrine Society clinical practice guidelines.

The treatment depends upon the underlying etiology

Cushing's disease

Paraneoplastic Cushing's syndrome

ACTH-independent Cushing's syndrome

Transsphenoidal surgery: Treatment of choice in patients with pituitary adenoma with distinct margins.

Resectable tumor

Nonresectable tumor

Adrenal adenoma

Bilateral adrenal hyperplasia

Pituitary irradiation carried out in patients with: Failure to resect tumor completely by surgery. The location of the tumor cannot be determined. The patient wishes to conceive in the future.

Resection of the primary tumor

Medical therapy: Inhibit the synthesis of adrenocortical enzymes: ketoconazole, metyrapone, and etomidate. Inhibits the secretion of ACTH from the ectopic site: Octreotide Inhibits hyperglycemia secondary to hypercortisolism: Mifepristone

Unilateral adrenalectomy

Bilateral adrenalectomy

Bilateral adrenalectomy is performed in patients with severe refractory hypercortisolism despite surgical and radiation therapy

Do's

• In ACTH-independent Cushing’s syndrome, glucocorticoid therapy should be given to patients post-operatively due to suppression of the hypothalamic-pituitary axis. Patients with medication-induced Cushing’s syndrome should taper the dose of glucocorticoid instead of sudden withdrawal of the medications.
• Thromboprophylaxis should be initiated preoperatively in patients with Cushing’s syndrome. There is a hypercoagulable state in patients with Cushing’s syndrome due to impaired fibrinolysis and activation of the coagulation cascade. These patients have an increased risk of developing deep venous thrombosis compared to the normal patient population.
• Rebound thymic hyperplasia can occur in patients whose hypercortisolism is controlled. On the chest imaging, it is seen as a mass in the anterior mediastinum and can be misinterpreted as tumor recurrence, or metastasis.

Don'ts

• The 24 hours urinary free cortisol measurement should not be used for diagnosis in subclinical hypercortisolism (mild hypercortisolism in adrenal incidentaloma) as it can yield false-negative results. False-positive results are present in patients with physiological hypercortisolism (patients with a polycystic ovarian syndrome or major depressive disorder). High fluid intake can result in an increased fraction of excretion of free cortisol yielding false-positive results.
• MRI is not a cost-effective diagnostic test. CT scan of the abdomen and adrenal glands is preferred as an imaging test to localize adrenal adenoma or carcinoma compared to MRI.

References

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