Cushing Syndrome, Emergency Medicine

Basics

Description

Cushing disease: Pituitary adenoma producing excess adrenocorticotropic hormone (ACTH)
Cushing syndrome: Excessive glucocorticoid effects

Risk Factors

Genetics

Multiple endocrine neoplasia type I
Carney complex (pigmented lentigines, atrial myxoma, germ-cell tumors with Cushing disease)

Etiology

Most commonly exogenous administration of glucocorticoids either therapeutically or surreptitiously
Pituitary adenoma secreting ACTH
Adrenal production of cortisol from adenoma, carcinoma, or micronodular disease
Tumor-producing ectopic ACTH:
- Small cell lung carcinoma:
  - Most common
- Uterine cervical carcinoma
- Islet cell tumor of pancreas:
  - Multiple endocrine neoplasia (MEN) I-type syndrome
- Medullary thyroid cancer
- Pheochromocytoma
- Ganglioneuroma
- Melanoma prostate carcinoma
- Carcinoid tumor:
  - Lung
  - Pancreas
  - GI tract
  - Thymus
  - Ovary

Diagnosis

Signs and Symptoms

The most important aspect of Cushing syndrome in the ED is recognizing the potential for addisonian (adrenal) crisis during periods of stress.
Although nonemergent, the early recognition of Cushing syndrome may prevent morbidity and mortality.

Suspect if increasing in obesity while failing to maintain height on the growth chart
Cushing syndrome rarely complicates pregnancy, but has been associated with severe pre-eclampsia and HELLP syndrome (hemolysis, elevated liver function, and low platelets)
History

Cushing disease previously diagnosed
Prior use of corticosteroids
Characteristic appearance should lead to questions concerning change in weight, facial appearance, hirsutism, or psychiatric symptoms

Physical Exam

Diagnosis suggested by:
- Abnormal fat deposition with moon facies
- Buffalo hump
- Central obesity with thin extremities
- Supraclavicular fat deposition:
  - Above findings raise suspicion in a stressed patient of potentially developing addisonian (adrenal) crisis
Cardiovascular:
- Uncontrolled hypertension
Neurologic:
- Atherosclerotic or embolic stroke
- Pseudotumor cerebri (primarily with exogenous glucocorticoid administration):
  - Check fundi
Spinal lipomatosis with cord or nerve-root compression
Gastroenterologic:
- Peptic ulcers
- GI hemorrhage
- Pancreatitis (primarily with exogenous glucocorticoid administration)
- Fatty liver
Psychiatric:
- Toxic psychosis
- Mood disorders (40%)
- Depression
- Memory impairment
- Euphoria
Musculoskeletal:
- Myopathy (proximal weakness)
- Pathologic fractures
- Osteoporosis
- Aseptic necrosis humeral or femoral heads (primarily with exogenous glucocorticoid administration)
Endocrine:
- Glucose intolerance
- Hyperlipidemia
- Amenorrhea, female with male pattern balding, or hirsutism
Hematologic:
- Increased neutrophils
- Decreased lymphocytes and eosinophils
- Opportunistic infections
Ophthalmologic:
- Cataracts (primarily with exogenous glucocorticoid administration)
- Glaucoma (primarily with exogenous glucocorticoid administration)
Dermatologic:
- Purple striae >1 cm in diameter
- Hyperpigmentation: Especially of buccal mucosa (from excess ACTH production)
- Facial plethora
- Thin skin
- Impaired wound healing
- Ecchymoses
- Acne
- Hyperhidrosis

Essential Workup

Cannot confirm diagnosis in ED
Anticipate impending addisonian (adrenal) crisis:
- Most frequent and common problem with Cushing syndrome is its recognition with concurrent illness to prevent acute Addisonian crisis
Search for life-threatening conditions:
- MI
- Stroke
- Sepsis
- Pathologic fracture
- Uncontrolled DM
- Psychiatric emergency necessitating admission

Diagnosis Tests & Interpretation

Lab

Electrolytes, BUN, creatinine, glucose:
- Hypokalemia
- 10% with metabolic alkalosis
- Diminished glucose tolerance (75%)
- 20% overt DM
Urinalysis:
- 50% have glycosuria
CBC:
- Increased WBCs
- Decreased eosinophils

Imaging

ECG for myocardial ischemia
CXR for tumor-causing ectopic ACTH
Plain films if suspect possible pathologic fractures:
- Delayed bone age

Diagnostic Procedures/Surgery
Nonemergent testing:

MRI for pituitary tumor
CT for adrenal carcinoma, adenoma, or hyperplasia
Dexamethasone-suppression test (follow-up study with primary physician):
- If suspicion of endogenous Cushing syndrome exists
- Low-dose (screening test): 1 mg at 11:00 pm with an 8 am cortisol level drawn:
  - Low specificity
False-positive results from alcohol, estrogens, spironolactone, phenytoin, barbiturates, and rifampin:
- High-dose dexamethasone-suppression test needed to confirm the diagnosis:
  - 2 mg QID of dexamethasone with cortisol level 6 hr later
  - Compare day 2 urine-free cortisol and 17-hydroxyketosteroids with baseline levels.

Differential Diagnosis

Alcohol-induced pseudo-Cushing syndrome
Obesity
Psychiatric states:
- Depression
- Obsessive-compulsive disorder
- Panic disorder
Physiologic states:
- Chronic stress
- 3rd-trimester pregnancy
- Chronic strenuous exercise

Treatment

Pre-Hospital

Acute addisonian (adrenal) crisis under stress may develop with iatrogenic Cushing syndrome
Patients may have extremely labile behavior with violent behavior
Leading causes of death in untreated Cushing syndrome are:
- Infection
- Stroke
- MI

Initial Stabilization/Therapy

Anticipate addisonian (adrenal) crisis.
Initiate treatment for associated complications:
- MI
- Stroke
- Psychiatric stabilization

Ed Treatment/Procedures

IV rehydration
Glucose-lowering agents for hyperglycemia
Appropriate cultures and antibiotics for suspected infection
Antihypertensive agents for uncontrolled BP
Administer steroids (hydrocortisone) with iatrogenic Cushing if patient under stress to prevent addisonian crisis.
Medications to lower cortisol levels (bromocriptine, ketoconazole, aminoglutethimide, metyrapone):
- Used rarely with severe symptoms in patients awaiting surgery
- Institute under the direction of an endocrinologist.
- Definitive therapy:
Iatrogenic:
- Taper steroids as rapidly as possible
- Calcium, vitamin D, and estrogen supplementation if possible
Pituitary Cushing:
- Transsphenoidal surgery
- Radiation for surgical failures and a few select patients
Adrenal adenoma/carcinoma:
- Adrenal resection with medical therapy for metastatic lesions not resectable
Ectopic ACTH:
- Tumor resection (if possible) with medical therapy for metastatic lesions not resectable

Medication

First Line
ONLY if in adrenal crisis: Hydrocortisone: 100 mg (peds: 1-2 mg/kg) IV q6h
Second Line

In consultation with an endocrinologist
SYMPTOMATIC TREATMENT ONLY as adjunctive therapy in patients awaiting surgery or refractory to other treatment
Steroidogenic inhibitors:
- Ketoconazole 200 mg PO BID
- Methyrapone 0.5-1 g/d PO in 4 div. doses
- Aminoglutethimide 250 mg PO q6h
- Mifepristone 300 mg PO daily
Adrenolytics:
- Mitotane 500 mg PO daily
ACTH release inhibitors:
- Cyproheptadine 4 mg PO BID
- Bromocriptine 2.5-30 mg/d
Other:
- Pasireotide 0.6 mg SQ initial
- Spironolactone for symptomatic relief of HTN or hypokalemia

Follow-Up

Disposition

Admission Criteria

Complications that require admission such as:
- MI
- Stroke
- Sepsis
- Pathologic fracture
- Uncontrolled DM
- Psychiatric emergency
Impending addisonian (adrenal) crisis

Discharge Criteria
Well-appearing, stable patient without admission criteria
Issues for Referral

Any patient suspected of Cushing syndrome for further evaluation
Conditions secondary to Cushing requiring treatment

Followup Recommendations

Follow-up testing to confirm diagnosis

Pearls and Pitfalls

Keep a high index of suspicion in the physiologically stressed patient by history or from body habitus and for the need to prevent against addisonian crisis
Suspect Cushing disease when there are supraclavicular fat pads

Additional Reading

Andreoli T, Carpenter C. Cecil Essentials of Medicine. 8th ed. Philadelphia, PA: Saunders-Elsevier; 2010.
Gilbert R, Lim EM. The diagnosis of Cushing syndrome: An endocrine society clinical practice guideline. Clin Biochem Rev. 2008;29:103-106.
Goldman L, Bennett JC, eds. Cecils Textbook of Medicine. 23rd ed. Philadelphia, PA: Saunders-Elsevier; 2008.
Guaraldi F, Salvatori R. Cushing syndrome: Maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.

Codes

ICD9

255.0 Cushings syndrome

ICD10

E24.0 Pituitary-dependent Cushings disease
E24.2 Drug-induced Cushing's syndrome
E24.9 Cushing's syndrome, unspecified
E24.8 Other Cushing's syndrome
E24.3 Ectopic ACTH syndrome

SNOMED

47270006 Hypercortisolism (disorder)
190502001 Pituitary-dependent Cushings disease (disorder)
237734007 ACTH-dependent Cushing's syndrome
41299009 Iatrogenic Cushing's disease
626004 Hypercortisolism due to nonpituitary tumor (disorder)

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