Cushing’s Syndrome
Julie Adkins, Jill C. Cash, Mellisa A. Hall, Cheryl A. Glass, Angelito Tacderas, and Jenny Nelson Mullen
Definition
A.Cushing’s syndrome is a cluster of symptoms, signs, and biochemical abnormalities arising from glucocorticoid overproduction. Iatrogenically induced Cushing’s syndrome is the most common cause.
Incidence
A.For endogenous cases, 10 to 15 new cases per 1,000,000 annually; most common in adults between 20 and 50 years of age; women account for 70% of the cases.
Pathogenesis
The cause of excess hormone production causing symptoms is exogenous (chronic glucocorticoid or adrenocorticotropic hormone (ACTH) administration) or endogenous (increased ACTH secretion). The endogenous type is due to either excessive pituitary or ectopic ACTH secretion (ACTH dependent), resulting in signs of androgen excess, or autonomous cortisol overproduction (ACTH independent [of ACTH regulation]), as well as depressed ACTH production and absent signs of androgen excess. The etiology of spontaneous Cushing’s (adults) comprises:
A.70% to 80% pituitary ACTH hypersecretion (90% pituitary adenoma, 10% pituitary hyperplasia).
B.10% to 15% autonomous adrenal tumor (adenoma or carcinoma).
C.5% to 15% ectopic ACTH secretion (nonpituitary neoplasm, usually lung).
D.Less than 1% bilateral nodular hyperplasia without ACTH.
Predisposing Factors
A.Exogenous glucocorticoid administration.
B.Excessive alcohol intake.
C.Pituitary adenoma.
D.Thoracic tumors.
E.Adrenal neoplasms.
F.Tumors of the pancreas.
G.Thyroid and thymus disease.
H.Pheochromocytoma.
Common Complaints
A.Excessive coarse hair on face, chest, and back.
B.Rapid weight gain.
C.Easy bruising.
D.Muscle weakness.
E.Oligo- or amenorrhea.
F.Impotence.
G.Depression.
H.Poorly controlled diabetes.
I.Irregular menses.
Other Signs and Symptoms
A.Cervicodorsal and supraclavicular fat pad.
B.Hirsutism in women.
C.Acne and/or folliculitis.
D.Increased intraocular pressure.
E.Purple striae.
F.Increased blood pressure (blood pressure).
G.Polydipsia/polyuria, increased serum glucose, and glycosuria.
H.Osteopenia/osteoporosis.
I.Mood lability/changes.
J.Spontaneous hypokalemia.
K.Erythrocytosis.
Subjective Data
A.Ask if the patient has taken exogenous glucocorticoids.
B.Determine whether the onset of complaints was acute or subacute.
C.Assess for bruising and determine if bruising was precipitated by trauma.
D.Assess for muscle weakness and, if present, whether it is proximal weakness.
E.Review the patient’s menstrual history, including characteristics of menstrual periods.
F.Identify the patient’s family history of similar problems.
G.Question the patient regarding any vision.
H.Rule out the presence of abdominal pain.
I.Review the patient’s history of neoplasms and location.
J.Identify the current pattern of sexual function.
K.Question the patient regarding mood swings or recent treatment for psychiatric disorder.
L.Identify the pattern of weight gain and effectiveness of weight loss interventions, if implemented.
M.Assess for the presence of leg or arm pain.
N.Review the patient’s history of fractures, especially if postmenopausal.
O.Determine the amount of alcohol consumed.
Physical Examination
A.Check pulse, height, and weight.
B.Inspect:
1.Inspect the skin, noting hair distribution, lesions, bruising, and striae.
2.Observe the face and note shape.
3.Observe the neck.
Note that a moon-shaped
face and fat pads in posterior neck (buffalo hump
) are characteristics of patients with Cushing’s syndrome.
4.Complete funduscopic examination. Be alert for cataracts, glaucoma, and/or signs of benign intracranial hypertension (HTN).
C.Auscultate:
1.Auscultate the heart and lungs.
D.Palpate:
1.Complete musculoskeletal examination. Be alert for septic necrosis of femoral and/or humeral head. Perform range of motion, noting decreased range of motion, pain, or weakness of joint. Consider diagnostic testing if abnormal exam.
Initial Diagnostic Tests
A.Serum electrolytes.
B.Complete blood count (CBC) and glucose.
C.Urine-free cortisol (at least two measurements).
D.Late-night salivary cortisol (at least two measurements).
E.Overnight dexamethasone suppression test, 1 mg.
F.Longer low-dose dexamethasone suppression test (2 mg/d for 48 hours).
The overnight dexamethasone suppression test has a false positive rate of 20% to 30%; false positives can occur with obesity, stress, depression, alcoholism, pregnancy, or medications that increase the hepatic metabolism of cortisol and dexamethasone (e.g., antiseizure drugs, estrogen, and rifampin). The false negative rate is less than 3%. Use the low-dose dexamethasone test as an alternative.
The 24-hour urine-free cortisol test is the most sensitive and specific test and is the best choice
for screening.
G.If any of the earlier initial screenings is positive, the patient should be referred to endocrinology for additional evaluation.
Differential Diagnoses
A.Iatrogenically induced Cushing’s syndrome.
B.Depression.
C.Severe obesity.
D.Chronic stress.
E.Familial cortisol resistance.
F.Medication-induced (e.g., phenytoin, phenobarbital, primidone).
G.Pituitary adenoma.
H.Adrenal and other neoplasms.
I.Alcoholism.
J.Nephrolithiasis.
K.Psychosis.
Plan
A.General interventions:
1.Taper glucocorticoid dose as appropriate for underlying disease.
2.Begin alcohol detoxification if applicable.
3.Consider hormone replacement therapy for postmenopausal women.
B. 
See Section III: Patient Teaching Guide Cushing’s Syndrome.
C.Medical–surgical management:
1.If noniatrogenic etiology, surgery is the treatment of choice, followed by irradiation and/or chemotherapy.
D.Pharmaceutical therapy:
1.Calcium 1,000 mg/d and vitamin D 400 IU/d.
2.Mitotane (Lysodren) 2 to 6 g daily for control of adrenocortical carcinoma progression.
3.Metyrapone inhibits adrenal steroid biosynthesis.
4.Ketoconazole (most useful for blocking adrenal steroidogenesis) and suramin inhibit adrenal steroid biosynthesis:
a.Ketoconazole should be started at a dose of 200 mg two or three times daily and increased rapidly to 400 mg three times daily; higher doses are seldom more effective. Increase every 4 to 7 days. Avoid use in pregnancy.
5.Hydrocortisone may be given in physiologic doses to avoid adrenal insufficiency.
Most persons on daily steroid program for over 2 to 4 weeks have some degree of hypothalamic-pituitary-adrenal axis suppression.
6.Mifepristone (RU 486) is given for ectopic ACTH production or adrenal carcinoma. Mifepristone is an abortifacient.
Follow-Up
A.At the provider’s discretion, 1 to 2 weeks after tests are complete, follow-up to discuss results and possible therapy.
Consultation/Referral
A.If Cushing’s syndrome is suspected, consult with an endocrinologist regarding treatment and therapy.
Individual Considerations
A.Pregnancy:
1.Urinary-free cortisol increases in the third trimester, but women still have normal 17-hydroxycorticosteroids and normal diurnal variability of serum cortisol. Dexamethasone testing is not recommended in the initial screening for Cushing’s syndrome during pregnancy.
B.Geriatrics:
1.Loss of brain volume and neurocognitive impairment has been evident in patients with Cushing’s syndrome. Haraguchi et al. (2015) noted that after surgical correction of adrenal hyperplasia, the psychotic symptoms decreased and progression of cognitive function and brain volume loss slowed. Results of these cases suggest that surgical treatment for Cushing’s syndrome in a patient suffering dementia is useful in treating neuropsychiatric symptoms, and could reduce the burden on the patient’s caregivers.
2.Assess for depression in elderly patients with Cushing’s syndrome; they are particularly susceptible to emotional as well as cognitive impairments when suffering from the disease.
3.Beers Criteria: Corticosteroids may worsen delirium in geriatrics. Use lowest effective dose for the shortest amount of time and avoid combining with aspirin (ASA)/nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent gastrointestinal (GI) formation.
Resource
Addison and Cushing International Federation (ACIE)
PO Box 52137
2505 CC The Hague, the Netherlands