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Cushing disease: A disease, a syndrome, or both?

Hurley, Shelia MBA/HC, MSN, RN; Piras, Susan E. MSN, RN

doi: 10.1097/01.NME.0000420368.31717.c1
Feature: CE Connection

Abstract: Cushing disease is a confusing subject for many healthcare team members. We give you a clear understanding of Cushing disease and Cushing syndrome and teach you how to effectively manage the care of these patients.

Assistant Professor • Tennessee Technological University • Cookeville, Tenn.

Assistant Professor • Tennessee Technological University • Cookeville, Tenn.

The authors and planners have disclosed that they have no financial relationships related to this article.

Occurring more frequently in women and young adults, Cushing disease affects 2.4 people per 1 million inhabitants per year. Although rare, the cardiovascular and metabolic effects of Cushing disease can lead to premature death if left untreated.

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Cushing disease is marked by the formation of a pituitary microadenoma (a tumor less than 10 mm in size). This benign, basophilic (highly granulated) tumor produces adrenocorticotropic hormone (ACTH) and is composed of corticotroph cells, which cause hyperplasia of the adrenal glands and result in excess secretion of cortisol. The excess production of cortisol, coupled with a lack of suppressive effects from the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, marks the pathology of Cushing disease. ACTH-producing adenomas may also lead to an overproduction of androgen sex hormones, resulting in androgen excess in women.

Cushing syndrome may be caused by Cushing disease (70% of cases), excessive cortisol production from an adrenal gland adenoma, or excess long-term steroid use. The clinical manifestations are the same for Cushing disease and Cushing syndrome (see Cushing disease vs. Cushing syndrome).

To further understand Cushing disease, let's take a look at the normal function of the HPA axis as it relates to the secretion of cortisol.

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Spinning on an axis

In response to either internal or external stress, the hypothalamus (located in the diencephalon of the brain) releases corticotropin-releasing hormone (CRH), which is transported to the anterior pituitary gland and causes the release of ACTH (see Picturing the pituitary gland). Under the direction of the hypothalamus, ACTH is released from the anterior pituitary gland and stimulates the cortex of the adrenal glands to release cortisol and other steroid hormones.

Cortisol is a glucocorticoid hormone made from cholesterol (see The highs and lows of cortisol). After it's secreted, cortisol relays back to the hypothalamus and pituitary gland to inhibit further secretion of CRH and ACTH, respectively. This relay response is the negative feedback system of the HPA axis.

The adrenal glands are situated on the superior aspect of the kidneys (see Picturing the adrenal glands). These paired glands consist of a cortex and a medulla. Under the influence of ACTH, the adrenal cortex secretes three types of steroids: glucocorticosteroids (cortisol), mineralocorticosteroids (aldosterone), and androgen sex steroids. However, ACTH primarily regulates cortisol.

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Know the signs

Cushing disease is marked by signs and symptoms caused by long-term excess cortisol levels; these symptoms develop over a period of time. Let's look at what signs and symptoms you may assess and the rationale for your assessment findings.

* Weight gain. Weight changes are caused by fat distributions, resulting in a moon face, dorsocervical hump (“buffalo” hump) on the upper back, and a large abdomen (centripetal obesity).

* Muscle and bone changes. The peripheral extremities exhibit signs of muscle wasting. The arms and legs have muscle atrophy due to protein loss, which results in patient complaints of fatigue and muscle weakness. The catabolic effects of cortisol cause the bones to become fragile. Your patient may experience hypocalcemia due to the excretion of calcium through the kidneys and the decreased absorption of calcium by the gastrointestinal system. The body tries to compensate for hypocalcemia by pulling calcium from the bones; this compensation may result in osteoporosis.

* Skin changes. The excess cortisol causes a decrease in collagen, resulting in thin, fragile skin. Large purple abdominal striae are also seen, which are different from the usual small, white striae seen after pregnancy or with weight gain. Your patient may also report an increase in acne.

* Sex hormone changes. Your patient's hair will become thin. Women are prone to coarse hair growth on their face, thighs, and chest (known as hirsutism). Women often report menstrual changes such as amenorrhea.

* Hypertension. This occurs due to many pathophysiologic changes in Cushing disease. An increase in cortisol can raise the BP and stress the heart, causing hypertrophy leading to congestive heart failure.

* Diabetes. An increase in blood glucose caused by gluconeogenesis and insulin resistance may lead to diabetes. This increase, coupled with the immunosuppressive effects from excess cortisol, places your patient at an increased risk for infection.

* Mental changes. Excess cortisol levels can affect your patient's mood and may even cause depression, anxiety, insomnia, and unpredictable behavior.

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Pinpointing the cause

When assessing a patient with apparent clinical manifestations of excess cortisol production for whom external steroid use isn't identified, diagnostic evaluation is needed. As you consider a diagnosis of Cushing disease, it's important to remember that the normal negative feedback system between cortisol secretion and ACTH suppression is absent; therefore, excess cortisol production won't inhibit the adenoma's production of ACTH. Furthermore, when a healthy individual takes external steroids, ACTH and resultant cortisol secretion is almost entirely suppressed. Keep this in mind as we navigate through some of the common tests used to diagnose Cushing disease.

The gold standard diagnostic test for excess cortisol production is a 24-hour urine analysis for free cortisol concentration. Normal free cortisol urinary excretion is less than 90 mcg/24 hours; a level over 300 mcg is diagnostic for Cushing disease.

Two classic diagnostic tests linked with Cushing disease are the low- and high-dose dexamethasone suppression test.

* Low-dose dexamethasone suppression testing requires the patient to take 0.5 mg of dexamethasone every 6 hours for eight doses. After taking the dexamethasone, the patient's urine cortisol level or morning serum cortisol is measured at the end of the test. If the results indicate ACTH and free cortisol suppression (normal response), Cushing disease may be ruled out. However, if lab results indicate an ACTH and cortisol level within normal limits or elevated, Cushing disease is considered.

* High-dose dexamethasone suppression testing requires the patient to take 2 mg of dexamethasone every 6 hours for eight doses or a single 8 mg dose may be given at midnight. Again, to rule out Cushing disease, urine or serum cortisol should result in ACTH and free cortisol suppression.

Imaging diagnostics may be conducted to identify the pituitary adenoma and the resultant hypertrophy of the adrenal glands. Magnetic resonance imaging is used to detect pituitary microadenomas. Computed tomography scanning is used to detect enlargement of the adrenal glands due to hyperplasia.

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Getting to the center of the problem

The surgical procedure to remove a pituitary adenoma is a transsphenoidal hypophysectomy, in which the surgeon gains access to the pituitary gland through the sphenoid sinus. This approach is performed using a small keyhole incision in the area of the upper lip and gingiva (upper gum). The adenoma or the entire pituitary can be removed through this incision, depending on the patient's condition.

The nasal cavity will be packed for up to 3 days. Occasionally, a fat graft may be needed to stop leakage of cerebral spinal fluid (CSF), which is a possible complication. If needed, this fat graft is taken from the abdomen and a dressing will be applied to the donor site. In some cases, the entire pituitary gland may need to be removed to treat Cushing disease.

Preoperatively, monitor and treat your patient for hyperglycemia, hypertension, potential electrolyte imbalance (sodium, potassium, and calcium), and infection. Your patient must be physically and nutritionally stable before surgery. He or she may be receiving beta-blockers and insulin to control the symptoms of hypertension and hyperglycemia. Expect a high-protein diet with potassium supplements to correct nutritional requirements before surgery.

Anticipate your patient's lab values to reflect hyperglycemia, hypernatremia, hypokalemia, and hypocalcemia. Assess for signs and symptoms, such as:

* hyperglycemia—excessive thirst, frequent urination, blurred vision, and headache

* hypernatremia—loss of appetite, nausea, vomiting, generalized weakness, and excessive thirst

* hypokalemia—abnormal heart rhythms, constipation, muscle weakness, fatigue, and paralysis

* hypocalcemia—tetany (hyperirritability of the muscle), paresthesias and numbness, facial twitching (positive Chvostek sign), muscle cramps, and carpal spasm (found with positive Trousseau sign).

Other considerations for your patient undergoing a transsphenoidal hypophysectomy include safety related to possible fractures; maintain a safe environment to prevent falls. Anxiety and depression can also be a problem related to an increase in cortisol levels. Your patient may need a quiet environment. Remember, it's important during the pre-op period to teach your patient what to expect after surgery.

If the tumor is inoperable, the medical treatment of choice is radiation. Chemotherapy isn't usually recommended, but may be used in conjunction with radiation. Although aminoglutethimide and ketoconazole may be used to inhibit adrenal function, they're used cautiously because these drugs are toxic at the levels required to decrease the synthesis of cortisol.

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Complication detective

Common complications of a transsphenoidal hypophysectomy include bleeding from the incision, infection of the brain, and increased intracranial pressure (ICP). Other less common complications include CSF leakage and fluid imbalance related to diabetes insipidus. Because of possible injury to the pituitary gland or complete removal, your patient may need post-op hormone replacement therapy.

Monitor for bleeding; the nose will be packed for approximately 3 days. Excessive bleeding isn't expected. Instruct your patient how to breathe through his or her mouth because of the nasal packing. Postoperatively, headaches can be a problem related to the packing. Keep the head of the bed at 30 degrees to decrease the pressure on the sella turcica (an area on the surface of the sphenoid bone). If your patient has a fat graft, the donor site will also need to be assessed and dressed.

Your patient won't be able to use a toothbrush for 10 days to prevent suture line disruption. Perform mouth care every 4 hours to remove debris from the incision area on the inside of the upper lip and gum to prevent infection. Your patient may also receive I.V. antibiotics prophylactically.

Persistent headaches unrelieved by mild analgesics may indicate an increase in ICP. Monitor your patient's neurologic status for changes in level of consciousness and pupillary response because this may indicate neurologic complications. Teach your patient to avoid straining with a bowel movement, coughing, and sneezing to decrease the risk of increased ICP.

If you assess clear nasal drainage, obtain a specimen for the lab to determine the presence of CSF. Leakage of CSF can increase the risk of meningitis. Persistent headaches may also be a sign of CSF leakage.

Strictly monitor your patient's intake and output and obtain daily weights. Your patient is at risk for transient diabetes insipidus postprocedure. Observe for large volumes of dilute urine output; if this occurs, your patient may become hypotensive and go into shock.

If your patient receives steroids postoperatively, the surgeon may choose to wean him or her off them within 24 hours after the surgery and monitor the cortisol levels daily, only giving corticosteroids if your patient shows symptoms of adrenal insufficiency. When taking steroids, the adrenal glands go to sleep; therefore, abruptly stopping steroids can result in mild-to-severe adverse reactions, such as muscle weakness, fatigue, depression, joint pain, difficulty breathing, and vascular collapse. If the entire pituitary gland was removed, this will leave your patient with a deficiency of ACTH and pituitary hormones. Your patient will then require hormone replacement therapy for cortisol, thyroid, and sex hormones.

Teach your patient the importance of taking prescribed steroid dosages to stabilize serum levels. Also make sure that he or she understands that steroids are essential for life and handling stress. Your patient's dosage may require frequent adjustments based on serum cortisol levels. Teach your patient to report any muscle weakness, fatigue, depression, or joint pain because this indicates insufficiency.

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What about Cushing syndrome?

To determine the cause of your patient's symptoms, first assess his or her history of steroid use. If Cushing syndrome is caused by excess use of steroids or long-term use, then weaning off the steroids, if possible, will allow the symptoms to subside.

Approximately 20% to 25% of the endogenous cases of Cushing syndrome are due to primary adrenocortical adenomas. If Cushing syndrome is caused by an adrenal adenoma, then the tumor will be surgically removed; the adrenal gland that's affected is often removed as well. If both adrenal glands are affected, your patient will have a bilateral adrenalectomy, which requires steroid replacement for the rest of the patient's life. You must teach your patient to take steroids as prescribed and never abruptly stop. Your patient must also understand that the steroid dosage may need to be adjusted.

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Rise to the challenge

Cushing disease, although not a common disease process, can be a challenge for the healthcare team. Knowing the signs and symptoms of and the diagnostics for this disease and targeting nursing care to address potential complications are essential to caring for your patient. Understanding why these signs and symptoms are occurring will help you manage your patient's condition. Your knowledge and decisions can make a difference in your patient's recovery process and the lifelong management needed when diagnosed with Cushing disease.

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did you know?

Historically, when discussing Cushing disease, we look to Harvey Williams Cushing (April 8, 1869 to October 7, 1939), a renowned neurosurgeon whose practice was predominantly at Johns Hopkins and Harvard Medical Center. He was puzzled when a 23-year-old woman presented with central obesity, bruising, large purple striae on the abdomen, and almost translucent skin. Her face was round, with a prominent accumulation of dorsal fat; she also presented with amenorrhea, hypertension, and hyperglycemia. Although little was known at the time about the HPA axis, in 1932, Cushing termed this condition pituitary basophilism.

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On the web

* American Association of Neurological Surgeons:

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* Mayo Clinic:

* National Adrenal Diseases Foundation:

* National Endocrine and Metabolic Diseases Information Service:

* Pituitary Society:

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Learn more about it

Hassan-Smith ZK, Sherlock M, Reulen RC, et al. Outcome of Cushing's disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab. 2012:97(4):1194–1201.
Kater CE, Vilar L, Newell-Price J. Harvey Cushing and Philip Hench: pituitary basophilism meets cortisone excess. Arq Bras Endocrinol Metabol. 2007;51(8):1182–1184.
Lahera Vargas M, da Costa CV. Prevalence, etiology and clinical findings of Cushing's syndrome. Endocrinol Nutr. 2009;56(1):32–39.
Lewis SL, Dirksen SR, Heitkemper MM, Bucher L, Camera I. Medical-Surgical Nursing: Assessment and Management of Clinical Problems. 8th ed. St Louis, MO: Elsevier Mosby; 2011.
Margulies P. Adrenal diseases—Cushing's syndrome—the facts you need to know.
Nemergut EC, Dumont AS, Barry UT, Laws ER. Perioperative management of patients undergoing transsphenoidal pituitary surgery.
Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006;367(9522):1605–1617.
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