"Sam" is a 16-year-old boy who presents to the family practice clinic with concerns about a 30-pound weight gain over the past 3 months. He states that the weight gain has been particularly pronounced over the last 3 weeks.
Sam is a previously healthy adolescent who does not take any medications and reports no changes to his diet or exercise routines. At this visit, he has an obviously rounded face, truncal obesity, facial plethora and acne. His blood pressure is 134/71 mm Hg and his weight is 177 pounds. Physical examination reveals purple striae on his abdomen, chest, hips and extremities. Additional questioning reveals that Sam has recently been experiencing weakness. The primary care provider has a high clinical suspicion for Cushing syndrome, which requires additional work-up.
The hallmark sign of Cushing syndrome is hypercortisolism as a result of long-term exposure to excessive amounts of glucocorticoids. The use of exogenous glucocorticoids (topical, oral, inhaled or injected steroid medications) is the most common cause of Cushing syndrome. Cushing syndrome is accompanied by abnormal feedback in the hypothalamic-pituitary-adrenal (HPA) axis. A disruption of the circadian rhythm of cortisol secretion is also present.1-4
Understanding of the normal physiology of the HPA axis is necessary before the abnormalities in Cushing syndrome can be understood. Corticotropin-releasing hormone (CRH) is produced in the hypothalamus. It is released to the anterior pituitary, which causes release of adrenocorticotropic hormone (ACTH) into the system circulation. ACTH stimulates the adrenal cortex to increase plasma cortisol production. The regulation of cortisol release is controlled by a negative feedback mechanism; high levels of cortisol inhibit both CRH and ACTH secretion.
The normal circadian rhythm of cortisol secretion features a peak around the time of awakening (approximately 7 a.m. to 8 a.m.). The lowest cortisol level is around midnight.5,6
Cushing syndrome affects people of all ages. It is more common in women than men and has an estimated incidence of 3 cases per million people per year. In recent years, experts have determined that the prevalence of Cushing syndrome is greater than average in patients with diabetes mellitus.2-4
The most common cause of Cushing syndrome is the use of glucocorticoids at supraphysiologic dosages. This is reversible with tapering and/or discontinuation of the medication.1,4 Two main forms of endogenous Cushing syndrome exist: ACTH-dependent (high cortisol is caused by high releases of ACTH from the pituitary or elsewhere) and ACTH-independent (cortisol from an independent cause).3
ACTH-dependent Cushing syndrome is responsible for 80% to 85% of cases of endogenous Cushing syndrome. ACTH-dependent cases can be further described as caused by pituitary tumors (80%) or by ectopic ACTH production (20%). If a pituitary tumor is the cause, it is termed Cushing disease. Ectopic sources of ACTH production are usually carcinoid tumors or small-cell lung carcinoma.3
ACTH-independent Cushing syndrome accounts for the remaining 15% to 20% of cases of endogenous Cushing syndrome. In these instances, ACTH levels are normal and the syndrome develops due to high levels of cortisol caused most commonly by an adrenal tumor. Other causes include rare adrenal diseases such as ACTH-independent macronodular adrenal hyperplasia, the Carney complex, primary pigmented nodular adrenal disease or McCune-Albright syndrome.1,3
The diagnosis of Cushing syndrome may be challenging due to its broad range of clinical presentations (see table). The most common signs and symptoms are central obesity, a rounded face ("moon face"), facial plethora and decreased libido.3
Central obesity is a result of excessive accumulation of fat around the abdomen, and it is associated with thinning of the extremities due to muscle atrophy. Fat also deposits in the posterior neck region. Other typical features are easy bruising and the presence of purple striae, usually on the lateral abdomen, the axilla and the medial thighs. Gonadal dysfunction is also relatively common in patients presenting with Cushing syndrome. This can manifest as decreased libido, erectile dysfunction, menstrual irregularities, hirsutism, alopecia and/or infertility.3
Although the clinical presentation of Cushing syndrome may be quite evident in severe cases, it may be difficult to establish the diagnosis when the patient has mild hypercortisolism. Some signs helpful in distinguishing Cushing syndrome from simple obesity include hypertension, easy bruising, proximal muscle weakness and purple striae larger than 1 cm.4
Various systemic effects of the disease highlight the importance of accurate diagnosis and prompt treatment. Components of metabolic syndrome - obesity, hypertension, glucose intolerance and dyslipidemia - are common.3 Hypokalemia may be present, typically in cases caused by ectopic sources.1 Other systemic effects that may be present include nephrolithiasis, osteopenia/osteoporosis, and neurologic or psychiatric syndromes. In children, the most important features are central obesity, delayed growth and late puberty.3
When exploring the probability of Cushing syndrome, the differential diagnosis list should include Cushing syndrome, obesity, depression, alcoholism and polycystic ovary syndrome (PCOS), all of which have a common feature of high cortisol levels. Upon encountering a patient whose clinical findings are suspicious for Cushing syndrome, the first step is to distinguish actual Cushing syndrome from pseudo-Cushing states such as obesity, depression, alcoholism and PCOS. This requires a combination of clinical findings, laboratory tests and radiologic examinations.3 Reviewing sequential photographs of the patient, especially from before the onset of symptoms, may be helpful.2,7
Clinical Practice Guidelines
The Endocrine Society has published clinical practice guidelines for the diagnosis of Cushing syndrome, and they are available at http://www.endo-society.org/guidelines/final/upload/cushings_Guideline.pdf.2 Primary components of the document are summarized here.
Screening. First and foremost, the use of exogenous steroid medications must be ruled out. Initial diagnosis for Cushing syndrome requires that the patient has documented hypercortisolism on one of the following tests: 24-hour urinary free cortisol (at least two measurements); late-night salivary cortisol (two measurements); and/or a dexamethasone suppression test (DST). These initial tests may be performed by the primary care provider, or the clinician may refer to an endocrinologist for diagnostic work-up. Patients whose symptoms are highly suspicious for Cushing syndrome but whose laboratory measurements for hypercortisolism are normal should be referred to an endocrinologist.2,4
Differential diagnosis. When endogenous Cushing syndrome is confirmed with documented hypercortisolism on two or more measurements, endocrinologist referral should follow. The second step in diagnosis is to differentiate which form is affecting the patient: ACTH-dependent (pituitary or ectopic source) or ACTH-independent (adrenal). Initially, a plasma ACTH level is measured. If the ACTH level is suppressed (< 5 pg/mL), the cause could be adrenal in origin (ACTH-independent) and an adrenal CT scan or MRI should be performed. An ACTH level that is not suppressed (> 15 pg/mL) requires further testing to differentiate ACTH-dependent causes (pituitary or ectopic source). The most common test in this situation is a high-dose dexamethasone suppression test (HD-DST). Generally, if a pituitary tumor (Cushing disease) is the cause, ACTH secretion will be partially suppressed with the HD-DST and a pituitary MRI will be the next step in diagnosis.
It is fairly common for the results of clinical, laboratory or radiologic exams for ACTH-dependent Cushing syndrome to be conflicting or unclear. In these situations, consider bilateral inferior petrosal sinus sampling (BIPSS) to determine whether ACTH is being secreted from the pituitary. This test has high sensitivity and specificity when performed in experienced centers. If ACTH secretion does not suppress with the test, an ectopic source should be investigated with imaging studies such as a CT scan or MRI of the neck, chest and abdomen and/or octreotide scanning.1-4 Imaging studies should not precede laboratory tests in the diagnostic work-up of Cushing syndrome due to the prevalence of adrenal and pituitary incidentalomas in the general population. Failing to follow the proper steps may lead to incorrect diagnosis.7
Treatment of Cushing syndrome is important due to increased morbidity and mortality risk as the disease progresses. This is primarily due to cardiovascular and infectious complications from the severe hypercortisolism.2 Research shows that the risk for coronary artery disease, heart failure and stroke can be four times higher among patients with Cushing syndrome than in the general population.2,6
(Click image to view larger image.)
The ultimate goal is to reduce high levels of circulating cortisol. Surgery is the first-line treatment for all causes. This may include transphenoidal removal of pituitary tumors, adrenalectomy for adrenal causes, or definitive removal of ectopic sources. A bilateral adrenalectomy for definitive treatment may be indicated if ectopic sources cannot be removed or if the cause is unknown.1-3
If surgery is delayed, is contraindicated or is unsuccessful, pharmacologic therapy can help decrease cortisol levels. Choices include steroidogenesis inhibitors such as metyrapone, ketoconazole and mitotane. Radiation therapy and/or chemotherapy may be indicated in select circumstances.1-3,8
Successful treatment of Cushing syndrome reverses the clinical features within 2 to 12 months, but the patient may not completely return to a "normal" pre-Cushing appearance. Patients often feel worse for many months after the correction of the hypercortisolism.1-3,8
Follow-up & Patient Education
Patients treated for Cushing syndrome require periodic lifelong follow-up to monitor for recurrence. Patients who have undergone a bilateral adrenalectomy require lifelong glucocorticoid replacement therapy. These patients, as well as others who require temporary replacement therapy, need education about the effects of stress and illness on glucocorticoid requirements and how much to increase their dosages during these times. All patients on glucocorticoid replacement therapy should wear a medical alert bracelet. Additionally, patients who have undergone bilateral adrenalectomy should be educated about the signs and symptoms of adrenal insufficiency and carry an injectable glucocorticoid for use when they are unable to take oral medication.6
Due to the high clinical suspicion of Cushing syndrome and the fact that Sam had not been taking any glucocorticoid medications, initial laboratory tests were ordered. These included a 24-hour UFC and a low-dose DST. The results confirmed the presence of hypercortisolism, and Sam was referred to endocrinology. Testing showed that his ACTH level was elevated, pointing to an ACTH-dependent source. A pituitary MRI was obtained and the results were suspicious for a 9-mm adenoma, but a high-dose DST did not suppress the ACTH level. An ectopic source was suspected, and Sam underwent a CT scan of the chest and abdomen. The results were unremarkable. A subsequent octreotide scan revealed a small bowel carcinoid tumor with hepatic metastasis. The primary tumor was resected and a bilateral adrenalectomy was performed for definitive cure of Cushing syndrome. After an uneventful hospitalization, Sam was sent home on glucocorticoid replacement therapy with education about adrenal insufficiency. He will follow up with endocrinology, surgery, and oncology for subsequent evaluation and management.
Janel Eckroth is a family nurse practitioner at The Clinics of St. Alexius in Bismarck, ND. She has completed a disclosure statement and reports no relationships related to this article.
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