When caring for a client with a diagnosis of Cushings syndrome the nurse understands the most common cause of Cushings syndrome is?

Cushing Disease and Cushing Syndrome

Cushing syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids.21 Excessive cortisol secretion and its attendant clinical disease states can arise from excessive release of ACTH by the pituitary (Cushing disease) or through the adenomatous or rarely malignant neoplastic process arising in the adrenal gland itself (Cushing syndrome).21 Well-characterized conditions of adrenal glucocorticoid and mineralocorticoid excess appear to result from the excessively high levels of (ectopic) ACTH produced by small cell carcinoma of the lung, carcinoid tumors, pancreatic islet cell tumors, medullary thyroid cancer, and other adenocarcinomas and hematologic malignancies.21 Clinical signs and symptoms of Cushing syndrome often develop in patients treated with exogenous steroids at doses equivalent to 20 mg of prednisone daily for more than 1 month.

Cortisol, a member of the glucocorticoid family of steroid hormones, binds to receptors located within the cytoplasm of many cell types (Fig. 92.1). After binding cortisol, these receptors are translocated to the nucleus and function as transcription factors. Several cardiac genes contain glucocorticoid response elements in their promoter regions that confer transcriptional-level glucocorticoid responsiveness. Such genes include those that encode voltage-gated potassium channels, as well as protein kinases, which serve to phosphorylate and regulate the voltage-gated sodium channels. In addition, there are more rapidly acting, nontranscriptional pathways by which cortisol may regulate the activity of voltage-gated potassium channels.

The cardiac effects of Cushing syndrome arise from the effects of glucocorticoids on the heart, liver, skeletal muscle, and fat tissue.22-24 LVH and concentric remodeling can result. Glucocorticoid excess is also associated with left ventricular dysfunction, myocardial fibrosis, and dilated cardiomyopathy.25 The increased cardiovascular morbidity and mortality rates of Cushing syndrome are largely due to cerebrovascular, peripheral vascular, and coronary artery disease and to chronic congestive heart failure.22-28 Compared with matched controls, patients with active disease have a hazard ratio (HR) of 6.0 (2.1 to 17.1) for heart failure, 2.1 (0.5 to 8.6) for acute myocardial infarction, and 4.5 (1.8 to 11.1) for stroke.26-28 Chronic cortisol hypersecretion causes central obesity, hypertension, insulin resistance, dyslipidemia, a prothrombotic state, and the metabolic syndrome. Cortisol-mediated hypertension has multiple mechanisms. The centripetal obesity characteristic of glucocorticoid excess resembles that seen in insulin resistance syndromes. In addition, the marked muscle weakness resulting from corticosteroid-induced skeletal myopathy contributes to impaired exercise tolerance.

Abstract

Cushing's disease (CD) is caused by a pituitary tumor secreting corticotropin (ACTH), leading to cortisol excess. Patients with CD comprise approximately 70% of patients with endogenous Cushing's syndrome (CS). If the diagnosis and treatment are delayed, patients with CD may suffer the deleterious consequences of hypercortisolism, leading to significant morbidity and mortality. The diagnosis of CD is complex and includes two separate steps: establishing the presence of pathologic hypercortisolism and identifying the underlying cause.

The management of CD usually includes transsphenoidal pituitary surgery (TSS) as the primary form of therapy. Pituitary surgery by the most experienced surgeons leads to remission of CD in 70–90% of patients. Recurrence of CD may occur in up to 25% of patients on long-term follow-up. Patients with recurrent CD may be treated with repeat TSS, radiation therapy to the pituitary with interim medical therapy (including steroidogenesis inhibitors, centrally acting agents or a glucocorticoid receptor antagonist) or bilateral adrenalectomy.

Improvements in diagnosis and management of CD have led to higher patient survival. However, quality of life is impaired on long-term follow-up in some patients, even those in remission. Better understanding of the pathogenesis of CD may lead to the development of more effective therapies.

Physical Findings & Clinical Presentation

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Hypertension

Central obesity with rounding of the facies (moon facies); thin extremities.Fig. 1 illustrates the distribution of adipose tissue in Cushing syndrome

Hirsutism, menstrual irregularities, hypogonadism

Skin fragility, ecchymoses, red-purple abdominal striae (Fig. E2), acne, poor wound healing, hair loss, facial plethora, hyperpigmentation (with ACTH excess). The frequency of individual findings in Cushing syndrome is summarized inTable 1

FIG. E2. Clinical features of Cushing syndrome.

A, Centripetal and some generalized obesity and dorsal kyphosis in a 30-yr-old woman with Cushing disease.B, Same patient as inA showing moon facies, plethora, hirsutism, and enlarged supraclavicular fat pads.C, Facial rounding, hirsutism, and acne in a 14-yr-old girl with Cushing disease.D, Central and generalized obesity and moon facies in a 14-yr-old boy with Cushing disease.E andF, Typical centripetal obesity with livid abdominal striae seen in a 41-yr-old woman(E) and a 40-yr-old man(F) with Cushing syndrome.G, Striae in a 24-yr-old patient with congenital adrenal hyperplasia treated with excessive doses of dexamethasone as replacement therapy.H, Typical bruising and thin skin of a patient with Cushing syndrome. In this case, the bruising occurred without obvious injury.

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Psychosis, emotional lability, paranoia

Muscle wasting with proximal myopathy

note: The previous characteristics are not commonly present in Cushing syndrome caused by ectopic ACTH production. Many of these tumors secrete a biologically inactive ACTH that does not activate adrenal steroid synthesis. These patients may have only weight loss and weakness.

Abstract

Cushing's disease is caused by an adrenocorticotropin-producing tumor of the pituitary gland, causing hypercortisolism and Cushing's syndrome. Cushing's disease is the most common cause of Cushing's syndrome but can be very difficult to diagnose and to treat. Most pituitary adenomas causing Cushing's disease are small (<10 mm) and often difficult to find on imaging studies. Confirmation that the tumor resides in the pituitary and not at an ectopic site often requires an inferior petrosal sinus sample, in which the concentration of adrenocorticotropin in the pituitary venous effluent is compared to that in mixed venous blood. Transsphenoidal pituitary microsurgery, when performed by an experienced neurosurgeon, is curative in the majority of cases, but even at the best centers recurrence rates are high. Bilateral adrenalectomy is curative when pituitary surgery is not, and recent advances in medical therapy hold promise for improving outcomes. The long-term health and quality of life in patients with Cushing's disease remain suboptimal, despite even the most advanced care.

Cushing disease and Nelson syndrome

The termCushing syndrome refers to the clinical picture resulting from exposure to excessive corticosteroids, either endogenous or exogenous. If the clinical manifestations are caused by excessive production of ACTH from the pituitary, the condition is referred to asCushing disease. Common clinical features of Cushing disease are listed inBox 50.4. The syndrome of hyperpigmentation and local compression of parapituitary structures that occurs in approximately 10% of patients with Cushing disease who have been treated with bilateral adrenalectomy is calledNelson syndrome. Given the generally good results from surgery on the pituitary gland in Cushing disease, bilateral adrenalectomy is seldom required today and Nelson syndrome is quite uncommon.

The diagnosis of Cushing syndrome, although simple in theory, is often quite difficult in practice (Findling and Raff, 2005). It is also often difficult for tests to distinguish between true Cushing syndrome and so-called pseudo-Cushing syndrome due to alcoholism, depression, and eating disorders.

As a screening test, the most sensitive and specific screening tool is an 11 p.m. salivary cortisol determination. Unfortunately, this test may not be readily available in many clinical centers, and 24-hour urine collections for urinary free cortisol are still used. The sensitivity and specificity of the 24-hour collection can be increased by doing two collections on consecutive days. A third screening test is the 1-mg overnight dexamethasone suppression test. For years now, the 2-day low-dose dexamethasone suppression test has been pivotal in the diagnosis of Cushing disease. For this test, 0.5 mg of dexamethasone is given every 6 hours for eight doses; during the second 24 hours of administration, the normal response is suppression of cortisol production as reflected by reduced urinary levels of 17-ketogenic steroids or urinary free cortisol and of serum ACTH and cortisol. Patients with Cushing disease usually show a similar suppression only when the dose of dexamethasone is increased to 2 mg every 6 hours for eight doses. The formal dexamethasone suppression test is cumbersome, requiring 6 consecutive days of collection of urine for urinary-free cortisol levels. Various modifications of this test may be useful and less cumbersome. More detailed discussion can be found in the literature, both for the screening (Findling and Raff, 2005) and diagnosis (Lindsay and Nieman, 2005) of Cushing syndrome.

In Cushing disease, ACTH levels are usually in the normal range or moderately elevated. Failure of cortisol to suppress on high-dose dexamethasone and unmeasurable ACTH levels is seen with primary adrenal problems such as adenoma or carcinoma. Ectopic ACTH production is not usually suppressible; the ACTH levels tend to be much higher than those seen in typical pituitary Cushing disease, although many exceptions to these rules have been found. In well-documented cases of ectopic ACTH production and primary adrenal problems, results of the dexamethasone suppression test have been compatible with a diagnosis of pituitary ACTH production. Intermittent excess ACTH production also can give rise to false-negative results in patients who actually have Cushing disease—so-called cyclic Cushing disease.

Epidemiology

Cushing disease is the most frequent cause of endogenous Cushing’s syndrome in adults, accounting for approximately 70% of cases, with a female preponderance in adults and a female/male ratio of around 3:1, whereas ectopic ACTH syndrome is more common in men [1]. The median age of onset is in the 30–40-year age range (Fig. 17.1). In contrast, in prepubertal children, there is a male predominance, but Cushing disease is unusual before the age of 9 years, with primary adrenal causes of Cushing’s more frequent in the earlier years [2–6]; and ectopic ACTH syndrome is extremely rare, occurring much less frequently than in adults. In a series of 384 cases of pediatric Cushing’s syndrome the causes were: 182 Cushing disease, 11 ectopic ACTH syndrome, 164 adrenocortical tumors, 16 McCune–Albright syndrome, and 11 primary bilateral adrenocortical hyperplasia. The peak incidence was 14.1 years in Cushing disease, 10.1 years in ectopic ACTH syndrome, 4.5 years in adrenocortical tumors, 1.2 years in McCune–Albright syndrome, and 13 years in primary bilateral adrenocortical hyperplasia [6].

The incidence of pituitary-dependent Cushing’s syndrome is estimated to be 2–3 cases per million population per year [7,8]. In Vizcaya, Spain, the prevalence of known cases of Cushing disease at the end of 1992 was 39.1 per million inhabitants [8]. According to the Nationwide Inpatient Sample database, the largest all-payer inpatient care database in the United States, which contains data from approximately 8 million discharges annually from 1004 hospitals located in 37 states, there were an estimated 3525 cases of transsphenoidal resection for Cushing disease between 1993 and 2002 [9]. Cushing’s syndrome may be more common than previously thought, although data are inconsistent [10–15]. For example, in one series definitive mild Cushing’s syndrome was identified in four patients (2%) among 200 overweight, type II diabetic patients with poor metabolic control (HbA1C >8%), with three Cushing disease and one surgically proven adrenal adenoma [15]. In contrast, however, other screening series in patients with newly diagnosed type II diabetes have failed to identify patients with Cushing disease [16].

Etiology

Cushing's syndrome is caused by any condition that produces excessive glucocorticosteroid levels or that requires the administration of this hormone. The hypercortisolism associated with Cushing's disease is secondary to excessive ACTH production by a pituitary adenoma. Approximately 70% of endogenous Cushing's syndrome is due to Cushing's disease, with about 15% of cases caused by a primary unilateral adrenal adenoma or carcinoma, and approximately 15% to ectopic ACTH secretion by non-endocrine neoplasms such as small cell carcinoma of the lungs. Lung tumors are responsible for over 50% of these cases. Iatrogenic Cushing's, caused by administration of glucocorticoids, is the most common cause of Cushing's syndrome.

Dog

CD is commonly encountered in canines, with an estimated incidence of 1–2 cases/1000 dogs/year [102]. Similar to human CD, approximately 70% of canine CD is caused by an ACTH-secreting pituitary adenoma. Clinical similarities between human and canine CD include fatigue, weight gain, truncal obesity, and muscle atrophy; differences include osteoporosis (which occurs in humans and not in dogs) and polyuria/polydipsia (which occurs in dogs and not observed in humans) [103]. Functional dopamine and somatostatin receptor subtypes are expressed in canine corticotroph cells similarly to humans. In particular, SSTR2 is highly expressed in canine adenomas, but human SSTR2 expression is low [103]. The high incidence of canine CD, along with its clinical similarities to human corticotroph adenomas, renders it a useful model for both in vitro and in vivo studies to better understand CD pathogenesis [18].

Cushing's disease

Cushing's disease remains the most common cause of endogenous cortisol excess. The disorder, due to increased ACTH secretion from the anterior pituitary, results in a syndrome characterized by overproduction of cortisol. Patients with untreated Cushing's disease have markedly increased 5-year mortality from cardiovascular disease, which is accounted for by hypertension, glucose intolerance, and dyslipidemia.2,41 Effective treatment of ACTH excess cures the condition. However, it is noteworthy that excess cardiovascular morbidity and mortality remain in patients following successful treatment of Cushing's disease,42 suggesting that glucocorticoid excess may confer increased long-term risk that is not relieved by normalizing cortisol levels.

Cushing's disease

Cushing's disease specifically results from the unregulated hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma and consequent hypercortisolism.

Systemic hypertension is among the most common manifestations of Cushing's disease. Indeed, as many as 80% of patients with Cushing's disease have systemic hypertension and 50% of untreated patients have severe hypertension with a diastolic blood pressure >100 mmHg (Ross et al 1966).

As in acromegaly, OSA is also common among patients with Cushing's disease. Polysomnographic studies indicate that as many as 33% of patients with Cushing's disease have mild sleep apnea and 18% of patients have severe sleep apnea (Shipley et al 1992). Complaints of daytime sleepiness are very common (Shipley et al 1992). Weight gain and centripetal obesity are commonly observed in Cushing's disease. As obese patients are more likely to have OSA than non-obese patients, it seems that obesity may play a role in a high prevalence of OSA observed among patients with Cushing's disease. In addition, patients develop fat deposits over the cheeks and temporal regions, giving rise to the rounded ‘moon-facies’ characteristic of the disease. It does not appear that these changes result in a higher incidence of difficult intubation (Nemergut et al 2006).

Glucose intolerance occurs in at least 60% (Smith et al 2000) of patients with Cushing's disease, with overt diabetes mellitus present in up to one-third of all patients. Indeed, there is evidence that a high prevalence of occult Cushing's disease may exist among patients with diabetes mellitus, type II (Catargi et al 2003). Diffuse osteoporosis may occur in up to 50% of patients presenting with Cushing's disease (Kaltsas et al 2002). Almost 20% of patients may have pathologic fractures and many patients with long-standing Cushing's syndrome have lost height because of osteoporotic vertebral collapse (Ross et al 1982). In addition, aseptic necrosis of the femoral and humeral heads can occur in Cushing's syndrome. Particular care should be taken when positioning patients during surgery.

Many patients with Cushing's disease report generalized weakness and a myopathy of the proximal muscles of the lower limb and the shoulder girdle have been described (Ross et al 1982). Hypercortisolism also results in skin thinning (Ferguson et al 1983). Patients may appear to have senile purpura with many small bruises and a loss of subcutaneous fat. Nevertheless, there are no data to suggest a change in the susceptibility to succinylcholine or nondepolarizing neuromuscular blockers. Cannulation of superficial veins for intravenous access can be extremely difficult and minimal trauma may result in bruising.