Which of the following are expected findings in a patient with Cushing disease?

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.

Definition and Manifestations

Cushing's syndrome refers to the constellation of clinical and laboratory findings that occur in patients exposed to excess glucocorticoids. Additional manifestations often coexist when the steroids present in excess possess other activities, particularly mineralocorticoid and androgenic activities. It is important to note that cortisol overproduction per se is not sufficient to constitute Cushing's syndrome. Patients with high cortisol production rates due to an overactive hypothalamic–pituitary–adrenal axis, as occurs in major depressive disorder and critical illness, are said to have a pseudo-Cushing state. In patients who are not critically ill, the sine qua non of Cushing's syndrome is sustained glucocorticoid exposure, whereas normal subjects and pseudo-Cushing state patients demonstrate an intact diurnal rhythm, with very low cortisol production during the night.

The most common cause of Cushing's syndrome is exogenous glucocorticoids therapy, used primarily for anti-inflammatory and oncological properties at supraphysiological doses. Cushing's syndrome can develop not only from orally administered drugs but also from topical, inhaled, and injectable preparations of potent synthetic glucocorticoids, which often cause the same syndrome but are not often suspected. The spectrum and severity of clinical manifestations depend on both the dose and the duration of glucocorticoid therapy. Metabolic consequences occur early after initiation of glucocorticoid therapy, and patients treated with high doses of prednisone or dexamethasone (e.g., lymphoma regimens) can develop symptomatic hyperglycemia and hyperlipidemia after only one or a few doses. With prolonged exposure, the numerous physical and psychological complications of Cushing's syndrome develop (Table 1). Although the clinical consequences of Cushing's syndrome due to endogenous and exogenous Cushing's syndrome are largely identical, two manifestations, cataracts and aseptic necrosis of the femoral head, occur almost exclusively as a result of exogenous glucocorticoids.

Table 1. Manifestations of Cushing's syndrome

In contrast, the consequences of mineralocorticoid excess rarely occur with synthetic glucocorticoids. Cortisol itself binds to and activates both the glucocorticoid receptor (GR), which is expressed in most (80%) cells of the body, and the mineralocorticoid receptor (MR), which is expressed mainly in kidney and colon, which transport fluid and electrolytes, and in brain. The kidney tubule cells, which express the MR, also contain the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which oxidizes cortisol to cortisone and thus prevents binding to MR. When cortisol production is normal, 11βHSD2 prevents binding to and activation of MR, but when cortisol production is very high, enough cortisol avoids inactivation to activate MR, which causes hypertension and hypokalemia. Symptoms and signs of androgen excess are sometimes part of the Cushing's syndrome as well but only develop when multiple steroids are overproduced by the adrenal gland as occurs in adrenocortical carcinomas (ACC) or states of adrenocorticotropin (ACTH) excess, which stimulates both cortisol and 19-carbon steroid production from the adrenal glands. When ectopic ACTH production from a highly functioning neoplasm causes rapidly progressive Cushing's syndrome with very high ACTH, the metabolic consequences also dominate, as in exogenous Cushing's syndrome, due to the abrupt and profound glucocorticoid excess.

The symptoms and signs of Cushing's syndrome are largely due to the catabolic actions of chronic glucocorticoid excess and insufficient tissue repair. In the skin, dermal atrophy is an early and very frequent finding, although skin thinning is also associated with smoking and aging. Blood vessel fragility leads to easy bruising but not bleeding or clotting problems. Fat redistribution is a prominent feature, with loss of peripheral fat and accumulation in the face, head and neck, and abdomen. The fat deposition causes the dorsocervical fat pad (‘buffalo hump’) and – more specific for Cushing's syndrome – supraclavicular fat pads, as well as central obesity and facial rounding (‘moon facies’). The expansion of fat depots in the abdomen, combined with the skin and capillary fragility, causes the classic violaceous striae of Cushing's syndrome. These striae, which are found mainly on the abdomen and flanks but can occur on the thighs, upper arms and axillae, breasts, and elsewhere, represent hemorrhage in areas of weak new skin. To be diagnostic of Cushing's syndrome, the striae must be nonblanching and 1 cm wide, but their appearance is less impressive early in their evolution. The catabolic action of glucocorticoids on muscle causes a characteristic proximal myopathy, and patients have difficulty rising from a chair, walking up the stairs, or brushing their hair. Osteopenia and osteoporosis with fragility fractures reflect the catabolic actions of glucocorticoids on bone. The proximal myopathy, osteoporosis in the face of obesity, wide purple striae, easy bruising, and disproportionate supraclavicular fat pads, particularly when found in combination, are all highly suggestive of Cushing's syndrome. Facial and upper chest plethora is also quite specific for Cushing's syndrome.

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.

I Introduction

Cushing syndrome refers to those clinical findings induced by excess circulating glucocorticoids, such as hypertension, central obesity, weakness, hirsutism (in women), depression, skin striae, and bruises. The most common cause is exogenous administration of corticosteroid hormones.1 Endogenous Cushing syndrome results from pituitary tumors producing the adrenocorticotropic hormone (ACTH; i.e., Cushing disease, 70% of all endogenous cases), ectopic production of ACTH (usually by small cell carcinoma of the lung or carcinoid tumors of the lung or mediastinum, 10% of cases), adrenal adenomas (10% of cases), or adrenal carcinoma (5% of cases).1 Cushing disease and the ectopic ACTH syndrome are referred to as ACTH-dependent disease, because the elevated cortisol levels are accompanied by inappropriately high ACTH levels. Adrenal tumors are indicative of ACTH-independent disease.

The bedside findings of Cushing syndrome were originally described by Harvey Cushing in 1932.2 Corticosteroid hormones were first used as therapeutic agents to treat patients with rheumatoid arthritis in 1949; within 2 years, clear descriptions of exogenous Cushing syndrome appeared.3

Cushing Syndrome

Just over 200 cases of Cushing syndrome in pregnancy have been reported.82-88 Only 28% of the pregnant patients described had pituitary adenomas, 44% had adrenal adenomas, 9% had adrenal carcinomas, and and 4% had the ectopic ACTH syndrome.89 Recently, cases have been reported of pregnancy-induced Cushing syndrome from human chorionic gonadotropin (hCG)–induced stimulation of ectopic luteinizing hormone (LH)/hCG receptors on the adrenal.88

Diagnosing Cushing syndrome during pregnancy may be difficult. Both conditions may be associated with weight gain in a central distribution, fatigue, edema, emotional upset, glucose intolerance, and hypertension. The striae associated with normal pregnancy are usually pale, but they are red or purple in Cushing syndrome. Hirsutism and acne may point to excessive androgen production, and proximal myopathy and bone fractures point to Cushing syndrome.

The laboratory evaluation is difficult. Elevated total and free serum cortisol and ACTH levels and urinary free cortisol excretion are compatible with that of normal pregnancy. The overnight dexamethasone test usually demonstrates inadequate suppression during normal pregnancy.8,86 ACTH levels are normal to elevated even with adrenal adenomas,8,82-84 perhaps because of the production of ACTH by the placenta or from the stimulation of pituitary ACTH by placental corticotropin-releasing hormone (CRH). Even though the 24-hour UFC level increases during pregnancy, a level higher than threefold of the upper limit of normal has been proposed to suggest Cushing syndrome during pregnancy.8,90

A persistent but blunted circadian variation in the serum cortisol during normal pregnancy may also be helpful in distinguishing Cushing syndrome from the hypercortisolism of pregnancy because this finding is characteristically absent in all forms of Cushing syndrome.7,8 For late-night salivary cortisol measurements, using the cutoff values of 0.255 µg/dL (7.0 nmol/L), 0.260 µg/dL (7.2 nmol/L), and 0.285 µg/dL (7.9 nmol/L) for the first, second, and third trimesters respectively yielded high sensitivity (>80%) and specificity (>90%) in separating Cushing disease from normal gestational changes in one study.91 However, in another study, no alteration of the usual cutoff was needed throughout pregnancy.92 In some cases, MRI scanning of the pituitary (without contrast) or ultrasound of the adrenal may be helpful, but the high frequencies of “incidentalomas” in both glands makes interpretation of imaging difficult.93,94 Little experience has been reported with CRH stimulation testing or petrosal venous sinus sampling during pregnancy.84,86,87

CHRONIC RENAL FAILURE

Cushing's syndrome has been described in the setting of chronic renal failure only rarely.398-400 Plasma levels of cortisol are normal in chronic renal failure when assessed with radioimmunoassays using an organic extraction procedure,401,402 but they may be increased if other assay techniques are used.403 ACTH levels are increased.401 Glomerular filtration rates of less than 30 mL/min result in decreased cortisol excretion, and the UFC may be normal despite excessive cortisol production.404 ACTH and cortisol responses to ovine CRH may be suppressed in patients with renal failure, except for those undergoing continuous ambulatory peritoneal dialysis.402 The metabolism of dexamethasone is normal in chronic renal failure, but oral absorption can be altered in some patients, which may necessitate measurement of plasma dexamethasone levels.405,406 The reduced degree of suppression of cortisol by dexamethasone suggests a prolonged half-life of cortisol. Normal suppression of the overnight 1 mg LDDST is uncommon, and the 2 day LDDST does better in this regard.132,406,407 The cortisol response to insulin-induced hypoglycemia is normal or absent.405,408

14 The patient has an elevated 24-hour urinary level of free cortisol, and serum cortisol levels are not suppressed after overnight 1-mg dexamethasone administration. What should I do?

It looks like the patient has Cushing's syndrome. However, it is still possible that the patient has other reasons for her symptoms and elevated cortisol levels. It can be difficult to distinguish mild or moderate Cushing's syndrome from stress-induced hypercortisolism, especially in patients who have active medical or psychiatric illnesses. The distinction between true Cushing's syndrome and pseudo-Cushing's syndrome (stress-induced hypercortisolemia) depends on the clinical suspicion and degree of elevation of the cortisol levels. In general, a 24-hour urine free cortisol level of greater than 3 times normal levels is diagnostic of true Cushing's syndrome in the absence of severe stress. Lesser elevations of urine free cortisol may require confirmatory tests for the presence of Cushing's syndrome.

Overview

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The most common cause of Cushing's syndrome is iatrogenic administration of exogenous glucocorticoids.

Spontaneous Cushing's syndrome can result from adrenal gland hyperplasia secondary to increased ACTH production from a pituitary tumor, or an ectopic non-endocrine ACTH tumor.

Other causes incl primary gland disorders such as adrenal adenoma or carcinoma.

Symptoms incl Htn, hyperglycemia, increased intravascular volume, hypokalemia, abdominal striae, truncal obesity, telangiectasias, muscle weakness and/or wasting leading to thin extremities, osteoporosis due to impaired calcium absorption, depression and insomnia.

A 24-hr urine cortisol test can demonstrate elevated cortisol levels.

Dexamethasone suppression test is used to aid in differentiating pituitary adenomas from adrenal tumors. Dexamethasone causes depression of cortisol and 17-hydroxycorticosteriod levels due to a negative feedback response, which is absent with ectopic ACTH or primary gland disease.

ACTH plasma levels can also be tested directly.

Radiologic evaluation incl: Abdominal CT scan to evaluate the adrenal glands, pituitary MRI scan with gadolinium contrast to evaluate the pituitary gland, and a chest CT scan when ectopic ACTH is the etiology.

ICD-9-CM Code: 255.0

CLINICAL ISSUES