Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (212 page)

   Imaging Studies (see Figure
6-3
)

  1.  Ultrasonography should be used to assess both morphology and size of the goiter and assist in screening and follow-up of thyroid nodules that are difficult to palpate. It may also be useful in directing a FNA biopsy in selected patients. However, this technique cannot distinguish between benign and malignant nodules.

  2.  Thyroid scintigraphy. Radionuclide scans can be performed with either iodine-123 or technetium-99m pertechnetate. Most thyroid carcinomas are inefficient in trapping and organifying iodine and appear as cold nodules. Unfortunately, most benign nodules also do not concentrate iodine and, therefore, are cold nodules. The only situation in which an iodine scan can exclude malignancy with reasonable certainty is in the case of a toxic adenoma, which is characterized by significantly increased uptake within the nodule, so-called “hot” nodule, and markedly suppressed or absent uptake in the remainder of the gland.

Suggested Readings

Khan F, Sachs H, Pechet L, et al.
Guide to Diagnostic Testing
. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.

Kronenberg HM, Melmed S, Polonsky KS, et al.
Williams Textbook of Endocrinology
, 11th ed. Philadelphia, PA: Saunders, Elsevier Inc.; 2008.

Ross DS. Clinical manifestations and evaluation of obstructive or substernal goiter. Rose B, (ed).
UpToDate
, Waltham, MA: UpToDate, Inc.; 2009.

Ross DS. Diagnostic approach to and treatment of thyroid nodules. In: Rose B, (ed).
UpToDate
, Waltham, MA: UpToDate, Inc.; 2009.

   
DISORDERS OF THE ADRENAL GLAND

CUSHING SYNDROME

   Definition

Cushing syndrome refers to hypercortisolism of any cause. Whereas, Cushing disease refers to hypercortisolism due to an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma.

   Overview

The incidence of Cushing disease is 5–25 cases per 1,000,000 people per year. Other causes of Cushing syndrome are much less common.

   Common Causes

Cushing syndrome may be either ACTH dependent or ACTH independent.

I.   ACTH-dependent Cushing syndrome

A.   Cushing disease is the most common cause of Cushing syndrome and comprises 65–70% of the cases. Almost all patients with Cushing disease have a pituitary adenoma. The adenomas are frequently small, and even a gadolinium-enhanced, high-resolution magnetic resonance imaging (MRI) of the sella identifies only 50% of them. Pituitary adenoma cells have a higher than normal set point for cortisol feedback inhibition. This feature is clinically important because it permits the use of dexamethasone suppression to distinguish between pituitary and ectopic ACTH secretion; the latter is usually very resistant to glucocorticoid negative feedback.

B.   Ectopic ACTH secretion by nonpituitary tumors accounts for 10–15% of the cases of Cushing syndrome. A wide variety of tumors, usually carcinomas rather than sarcomas or lymphomas, have been associated with ectopic ACTH secretion. The most common causes are small cell carcinomas of the lung, bronchial or pulmonary carcinoid tumors, and pancreatic islet cell tumors and thymic tumors. Ectopic secretion of ACTH causes bilateral adrenocortical hyperplasia and hyperfunction.

C.   Ectopic corticotropin-releasing hormone (CRH) syndrome constitutes <1% of Cushing syndrome. CRH secretion by nonhypothalamic tumors causes pituitary hyperplasia, hypersecretion of ACTH, and bilateral adrenal hyperplasia.

II.  ACTH-independent Cushing syndrome

A.   Adrenal tumors account for 18–20% of the cases of Cushing syndrome. It is important to be sure of the biochemical diagnosis prior to performing any adrenal imaging, since 4% of patients have an adrenal incidentaloma.

B.   Iatrogenic or factitious Cushing syndrome is usually caused by the use of prednisone, or potent inhaled, injected, and topical glucocorticoids, such as beclomethasone and fluocinolone. Exogenous glucocorticoids inhibit CRH and ACTH secretion, leading to bilateral adrenocortical atrophy. Plasma ACTH, serum cortisol, and urinary cortisol excretion are all low.

   Who Should Be Suspected?

Symptoms and signs of Cushing syndrome include hypertension, type 2 DM, and menstrual and psychiatric disorders. Physical examination findings include central obesity, proximal muscle weakness, wide purple striae, spontaneous ecchymoses, and facial plethora (moon face).

   Laboratory Findings

I.   Diagnosis of Cushing syndrome involves three steps (Figure
6-4
). The first step is to suspect Cushing syndrome based on the symptoms and signs. The second step is to confirm the presence of excess cortisol production by biochemical testing. The third step is to determine if the hypercortisolism is ACTH dependent, and, if so, the source of the ACTH.

II.  Tests used to establish the diagnosis of Cushing syndrome are listed in Table
6-2
. Urinary cortisol, late night salivary cortisol, and low-dose dexamethasone suppression tests are now recommended as first-line tests. At least two first-line tests should be unequivocally abnormal to establish the diagnosis of Cushing syndrome. Urinary and salivary cortisol measurements should be obtained at least twice.

A.   Twenty-four–hour urinary cortisol excretion provides a direct and reliable practical index of cortisol secretion. It is an integrated measurement of plasma free cortisol; as cortisol secretion increases, the binding capacity of cortisol-binding globulin is exceeded and results in a disproportionate rise in urinary free cortisol. The two most important factors in obtaining a valid result are collection of a complete 24-hour specimen and a reliable reference laboratory.

B.   Late-night or midnight salivary cortisol concentration can also be used. Saliva is easily collected, and cortisol is stable in saliva for several days even at room temperature. The criteria used to interpret salivary cortisol results vary among different studies. Midnight salivary cortisol is an accurate diagnostic test. A cortisol value >2.0 ng/mL has 100% sensitivity and 96% specificity for diagnosing Cushing syndrome.

C.   Low-dose dexamethasone suppression tests include an overnight 1-mg test and a standard 2-day test. In normal patients, the administration of glucocorticoid results in suppression of ACTH and cortisol secretion. Whereas in Cushing syndrome of whatever cause, there is a failure of this suppression and the cortisol concentration remains elevated.