Cushing's disease.

Saturday, October 13, 2012 4:52 PM

Describe the presentation, etiology, pathophysiology, and diagnosis of Cushing's disease.

The adrenal glands lie at the superior pole of each kidney and are composed of two distinct regions: the cortex and the medulla. -The adrenal cortex consists of three anatomic zones: the outer zona glomerulosa, which secretes the mineralocorticoid aldosterone; the intermediate zona fasciculata, which secretes cortisol; and the inner zona reticularis, which secretes adrenal androgens. The adrenal medulla, lying in the center of the adrenal gland, is functionally related to the sympathetic nervous system and secretes the catecholamines epinephrine and norepinephrine in response to stress.

-Glucocorticoids affect metabolism, cardiovascular function, behavior, and the inammatory/immune response (Cortisol, the natural human glucocorticoid, is secreted by the adrenal glands in response to ultradian, circadian, and stress-induced hormonal stimulation by adrenocorticotropic hormone (ACTH). - The secretion of ACTH by the pituitary gland is regulated primarily by two hypothalamic polypeptides: corticotropin-releasing hormone (CRH) and the vasopressin. -Glucocorticoids exert negative feedback upon CRH and ACTH secretion.

Cushing triad = hypertension, bradycardia, respiratory depression.

Cushings Disease :
Pathophysiology:

-The term Cushing's disease is reserved for Cushing's syndrome that is caused by excessive secretion of adrenocorticotropin hormone (ACTH) by a pituitary tumor, usually an adenoma. -The pituitary tumors in Cushing's disease are usually microadenomas, which, by denition, are 10 mm or less in diameter. Micro-adenomas generally do not cause symptoms by local mass effect. These tumors are most often discovered when clinical manifestations of hypercortisolism resulting from hypersecretion of ACTH prompt an appropriate diagnostic work-up. -Macroadenomas are uncommon in patients with Cushing's disease. T -A common effect of elevated ACTH levels (whatever the source) is bilateral adrenocortical hyperplasia, which may be diffuse or nodular. Rarely, micronodular or macronodular ACTH-independent adrenal 3 hyperplasia can be the cause of Cushing's syndrome. _ When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid hormones. ACTH is produced by the pituitary gland and released into the petrosal venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH) from the hypothalamus. - ACTH is released in a diurnal pattern that is independent of circulating cortisol levels: peak release occurs just before awakening, and ACTH levels then decline throughout the day. -Control of CRH and ACTH release is maintained through negative feedback by cortisol at the hypothalamic and pituitary levels. Neuronal input at the hypothalamic level can also stimulate CRH release.

Signs and Symptoms

Typical features of chronic cortisol excess include: thin skin, central obesity, hypertension, plethoric moon facies, purple striae and easy bruisability, glucose intolerance or diabetes mellitus, gonadal dysfunction, osteoporosis, proximal muscle weakness, signs of hyperandrogenism (acne, hirsutism), and psychological disturbances (depression, mania, and psychoses) - Hematopoietic features of hypercortisolism include leukocytosis, lymphopenia, and eosinopenia. Immune suppression includes delayed hypersensitivity. These protean yet commonly encountered manifestations of hypercortisolism make it challenging to decide which patients mandate formal laboratory evaluation. -Certain features make pathologic causes of hypercortisolism more likely; they include characteristic central redistribution of fat, thin skin with striae and bruising, and proximal muscle weakness. In children and in young females, early osteoporosis may be particularly prominent. The primary cause of death is cardiovascular disease, but infections and risk of suicide are also increased.

Diagnoses: recheck
-Dexamethasone suppression test -Urinary free cortisol (UFC) level -ACTH levels; if detectable, provocative testing

The diagnosis of Cushing's syndrome is based on laboratory documentation of endogenous hypercortisolism. Measurement of 24-h urine free cortisol (UFC) is a precise and cost-effective screening test. Alternatively, the failure to suppress plasma cortisol after an overnight 1-mg dexamethasone suppression test can be used to identify patients with hypercortisolism. As nadir levels of cortisol occur at night, elevated midnight samples of cortisol are suggestive of Cushing's syndrome. Basal plasma ACTH levels often distinguish patients with ACTHindependent (adrenal or exogenous glucocorticoid) from those with ACTH-dependent (pituitary, ectopic ACTH) Cushing's syndrome. Mean basal ACTH levels are about eightfold higher in patients with ectopic ACTH secretion than in those with pituitary ACTH-secreting adenomas. However, extensive overlap of ACTH levels in these two disorders precludes using ACTH measurements to make the distinction. Instead, dynamic testing based on differential sensitivity to glucocorticoid feedback or ACTH stimulation in response to CRH or cortisol reduction is used to distinguish ectopic from pituitary sources of excess ACTH (Table 339-13). Very rarely, circulating CRH levels are elevated, reecting ectopic tumor-derived secretion of CRH and often ACTH.

Treatment:

Treatment of Cushing's Disease

Transphenoidal removal of the tumor is the treatment of choice for Cushing's disease.2931 Cure is likely if the patient develops hypocortisolism in the rst few days to weeks after surgery.28,32 Most patients are rendered hypoadrenal for months to years after the procedure.33 During this period, they require glucocorticoid replacement therapy. Pituitary irradiation can induce remission of disease in more than one half of patients with recurrence after surgery.33 Patients who are not cured may require total bilateral adrenalectomy to control their symptoms.29 Ketoconazole (Nizoral) and aminoglutethimide (Cytadren), which are inhibitors of adrenal steroid biosynthesis, may be used in the perioperative period to decrease the clinical effects of hypercortisolism.3 Patients who have been surgically treated for Cushing's disease require careful long-term follow-up and monitoring for signs and symptoms of tumor recurrence. The pituitary adrenal axis must be evaluated six to 12 months after surgery to determine the potential need for lifetime exogenous steroid replacement therapy. Patients with panhypopituitarism subsequent to surgery require lifetime monitoring and titration of hormone therapy. All patients who need glucocorticoid replacement therapy should be given careful instructions about the effects of stress and illness on glucocorticoid dosages. In addition, these patients should wear appropriate medical alert labels.