Adrenal Gland Disorders PDF

Adrenal Gland Disorders INTRODUCTION Hyper function of the adrenal glands involves excess production of the adrenal hormones cortisol (resulting in Cushing syndrome) or aldosterone (resulting in hyperaldosteronism). Adrenal gland hypofunction is asso...

Adrenal Gland Disorders INTRODUCTION Hyper function of the adrenal glands involves excess production of the adrenal hormones cortisol (resulting in Cushing syndrome) or aldosterone (resulting in hyperaldosteronism). Adrenal gland hypofunction is associated with primary (Addison disease) or secondary adrenal insufficiency. CUSHING SYNDROME: PATHOPHYSIOLOGY Cushing syndrome results from effects of supraphysiologic glucocorticoid concentrations originating from either exogenous administration or endogenous overproduction by the adrenal gland (adrenocorticotropic hormone [ACTH] dependent) or by abnormal adrenocortical tissues (ACTH independent). ACTH dependent Cushing syndrome (80%of all Cushing syndrome cases) is usually caused by overproduction of ACTH by the pituitary gland, causing bilateral adrenal hyperplasia. Pituitary adenomas account for about 85% of these cases (Cushing disease). Ectopic ACTH secreting tumors and nonneoplastic corticotropin hypersecretion cause the remaining 20% of ACTH dependent cases. Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or nonendocrine tumor, usually of the pancreas, thyroid, or lung (eg, small cell lung cancer). ACTH-independent Cushing syndrome is usually caused by adrenal adenomas and carcinomas. CLINICAL PRESENTATION The most common findings in Cushing syndrome are central obesity and facial rounding (90% of patients). Peripheral obesity and fat accumulation occur in 50% of patients. Fat accumulation in the dorsocervical area (buffalo hump) is nonspecific, but increased supraclavicular fat pads are more specific for Cushing syndrome. Patients are often described as having moon facies and a buffalo hump. Other findings may include myopathy or muscular weakness, abdominal striae, hypertension, glucose intolerance, psychiatric changes, gonadal dysfunction, facial plethora (reddish complexion), and amenorrhea and hirsutism in women. 1  Up to 60% of patients develop Cushing induced osteoporosis; about 40% present with back pain, and 20% progress to spinal compression fractures. DIAGNOSIS Hypercortisolism can be established with one or more of the following tests: 24 hour urinary free cortisol (UFC), midnight plasma cortisol, late night (11 PM) salivary cortisol, and/or low dose dexamethasone suppression test (DST). Other tests to determine etiology are plasma ACTH; adrenal vein catheterization; metyrapone stimulation test; adrenal, chest, or abdominal computed tomography (CT); corticotropin releasing hormone (CRH) stimulation test; inferior petrosal sinus sampling; and pituitary magnetic resonance imaging (MRI). Adrenal nodules and masses are identified using high resolution CT scanning or MRI. TREATMENT Goals of Treatment: Limit morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies. Treatment plans in Cushing syndrome based on etiology: Table1: Treatment Options in Cushing Syndrome Based on Etiology Etiology Nondrug Drug Name Dosing Initial Dose Usual Range Maximum Ectopic Surgery, Metyrapone 6 g/day Metyrapone ACTH chemotherapy, 1–2 g/day, syndrome irradiation 250-mg divided every 250-mg capsules 4–6 hours capsules Ketoconazole 200–1200 1600 mg/day Ketoconazole 200- mg tablets divided four 200- mg tablets mg/day, divided Pituitary Surgery, Mitotane 500- 0.5–1 g/day, 1–4 g 12 g/day dependent irradiation mg tablets increased by daily, with 0.5–1 g/day food to every 1–4 decrease weeks GI effects Metyrapone See above See above See above Mifepristone 300 mg once 300- mg tablets daily, increased 1200 mg/day 600–1200 by mg/day 300mg/day every or 20 2–4 mg/kg/day 2  Cabergoline 0.5 mg once 0.5–7 mg once 7 mg/week 0.5- mg tablets weekly weekly Pasireotide 1.8 mg/day 0.3-, 0.6-, and 0.6–0.9 mg twice 0.3–0.9 mg twice 0.9mg/mL daily daily solution Adrenal adenoma Surgery, Ketoconazole See above See above See above postoperative replacement Adrenal Surgery Mitotane See above See above See above carcinoma a Nonpharmacologic Therapy Treatment of choice for both ACTH dependent and ACTH independent Cushing syndrome is surgical resection of offending tumors. Transsphenoidal resection of the pituitary tumor is the treatment of choice for Cushing disease. Radiotherapy may be preferred for tumors invading the dura or cavernous sinus and provides clinical improvement in ∼50% of patients within 3– 5 years but increases the risk for pituitary dependent hormone deficiencies (hypopituitarism Laparoscopic adrenalectomy is often preferred for unilateral adrenal adenomas or when transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used. Pharmacologic Therapy Pharmacotherapy is generally used as second line treatment in patients who are not surgical candidates and may also be used preoperatively or as adjunctive therapy in postoperative patients awaiting response Rarely, monotherapy is used as a palliative treatment when surgery is not indicated. Steroidogenesis Inhibitors Metyrapone inhibits 11 β hydroxylase, thereby inhibiting cortisol synthesis. After administration, a sudden decrease in cortisol concentration prompts a compensatory rise in plasma ACTH levels. With cortisol synthesis blocked, adrenal steroidogenesis shunts toward androgen production, resulting in androgenic side effects such as acne and hirsutism. Inhibition of aldosterone synthesis can result in natriuresis and blood pressure changes. Nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash have been reported after oral administration. Ketoconazole inhibits cytochrome P 450 enzymes, including 11 β hydroxylase and 17 α hydroxylase. It is effective in lowering serum cortisol levels after several weeks of therapy. It also has antiandrogenic activity, which may be beneficial in women but can 3 cause gynecomastia and hypogonadism in men. The most common adverse effects are reversible elevation of hepatic transaminases, GI discomfort, and dermatologic reactions. Because of the risk of severe hepatotoxicity, monitoring should include liver function tests at baseline followed by weekly monitoring of serum ALT throughout therapy. Ketoconazole may be used concomitantly with metyrapone to achieve synergistic reduction in cortisol levels; in addition, ketoconazole’s antiandrogenic actions may offset the androgenic potential of metyrapone. Etomidate is an imidazole derivative similar to ketoconazole that inhibits 11 β hydroxylase and may have other mechanisms. Because it is only available in a parenteral formulation, use is limited to patients with acute hypercortisolemia requiring emergency treatment or in preparation for surgery. Frequent monitoring of serum cortisol is advised to prevent hypocortisolemia. Side effects include sedation, injection site pain, hypotension, myoclonus, nausea, and vomiting. Osilodrostat (Itsurisa) prevents cortisol synthesis via inhibition of 11β hydroxylase and is indicated for patients with Cushing disease who are either not candidates for surgery or in whom symptoms persist after surgery. Osilodrostat is available as an oral tablet taken twice daily, with or without food. Hypokalemia and hypomagnesemia should be corrected prior to use, and an ECG should be obtained at baseline and again one week after treatment initiation to monitor possible QTc prolongation. Adverse effects are similar to other 11β hydroxylase inhibitors, including hypocortisolism, QTc prolongation, nausea, and headache. Adrenolytic Agents Mitotane is a cytotoxic drug that inhibits the 11hydroxylation of 11-deoxycortisol and 11desoxycorticosterone in the adrenal cortex, reducing synthesis of cortisol and corticosterone. Similar to ketoconazole, mitotane takes weeks to months to exert beneficial effects. Sustained cortisol suppression occurs in most patients and may persist after drug discontinuation in up to one third of patients. Mitotane degenerates’ cells within the zona fasciculata and reticularis, resulting in atrophy of the adrenal cortex; the zona glomerulosa is minimally affected during acute therapy but can be damaged during long term treatment. Mitotane can cause significant neurologic and GI side effects, and patients should be monitored carefully or hospitalized when initiating therapy. Nausea and diarrhea are common at doses greater than 2 g/day and can be avoided by gradually increasing the dose and/or administering it with food. Lethargy, somnolence, and other CNS effects are also common. Reversible hypercholesterolemia and prolonged bleeding times can occur. Neuromodulators of ACTH Release Pituitary secretion of ACTH is normally mediated by neurotransmitters such as serotonin, γ aminobutyric acid (GABA), acetylcholine, and catecholamines. Although ACTH secreting pituitary tumors (Cushing disease) self-regulate ACTH production to some degree, these neurotransmitters can still promote pituitary ACTH production. Consequently, agents that target these transmitters have been proposed for treatment of Cushing disease, including cyproheptadine, bromocriptine, cabergoline, valproic acid, octreotide, lanreotide, 4  pasireotide, rosiglitazone, and tretinoin. With the exception of pasireotide, none of these drugs have demonstrated consistent clinical efficacy for treating Cushing disease. Cyproheptadine, a nonselective serotonin receptor antagonist and anticholinergic drug, can decrease ACTH secretion in some patients with Cushing disease. However, side effects such as sedation and weight gain significantly limit its use. Pasireotide (Signifor) is a somatostatin analog that binds and activates somatostatin receptors, thereby inhibiting ACTH secretion, leading to decreased cortisol secretion. It is approved for treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative. Side effects include nausea, diarrhea, cholelithiasis, increased hepatic transaminases, hyperglycemia, sinus bradycardia, and QT prolongation. Glucocorticoid Receptor Blocking Agents Mifepristone (Korlym) is a progesterone and glucocorticoid receptor antagonist that inhibits dexamethasone suppression and increases endogenous cortisol and ACTH levels in normal subjects. Evidence suggests that mifepristone is highly effective in reversing the manifestations of hypercortisolism (hyperglycemia, hypertension, and weight gain). It is FDA approved for treatment of endogenous Cushing syndrome in patients who have type 2 diabetes or glucose intolerance and who are not eligible for, or have had poor response to, surgery. Common adverse effects include fatigue, nausea, headache, arthralgia, peripheral edema, endometrial hyperplasia, and hypokalemia. EVALUATION OF THERAPEUTIC OUTCOMES Close monitoring of 24-hour UFC and serum cortisol is essential to identify adrenal insufficiency in patients with Cushing syndrome. Monitor steroid secretion with all drug therapy (except mifepristone) and give corticosteroid replacement if needed. HYPERALDOSTERONISM: PATHOPHYSIOLOGY Hyperaldosteronism involves excess aldosterone secretion and is categorized as either primary (stimulus arising from within the adrenal gland) or secondary (stimulus from extra adrenal etiologies). Primary hyperaldosteronism (PA) is usually caused by bilateral adrenal hyperplasia and aldosterone producing adenoma (Conn syndrome). Rare causes include unilateral (primary) adrenal hyperplasia, adrenal cortex carcinoma, renin responsive adrenocortical adenoma, and three forms of familial hyperaldosteronism (FH): Type I (glucocorticoid remediable aldosteronism); Type II (familial occurrence of adenoma or hyperplasia type II); and Type III. Secondary hyperaldosteronism results from excessive stimulation of the zona glomerulosa by an extra adrenal factor, usually the renin– angiotensin system. Elevated aldosterone 5  secretion can result from excessive potassium intake, oral contraceptives, pregnancy, and menses. Heart failure, cirrhosis, renal artery stenosis, and Bartter syndrome also can lead to elevated aldosterone concentrations. CLINICAL PRESENTATION Patients may complain of muscle weakness, fatigue, paresthesias, headache, polydipsia, and nocturnal polyuria. Signs may include hypertension, tetany/paralysis, and olydipsia/nocturnal polyuria. A plasma aldosterone concentration to plasma renin activity (PAC to PRA) ratio or aldosterone to renin ratio (ARR) >30 ng/dL per ng/(mL·h) (830 pmol/L per mcg/(L·h) and a PAC >15 ng/dL (420 pmol/L) is suggestive of PA. Other laboratory findings include suppressed renin activity, elevated plasma aldosterone, hypernatremia (>142 mEq/L), hypokalemia, hypomagnesemia, elevated serum bicarbonate (>31 mEq/L), and glucose intolerance. DIAGNOSIS Initial diagnosis is made by screening patients with suspected PA. Any patient with a blood pressure >150/100 mm Hg measured on three separate days, and those meeting the criteria for treatment resistant hypertension should be screened. Additional patients at risk for PA include those with diuretic induced hypokalemia, hypertension and adrenal incidentaloma, hypertension and sleep apnea, hypertension and a family history of early onset hypertension or cerebrovascular accident at an age