ne loss relies on direct measurement of bone density with Dual-emission X-ray absorptiometr y (DXA) scanning (Table 9.15). Screening evaluation with DXA may show low BMD at one or mor e sites of interest (lumbar spine, femoral neck, total hip, distal third forearm). Regardle ss of BMD, likely diagnosis of osteoporosis if an individual presents with a minimally trau matic hip, wrist, or vertebral compression fracture. Asymptomatic presentation may be assoc iated with progressive height loss attributed to vertebral compression fractures. Plain 305 Table 9.15 DXA scanning Provides an estimate of areal density of bone measured in g/cm 2 . Most commonly scanned si tes are the lumbar vertebrae, hip, and distal fore- arm. Scoliotic changes, osteoarthritis, hardware, and vertebral compres- sion fractures may distort lumbar vertebral readings and should prompt forearm DXA, which is less distorted by these factors. Generates actual measu rements along with T-scores that represent number of standard deviations above or below the mean for healthy young adults. Z-scores represent number of standard deviations above or b elow mean for representative age group and are used in premenopausal individuals. T-scores have been correlated with associated fracture risk to assign classifications. WHO definitio ns T-score 0 to \200\2231.0 = normal T-score \200\2231.0 to \200\2232.5 = low BMD(osteop enia) T-score \211 \200\2232.5 or fragility fracture = osteoporosis films may reveal low bone mineral density and anterior wedging of vertebral bodies. Screeni ng The National Osteoporosis Foundation 5 recommends screen- ing with DXA scanning be consi dered for (a) all women \211 65 or (b) younger postmenopausal women with more than one pr edisposing risk factor (see above). Screening in men should begin at \211 70 years or in t hose with more than one predisposing risk factor. Preventive measures Include regular weigh t-bearing exercise, mainte- nance of good nutritional status, adequate calcium intake (>1,0 00 \200\2231,200 mg elemental calcium daily, divided doses), adequate vitamin D intake (600 \200\223800 IU daily), smoking cessation, and moderation of alcohol intake. Postmenopausal estrogen replacement therapy is no longer recommended as a preventive measure. See also Ta ble 9.16. 306 Paget \200\231s disease of the bone Disorder characterized by focally accelerated remodelin g of bone resulting in bone overgrowth anddisruption of normal architecture. Affected bone has impaired strength. May be at one (monostotic) or more (polyosto- tic) sites. Commonly i nvolves the sacrum, spine, femur, skull, and pelvis. May present with bone pain, fractures, deformities, or manifestations of associated neurologic, cardiac, malignant, or metabolic complications. Examination may reveal cutaneous erythema, warmth, and tenderness localized to the soft tissue overlying affected regions. Characteristic find- ings may include enlarg ement of the skull, frontal bossing, and bowing of the lower extremities. Associated with a n increased risk of fractures, sen- sorineural deafness, facial palsies, osteoarthritis, an d spinal stenosis. Rarely, patients may develop high-output heart failure, hypercalcemia (u sually if underlying primary hyperparathyroidism), orosteosarcoma. Diagnosis Asymptomatic d isease detected when routine chemistry pan- els reveal elevated alkaline phosphatase. Local ized symptoms may prompt evaluation with plain films that reveal characteristic ragged lyti c lesions and coarsened trabeculae. Radio nucleotide bone scanning may reveal other sites o f involvement that may be confirmed with dedicated plain films. 5 National Osteoporosis Foundation, www.nof.org y g o o n i r c o d n E Table 9.16 Treatment of osteoporosis l Available agents include bisphosphonates, raloxifene, teriparatide, deno- sumab, and calcit onin. Bisphosphonates Agents that bind to hydroxyapatite crystals in miner- alized bone. Ac t to inhibit bone resorption by quieting osteoclast activ- ity. Oral bisphosphonates includ e alendronate (Fosamax 70 mg once a week), risedronate (Actonel 35 mg once a week or 15 0 mg once a month), and ibandronate (Boniva 150 mg once a month). Monthly dos- ing may im prove compliance and limit risk of side effects. May cause severe esophageal or GI irritati on, as well as bone pain or, less com- monly, osteonecrosis of the jaw (see below). Should be swallowed with 8 oz of water with directions to remain in an upright position for 30 min afterward. Patients who cannot tolerate oral bisphosphonates (reflux disease, abdominal sy mptoms, etc.) may be treated with doses of IV zoledronic acid (Reclast 5 mg in 250 mL nor mal saline [NS] infused over 30 min) administered every 12 months. Side effects of zoledron ic acid include first-dose reaction (10 \200\22320% patients, self-limited flu-like illness for 2 \200\2233 days)and osteonecrosis of the jaw (1 case per 200,000 persons per year) in those receiving high-dose, frequent IV bisphosphonates (mul- tiple myeloma, breast cancer) or those with recent dental procedures (implants, extractions). CI : GFR <30 mL/min, hypoc alcemia. Raloxifene (Evista 60 mg/d). Antiresorptive selective estrogen receptor modulato r (SERM) targeting estrogen receptors on the bone, not breast or uterus. May be used to pre vent and treat osteoporosis. Often precipi- tates hot flashes. Associated with an increased risk of deep venous throm- bosis. CI : History of venous thromboembolic disorders, pregnan cy. Teriparatide (Forteo 20 mcg SQ daily). Recombinant form of the N-terminal segment of PTH that must be administered as a daily sub- cutaneous injection. The only anabolic agent that promotes new bone formation. Often consideredwhen patients have continued to lose bone density or sustain fractures during treatment with bisphosphonates. Treatment course limit ed to 2 yrs and must be followed with an anti- resorptive medication (bisphosphonate, denos umab) or rapid bone loss will ensue. Side effects include transient hypercalcemia/hypercalc iuria and bone pain. CI : Hyperparathyroidism, hypercalcemia, history of skeletal metastase s. Denosumab (Prolia 60 mg SQ every 6 months). Monoclonal antibody against RANK-L to inhi bit osteoclast-mediated bone resorption.Can be used in patients with severe chronic kidney disease.Side effects include dermatitis, bone pain, and weakness; higher rate of infectious complica- tions reported. CI : Preexisting hypocalcemia. Calcitonin (Miacalcin 200 units intranasally daily). Pharmacologic preparation of salmon calcitonin. Can be administered a t home as an intranasal spray. May help to relieve bone pain after an acute osteoporo- tic vertebral fracture. Tachyphylaxis limits long-term utility in prevention and treatment of o steoporosis. DXA scanning may be repeated after 1 \200\2232 yrs to assess responses to trea t- ment. Comparisons should be based on measurements taken with similar types of equipment loaded with valid databases. BMD changes that are considered significant depend on the cali bration of the machine. 307 Calcium and phosphorus levels are usually normal. Urinary bone turnover markers (N-telopept ides, pyridinoline) are usually elevated. Treatment Treat biochemically active disease loca ted at sites of high skeletal fragility (spine, weight bearing bones, joints) or in the sku ll. Also reasonable to treat if alkaline phosphatase >2 \200\2234 times upper limit of nor- mal. For symptomatic disease, bone pain may respond to treatment with NSAIDs. Limited cour ses of treatment with bisphosphonates may help to alleviate symptoms and stabilize deformit ies. Alendronate (Fosamax 40 mg/d for 6 months) and risedronate (Actonel 30 mg/d PO for 2 months) may be equally effective. IV bisphosphonates include pamidronate (Aredia 30 mg /d \227 3d) and or zoledronic acid (Reclast 5 mg IV once).An advantage of IV bisphosphon ate administration may be more sustained biochemical remissions (1 \200\2232 yrs) compared to oral bisphosphonates. Changes in alkaline phosphatase levels may be tracked over time to assess responses to treat- ment. Patients who continue to manifest symptoms after an initi al course of treatment with a bisphosphonate may respond to subsequent courses of treatment with the same agent. Patients requiring surgery on a pagetic site should be treated prior to surgery with a bisphosphonate to reduce hypervascularity to site and resultant blood los s. Osteomalacia Condition characterized by decreased mineralization of bone matrix. May be pre cipitated by disorders that limit effective reserves of circulating cal- cium and phosphoru s. Impairment of mineralization that occurs during growth may lead to development of ricket s associated with short stature (if occurring in childhood), proximal muscle weakness, and bony deformities. Demineralization that occurs after the epiphyses have fused may give rise to bone pain and tenderness. Fractures of the collarbone, ribs, and other \200\234stress fractures \200\235 may be associated with osteomalacia, particularly when DXA testing revea ls otherwise-normal to fair BMD. Vitamin D deficiency Most common cause of osteomalacia in adults. Vitamin D stores measured with serum 25-hydroxy vitamin D. Pure nutri- tional defic iency is becoming more common due to decreased intake of dairy products and rise of vegan d iets. Sun is a limited source of vitamin D for most. Malabsorption of vitamin D may occur i n the setting of disorders asso- ciated with pancreatic insufficiency, impaired biliary sec retion, or intestinal malabsorption. Treatment with anticonvulsants may enhance metabolism of vitamin D in the liver, diminishing effective stores of 25-hydroxyvitamin D. In rare ins tances, severe liver disease may diminish stores of 25-hydroxyvitamin D. In cases where no obvious underlying cause is evident, a confirmed diag- nosis of vitamin D deficiency may pr ompt serologic (positive antiendomysial or anti-tissue transglutaminase antibodies) with co nfirmatory endoscopic evaluation to check for evidence of unsuspected celiac disease. Evalu ation Should initially focus on measurement of Ca 2+ , fasting PO 4 \200\223 , PTH, alkali ne phosphatase, and 25-hydroxyvitamin D levels. Moderate-to-severe cases of vitamin D defic iency may present with secondary hyperparathyroid- ism characterized by low Ca 2+ and PO 4 , levels in conjunction with elevated PTH and alkaline phosphatase levels. Mild cases may p resent with normal Ca 2+ , PO 4 \200\223 , and alkaline phosphatase levels in conjunction with normal or slightly elevated PTH levels. Confirmation of a suspected diagnosis based on documentation of a low 25-hydroxyvitamin D level. Although the tradi- tional goal level fo r 25-hydroxy vitamin D is >30 ng/mL, recent guidelines published by the Institute of Medici ne 6 state 25-hydroxy vitamin D level 308 6 Consensus Report, Institute of Medicine, dietary reference intakes for calcium and vitami n D. November 2010. >20 ng/mL is sufficient for most adults.Elevated parathyroid hormone or known metabolic bon e disease in a patient may prompt supplementation to a 25-hydroxy vitamin D level of >30 ng /mL. Treatment Vitamin D deficiency repletion requirements may vary depend- ing on the unde rlying cause and severity of the disorder. Mild cases may respond to repletion with ergocal ciferol 50,000 IU PO weekly for 6 \200\2238 wks, followed by daily administration of a supp lement containing 400 \200\223800 IU of cholecalciferol. Severe cases associated with persi stent malabsorption (gas- tric bypass, short gut) may require long-term treatment with a co mbination of calcium supplements and ergocalciferol administered in much higher, supervised doses. Patients with underlying liver disease may require treat- ment with calcifediol , a metabolite of cholecalciferol. Patients with chronic kidney disease often require a combin ation of ergocalciferol and calcitriol supplementation. Ca 2+ levels should be monitored du ring treatment, as vita- min D toxicity may precipitate hypercalcemia. Hypophosphatemic dis orders Persistent renal phosphate wasting may lead to hypophosphatemia with associated oste omalacia. X-linked hypo- phosphatemic rickets (XLH) is the most common inherited disorder a ssoci- ated with renal phosphate wasting and is caused by a mutation in the PHEX gene. Auto somal dominant hypophosphatemic rickets has a similar presen- tation and is related to an a ctivating mutation of fibroblast growth factor-23 (FGF-23) gene.Both conditions result in e levated serum FGF-23 levels that promote phosphaturia and inhibit conversion of 25-hydroxy vitamin D to 1, 25-dihydroxy vitamin D. Affected individuals present in early child- hood w ith poor growth complicated by severe rickets, hypophosphatemia, phosphaturia, and low 1,25 -vitamin D levels. Defects in dentin may cause tooth decay and dental abscesses. Treatment involves administration of large amounts of supplemental phosphate along with calcitriol ta ken to prevent secondary hyperparathyroidism. Treatment may not be necessary in asymptomati c adults. Oncogenic osteomalacia represents an acquired form of renal phosphate wasting tha t may develop in patients diagnosed with benign and malignant mesenchymal tumors producing excess FGF-23. In most cases, resection of neoplastic tissue has proven to be curative, alt hough tumors can be hard to localize. y g o o n i r c o d n E l 309 Cushing \200\231s syndrome Physiology Corticotropin-releasing hormone (CRH) secreted by the hypothalamus stimulates secretion of ACTH from corticotroph cells in the anterior pituitar y. ACTH binds to receptors on cells in the zona fasciculata and zona reticularis of the adr enal cortex, stimulating the production and secretion of cortisol and androgens. Basal secr etion of cortisol follows a circadian pattern. Cortisol levels fall to nearly undetectable levels in the late evening, then gradually increase to peak after 6 \200\2238 h of sleep. P hysiologic stress may stimulate increased secretion of cortisol. Most of the cortisol secre ted by the adrenal cortex binds to transportation proteins in the circula- tion. Free (unbo und) cortisol binds to cytosolic receptors to exert different regulatory effects. Free cort isol exerts negative regulatory effects on the secretion of CRH from the hypothalamus and t he secretion of ACTH from the anterior pituitary. Cushing \200\231s syndrome Represents the sequelae of prolonged exposure to chronically elevated glucocorticoid levels. Endogenous C ushing \200\231s syn- drome is caused by the increased production and secretion of cortisol (hypercortisolemia). Underlying causes may be mechanistically classified as ACTH-dependent (hypercortisolemia driven by increased secretion of ACTH from a pituitary or nonpituitary source) or ACTH-independent (hypercortisolemia that develops as a result of the growth of a utonomously functioning adrenal cortex tissue). Iatrogenic Cushing \200\231s syndrome may be caused by prolonged exposure to supratherapeutic doses of pharmacologic glucocorticoid preparations. See Table 9.17. ACTH-dependent Cushing \200\231s syndrome Most common cause is growth of an ACTH-secreting pituitary adenoma (Cushing \200\231s disease). May also be caused by ectopi c secretion of ACTH from other occult neoplasms includ- ing small cell lung carcinoma, carc inoid tumors, pancreatic islet cell tumors, medullary thyroid carcinoma, and pheochromocyto mas. Rare cases caused by ectopic secretion of CRH. ACTH-independent Cushing \200\231s synd rome Most common cause is growth of an isolated cortisol-secreting adrenal adenoma. May als o be caused by secretion of cortisol from functional adrenal carcinomas. Rare cases caused by growth of pigmented micronodules (Carney complex) or macronodular adrenal hyperplasia. S ymptoms May include weight gain, weakness, fatigue, oligomenorrhea, impotence, easy bruisin g, anxiety, irritability, depression, and impaired con- centration. Larger pituitary adenom as may cause blurred or double vision secondary to compression of the optic chiasm. Signs M ost common manifestation is fat deposition in a central distribu- tion with relative sparin g of the limbs. Central fat deposition may lead to expansion of the cheeks (producing chara cteristic \200\234moon \200\235 facies), protru- sion of supraclavicular fat pads, protrus ion of the dorsocervical fat, and truncal obesity. Atrophy of connective tissue in the derm is may lead to facial plethora and development of expanding darkened or violaceous striae ( >0.5 cm wide) in the axillae and lower abdominal quadrants. Other mani- festations may incl ude hypertension, development or worsening of diabe- tes, osteoporosis and fracture, proxim al muscle weakness, nephrolithiasis, hypertriglyceridemia, and evidence of hirsutism or vir ilization. Treatment of ACTH-dependent Cushing \200\231s syndrome Confirmation of endogenou s hypercortisolism with biochemical testing (see below) should always precede imaging evalu ation due to high risk of \200\234incidenta- loma \200\235 discovery. Treatment then depen ds on underlying cause and rate of progression. Whenever feasible, confirmed ACTH-secreting pituitary ade- nomas should be surgically resected. Microadenomas (<1 cm in diameter) can usually be removed via transsphenoidal approaches. Removal of larger macroadenomas may requ ire craniotomy. Success rates following initial sur- gery vary and are highly dependent on surgical expertise. Persistent disease may require repeat surgery, treatment with external beam radiation, and/ or medical therapies. Successful treatment of ectopic secretion of ACT H depends on accurate localization and surgical resection of functional tissue. In either s etting, severe refractory hypercortisolemia may lead to consider- ation of bilateral surgic al adrenalectomy or temporizing use of adrenolytic agents ( mitotane , ketoconazole , metyr apone , etomidate ) to inhibit excessive cortisol production. Surgical or medical eradicati on of adrenal glands will require monitored steroid replacement. Treatment of ACTH-independ ent Cushing \200\231s syndrome Principal treatment is surgical resection of cortisol-secret ing neoplastic adrenal tissue. 310 y g o o n i r c o d n E Table 9.17 Evaluation of suspected Cushing \200\231s syndrome l 1 For the initial evaluation of Cushing \200\231s, 7 one of the following tests should be p erformed to confirm the presence of hypercortisolemia: \212 a. Urine free cortisol level, measured in a 24 h urine collection \200\224con- comitant mea surement of creatinine may confirm adequate collection volume (>1 g/24 h); upper limit of n ormal range may vary depending on assay used. Perform two collections for verification. b. Salivary cortisol level, measured by having the patient chew a cotton pledget to collect 2. 5 mL sample of saliva at 11:00 pm. Upper limit of normal range may vary depending on assay used. Two samples should be checked for verification. c. Overnight low-dose dexamethasone s uppression test. In the normal patient, dexamethasone should suppress ACTH secretion, suppr essing cortisol secretion, in turn. Test performed by having the patient take 1 mg of dexam ethasone (Decadron ) at 11:00 pm, then measuring a cortisol level at 8:00 am the next morn ing. \212 Cortisol <1.8 mcg/dL = normal response \212 Cortisol >1.8 mcg/dL = hypercortiso lemia \212 \212 2 If the initial test for Cushing \200\231s is abnormal, patient should be referred to endo crinology for additional evaluation. In endocrinology, the following steps may be taken: 3 a. If hypercortisolemia has been confirmed, check a plasma ACTH level to distinguish betwee n ACTH-dependent and ACTH-independent Cushing \200\231s syndrome. \212 Plasma ACTH elevated or inappropriately normal = ACTH-dependent Cushing \200\231s syndrome Plasma ACTH suppressed = ACTH-independent Cushing \200\231s syndrome \212 b. If ACTH-dependent Cushing \200\231s syndrome is suspected, check an over- night high-dos e (8 mg) dexamethasone suppression test to distinguish between an ACTH-secreting pituitary adenoma and nonsuppressible ectopic secretion of ACTH. If overnight high-dose dexamethasone sup- pression test reveals suppression of cortisol by >50% = ACTH-secreting pituitary aden oma. c. If an ACTH-secreting pituitary adenoma is suspected, consider pitu- itary MRI scann ing. Cases that localize to the pituitary in which there is no lesion on MRI may require in ferior petrosal sinus sampling. If ecto- pic secretion of ACTH is suspected, consider targe ted imaging with high-resolution thoracic CT scanning, thoracic MRI scanning, or oct- reoti de scanning to attempt to localize an ACTH-secreting neoplasm d. If ACTH-independent Cushin g \200\231s syndrome is suspected, consider tar- geted imaging with abdominal CT scanning, abdominal MRI scanning, or iodo-cholesterol scintigraphy scanning to identify and character ize adrenal abnormalities. 311 7 The diagnosis of Cushing \200\231s syndrome: An Endocrine Society clinical practice guide line. J Clin Endocrinol Metabol . 2008. Adrenal insufficiency A systemic syndrome caused by deficiency of hormones secreted by the adrenal cortex. Primary adrenal insufficiency represents a deficiency of cor- tisol and ald osterone caused by intrinsic dysfunction and/or destruction of the adrenal cortex. Central (secondary) adrenal insufficiency represents a deficiency of cortisol only caused by dysfun ction of the hypothalamus or pituitary gland. Symptoms May vary depending on specific defic iencies and duration of condition. Symptoms associated with deficiency of cortisol may incl ude weight loss, fatigue, weakness, anorexia, nausea, and vomiting. Deficiency of aldostero ne may precipitate orthostatic dizziness and lightheadedness with positional changes and sa lt craving. Signs Deficiency of cortisol may present with orthostatic hypotension, hypoglyc emia, and hyponatremia. Deficiency of aldosterone may present with hyperkalemia, metabolic acidosis, and exacerbation of orthostatic hypotension and hyponatremia. Prolonged primary a drenal insufficiency may eventually cause diffuse hyperpigmentation of the skin and mucous membranes. Auricular-cartilage calcification, splenomegaly, eosinophilia, and tonsillar lym phoid hyperplasia are also observed in long-standing disease. Causes of primary adrenal ins ufficiency Common causes include autoimmune adrenalitis, bilateral adrenal hemorrhage, diss eminated tuber- culosis, and HIV infection. Rare causes include disseminated histoplasmosis , bilateral adrenal metastases, lymphoma, and adrenoleukodystrophy. Most clinically signifi cant cases of primary disease are associated with destruc- tion of >90% of functioning adre nal cortical tissue. In undiagnosed cases, physiologic stress associated with acute illness , infection, trauma, or sur- gery may precipitate an adrenal crisis.Adrenal crisis (describ ed below) is a medical emergency characterized by fever, refractory hypotension, volume dep letion, severe weakness, nausea, vomiting, abdominal pain, and delirium leading to obtundat ion and coma. Autoimmune adrenalitis Known as Addison \200\231s disease, lymphocytic infil- tration of bilateral adrenal glands associated with progressive destruction of functioning adrenal cortical tissue. May be associated with other autoim- mune disorders including aut oimmune thyroiditis, T1DM, vitiligo, primary ovarian insufficiency, and idiopathic hypopara thyroidism. Causes of central (secondary) adrenal insufficiency Most common cause is long-t erm treatment with exogenous steroids leading to suppres- sion of intrinsic hypothalamus-pi tuitary-adrenal axis.Resection of pituitary tumors for Cushing \200\231s can cause permanen t ACTH deficiency, although any pituitary process (infiltration, infection, tumor, hemorrha ge, ischemia) can cause central adrenal insufficiency. Long-term, high-dose opiate therapy may be associated with central adrenal insufficiency. See Table 9.18. Adrenal crisis Treatm ent of a suspected adrenal crisis should not be delayed for any reason. Confirmatory testin g may be performed once a patient has been stabilized. Effective therapy incorporates (a) a ggressive IV volume reple- tion with large volumes of isotonic fluid (D5 NS administered as rapidly as possible through a central line or large-bore IVs), (b) concomitant adminis- tr ation of dexamethasone (Decadron ) 4 mg IV q12h (other glucocorticoid preparations may int erfere with plasma cortisol assays used later to confirm diagnosis), and (c) identification and treatment of precipitating causes. Treatment Primary and central (secondary) adrenal i nsufficiency require treatment with glucocorticoid replacement therapy. 8 One commonly 312 8 Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endo crinol Metabol. 2009. 94(4):1059 \200\2231067. y g o o n i r c o d n E Table 9.18 Evaluation of suspected adrenal insufficiency l 1 Perform a cosyntropin (ACTH) stimulation test to evaluate the intrin- sic function of the adrenal cortex. \212 Cosyntropin stimulation test is performed by measuring a baseline cortisol level, administe ring 250 mcg of cosyntropin (Cortrosyn ) IV, and measuring cortisol levels at 30 and 60 mi n. Peak cortisol (at any time point) Peak cortisol (at any time point) <18 mcg/dL = adrenal insufficiency 2 If adrenal insufficiency has been confirmed, check a plasma ACTH level to distinguish between primary and central (secondary) adrenal insufficiency. \212 \212 \212 \212 > 18 mcg/dL = normal response Plasma ACTH >50 pg/mL = primary adrenal insufficiency Plasma ACTH <30 pg/mL = central (seco ndary) adrenal insufficiency 3 Consider referral to an endocrinologist for complicated cases. employed regimen is based on twice-daily administration of hydrocortisone (Cortef 7.5 \200\22330 mg/d split into two doses, with two-thirds of the daily dose taken before breakf ast and one-third taken in the late afternoon). Other regimens are based on once-daily admi nistration of prednisone (2.5 \200\22310 mg taken before breakfast or at bedtime), or dexam ethasone (Decadron 0.25 \200\223 0.75 mg taken at bedtime). There are no specific tests o r assays that provide an accurate index of the adequacy of glucocorticoid replacement. Clin ical assessment is required to identify doses that strike a balance between inad- equate re placement with residual symptoms and signs of adrenal insuffi- ciency and overreplacement p redisposing to iatrogenic Cushing \200\231s syndrome. As such, monitor patient weight, bloo d glucose levels, and overall sense of well-being to monitor and modify therapy. Intercurre nt illness, trauma, or planned surgery may require transient doubling of doses of pharmacol ogic glucocorticoid preparations to meet the demands of superimposed physi- ologic stress. Patients should be provided with prefilled syringes containing dexamethasone (4 mg Decadron in 1 mL NS) that can be administered intramuscularly or subcutaneously in emergency situ ations (i.e., illness that prevents PO dosing of home medications). Primary adrenal insuffi ciency may also require treatment with mineralocorticoid replacement therapy. Fludrocortiso ne (Florinef 0.1 \200\2230.2 mg/d) is the agent of choice. Orthostatic vital signs, serum potassium levels, and plasma renin activity levels may be measured to assess the adequacy of mineralocorticoid replacement. 313 Hyperaldosteronism Primary aldosteronism Secretion of aldosterone from the zona glom- erulo sa of the adrenal cortex is mediated by the renin-angiotensin axis. Excessive secretion of aldosterone leads to increased uptake of sodium (Na + ) and increased excretion of potassiu m (K + ) in the collecting tubules of the kidney. Over time, this may lead to development o f hypertension and hypokalemia. See Table 9.19. Symptoms Tend to be nonspecific. May includ e fatigue, weakness, head- aches, polydipsia, and polyuria. Signs Hypertension in young adu lts without personal or family risk fac- tors, hypertension refractory to multiple medicati ons, and concomitant hypokalemia. Note that hypokalemia is not necessary to make a diagno- sis of primary hyperaldosteronism and may only be present in later-stage disease. Causes of primary aldosteronism Approximately 75% of all cases caused by growth of an auton omously functioning, aldosterone-producing adrenal adenoma (also known as Conn \200\231s sy ndrome). The remainder are caused by idiopathic hyperaldosteronism, a condition characteriz ed by bilateral micronodular or macronodular hyperplasia of the adrenal cor- tex. Rare caus es include adrenal carcinoma and glucocorticoid-remediable hypertension. Treatment of aldos terone-producing adrenal adenomas Mild cases of primary aldosteronism may be treated medica lly (see medical treat- ments, below). Localized lesions in the appropriate candidate shoul d be surgically resected by unilateral laparoscopic adrenalectomy. Pre-treatment with spiro nolactone (Aldactone 12.5 \200\223200 mg bid) or eplerenone (Inspra 25 \200\22350 mg bi d) titrated to control BP for 2 \200\2234 wks prior to surgery may reduce risk of periopera tive complications associated with changes in BP. Medical treatment of bilateral disease or idiopathic hyperaldos- teronism Long-term medical therapy based on treatment with aldoster - one receptor blockers titrated to control BP and normalize serum K + levels should be emp loyed in these cases. Available agents include spironolactone (Aldactone 12.5 \200\223200 mg bid) and eplerenone (Inspra 25 \200\22350 mg bid). Patients who cannot tolerate aldos terone receptor blockers may be treated with amiloride (Midamor 5 \200\22315 mg bid) in c ombination with other antihy- pertensive agents. Glucocorticoid-remediable aldosteronism (G RA) should be sus- pected in patients <20 yrs with confirmed primary aldosteronism and in t hose with a family history of (1) hyperaldosteronism or (2) strokes at a young age (<40). G enetic testing is available. GRA should be managed medically with a low dose of glucocortic oid to normalize BP and serum potassium rather than a mineralocorticoid antagonist. Table 9.19 Evaluation of suspected primary aldosteronism 9 1 Screen for inappropriate aldosterone secretion by checking a plasma aldosterone level and a plasma renin activity level * \212 314 Plasma aldosterone >15 ng/dL and/or plasma aldosterone/plasma renin activity ratio >30 = in appropriate aldosterone secretion con- sistent with possible primary aldosteronism If the r esults of above testing are not diagnostic and suspicion remains high, refer to endocrinolo gy for possible discontinuation of other confounding medications ** and retesting. \212 2 If primary aldosteronism is suspected, refer to endocrinology for one of four confirmator y tests: (1) Oral sodium loading test, (2)saline infu- sion test, (3) fludrocortisone suppr ession testing, or (4) captopril chal- lenge test. 3 If primary aldosteronism is confirmed, consider targeted adrenal imaging with abdominal C T scanning, abdominal MRI scanning, or iodo-cholesterol scintigraphy scanning to identify a nd characterize adrenal abnormalities. 4 If targeted imaging is unrevealing or equivocal, consider bilateral adrenal vein sampling at an experienced center to determine whether lateraliza- tion of aldosterone secretion co nsistent with an aldosterone-producing adrenal adenoma is present. If the patient is being treated with an aldosterone receptor blocker (spironolactone, epler enone, amiloride, triamterene)or potassium-wasting diuretic, or is using products derived f rom licorice root (confections or chewing tobacco), discontinue treatment and wait at least 4 wks before testing. ** Withdraw for additional 2 wks: -blockers, central 2 -agonis ts, NSAIDs, ACE-inhibitors, ARBS, rennin inhibitors, dihydropyridine calcium channel antago nists. Pheochromocytoma Represents a rare catecholamine-secreting neoplasm (Table 9.20). 85% deve lop within the adrenal medulla, with 5 \200\22310% presenting in bilateral distri- butions and 10% eventually proving to be malignant. Catecholamine-secreting neoplasms that are iden tified in extra-adrenal locations (abdomen, thorax, head, neck) are called paragangliomas . 15 \200\22320% of pheochromocytomas are associated with familial (genetic) disorders: MEN -2 syndromes, von Hippel \200\223 Lindau (VHL) syndrome, and neurofibromatosis type 1. Over all, pheochro- mocytomas account for <0.2% of all cases of newly diagnosed hypertension. Sy mptoms Episodic paroxysms that may present with varying constella- tions of symptoms includ ing episodic headaches, sweating, and palpitations. Other symptoms may include diaphoresis, anxiety, tremulousness, fatigue, nausea, vomiting, abdominal pain, chest pain, polyuria, po lydipsia, and visual disturbances. Signs Sustained or paroxysmal hypertension is characteri stic, although 5 \200\22315% of patients present with normal BP. Peripheral vasoconstrictio n dur- ing paroxysms may produce transient pallor. Resultant increase in core body temperat ure may lead to subsequent flushing. Increased ESR, hyperg- lycemia, and stress-induced car diomyopathy have been reported. y g o o n i r c o d n E l Table 9.20 Evaluation of suspected pheochromocy toma 1 Screen for increased catecholamine secretion by checking a plasma free metanephrine level s or 24 h urine metanephrine and catecholamine levels. \212 Plasma free metanephrine levels; screening test of choice when avail- able; sensitivity is >99%, specificity is 89%. Urine metanephrine and catecholamine levels (24 h collection). La betalol, tricyclic antidepressants, levodopa, decongestants, amphet- amines, reserpine, eth anol, prochlorperazine, acetaminophen, and buspirone may artifactually increase levels. Nor mal plasma free metanephrine or urine metanephrine/cate- cholamine levels = excluded Marked ly elevated plasma free metanephrine or urine metanephrine/ catecholamine levels (2 \200 \2234 \227 >normal) = pheochromocytoma Marginally elevated plasma free metanephrine or uri ne metanephrine/ catecholamine levels = increased catecholamine secretion consistent with a possible pheochromocytoma versus other stressor (hyperten- sion, myocardial infarction, se psis, etc.) \212 \212 315 \212 \212 2 If a possible pheochromocytoma is suspected, check repeat plasma free metanephrine levels or urine metanephrine/catecholamine levels. 3 Normal repeat plasma free metanephrine or urine metanephrine/cat- echolamine levels = excluded 4 Marginally elevated repeat plasma free metanephrine or urine meta- nephrine/catecholamine levels = increased catecholamine secretion consistent with a possible pheochromocytoma.Con sider referral to an endocrinologist who may perform confirmatory tests. 5 If a pheochromocytoma is confirmed, consider targeted adrenal imag- ing with abdominal CT scanning or abdominal MRI scanning to iden- tify and characterize adrenal abnormalities; p heochromocytomas may show a characteristic bright intensity on T2-weighted MRI images. 6 If targeted imaging is unrevealing or equivocal, consider whole-body imaging with metaiodoben zylguanidine (MIBG), 111-IN-pentetreotide scintigraphy, total body MRI or positron emission tomography (PET) scanning to attempt to localize a suspicious focus of increased cat- echo lamine secretion. Treatment Surgical resection of benign pheochromocytomas and para- gangliomas may be curati ve. Patients require preoperative treatment with -blockers started at least 2 wks (and p referably 1 month) prior to planned procedures. Agents used for this purpose include phenox ybenzamine (Dibenzyline 10 \200\223100 mg/d) and doxazosin (Cardura 2 \200\2238 mg/d). Doses should be titrated every few days to target normotensive BPs. Patient should feel ort hostatic if dosing is correct. Intraoperative hypertensive crises may require treatment wit h phentolamine or nitroprusside . Postoperatively, patients may require aggressive volume r epletion and monitoring for symp- toms and signs of incipient hypoglycemia. MEN-2a and -2b See section on Hyperparathyroidism. Von Hippel Lindau syndrome Includes pheochromocytoma (f requently bilateral), rarely paraganglioma, with retinal angiomas, cerebellar heman- giobla stoma, epididymal cystadenoma, renal and pancreatic cysts, renal cell carcinoma, and pancre atic neuroendocrine tumors.Mutations in the VHL tumor suppressor gene leading to loss of fu nction of VHL protein. Neurofibromatosis type 1 (NF1) Includes bilateral or unilateral pheo - chromocytoma, rarely paraganglioma, with neurofibromas, axillary and inguinal freckling, iris hamartomas (Lisch nodules), and caf au lait spots. Genetic testing for autosomal do minant mutations in NF1, although not always necessary if clinical phenotype is clear. Gene tic screening Referral to an endocrinologist for genetic testing for familial types of pheo chromocytoma and paraganglioma should be made in the following cases: \212 \212 \212 Paraganglioma at any site Bilateral adrenal pheochromocytoma Unilateral pheochromocytoma with family history of pheochromocytoma/ paraganglioma \212 \212 Unilateral pheochromocytoma at a young age (<30 years) Other clinical findings suggesting g enetic syndromes (MEN-2a or -2b, VHL, NF1) 316 Hirsutism Defined as new or increased abnormal growth of thick, coarse, pigmented terminal hair in females. May be distributed in regions commonly associated with male secondary sexu al characteristics including the face, chest, back, lower abdomen, and inner thighs. May be caused by (a) increased secre- tion of androgens from the ovaries, (b) increased secretion of androgens from the adrenal cortex, or (c) increased 5 -reductase activity leading to increased conversion of testosterone to dihydrotestosterone at target tis- sues.Hirsutism may be idiopathic in nature or based on ethnic heritage. Hyperprolactinemia is a rare cause of hirsutism. Increased secretion of androgens from the ovaries Most common cause is polyc ystic ovary syndrome (see below). May also be associated with ovarian hyperthecosis or, rar ely, the growth of androgen-secreting ovarian neoplasms. Increased secretion of androgens f rom the adrenal cortex Most common cause is nonclassic (late-onset) congenital adrenal hype rplasia (CAH) associated with 21-hydroxylase deficiency. May also be caused by Cushing \200 \231s syndrome, growth of androgen-secreting adrenal adenomas, or growth of adrenal carcino mas. Evaluation Should initially focus on identification and quantification of abnormal ter minal hair growth using a Ferriman- Gallwey score. Patients