295 3 Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metabol . 2009. (quinolones, quinine, IV pentamidine, aminoglutethimide) are less clear. Investigation of h ypoglycemia usually focuses on sequentially (1) ruling out disorders associated with non-in sulin-mediated hypoglycemia, (2) conduct- ing a monitored fast to confirm insulin-mediated hypoglycemia, and (3) determining whether detectable insulin is endogenously secreted or fa cti- tiously administered. See Table 9.8. Insulinoma Very rare. May develop in the setting of multiple endocrine neoplasia type 1 (MEN-1) syndrome (pituitary tumor, parathyroid hyper - plasia, pancreatic mass). The majority of confirmed insulinomas represent isolated benign neoplasms. <10% prove to be malignant following patho- logic evaluation. Principal treatme nt is surgical enucleation. Preoperative localization may be difficult. Imaging modalities include computed tomog- raphy (CT) scanning, MRI scanning, transabdominal ultrasound, endos copic ultrasound, and octreotide scanning. Measurement of insulin levels drawn from hepatic veins after arterial administration of calcium gluconate may help to localize regions of e xcessive secretion. In cases where imaging fails to identify a suspicious mass, intraoperat ive localization may be attempted through exploration, palpation, and direct ultrasonograph y. Distal or partial pancreatectomy may be considered as an empiric measure when a suspi- c ious mass cannot be localized, although this will likely commit the patient to lifelong ins ulin therapy following surgery. Persistent or malignant disease may require treatment with diazoxide to suppress insulin secretion. Postprandial hypoglycemia Recurrent episodes of hy poglycemia may occur in patients who have undergone upper GI surgical procedures (gastric b anding, Roux-en-Y).This can occur immediately following sur- gery or years after. Transient episodes related to excessive physiologic Table 9.8 Monitored fast May be conducted in any inpatient or outpatient setting that allows for monitoring of intak e and activity. The patient may drink sugar-free and noncaffeinated beverages. Physical act ivity should be encouraged. Protocol Draw blood samples q6h to measure plasma glucose, insu lin, C-peptide, proinsulin, and -hydroxybutyrate. Once plasma glucose drops to <60 mg/dL , increase frequency of blood draws to every 1 \200\2232 h. Terminate the fast once (a) pla sma glucose drops to <45 mg/dL and the patient has signs/symptoms of hypoglycemia, (b) plas ma glucose >45 mg/dL if symptoms present, or (c) 72 h have elapsed without symptoms. At the end of the fast, draw blood samples to measure plasma glucose, insulin, C-peptide, proinsu lin, -hydroxybutyrate, and oral hypoglycemic agents. Then inject 1.0 mg of glucagon IV a nd measure plasma glucose 10, 20, and 30 min later. Interpretation In a blood sample collec ted when plasma glucose is <55 mg/dL, an insulin level >3 U/mL may be considered to be in appropriately elevated. An insulinoma may be suspected when a concomitant C-peptide level i s >0.6 ng/mL with a proinsulin level >5 pmol/L. Plasma glucose levels that increase by >25 mg/dL or less following administration of glucagon and -hydroxybutyrate levels of 2.7 mm ol suggest mediation of hypoglyce- mia by insulin (or IGF-1). Factitious administration of insulin may be suspected when C-peptide and proinsulin levels are lower than these threshol ds. In situations where factitious administration of insulin secre- tagogues may be suspect ed, blood samples can be checked to screen for sulfonylurea exposure. 296 insulin secretion may occur during the initial onset of T2DM. Self-identified \200\234reac tive \200\235 hypoglycemia in otherwise healthy individuals is considered a controversial d iagnosis. Experimental attempts to provoke and correlate symptoms have reported conflicting results. Oral glucose tolerance testing or mixed meal testing has not proven to reliably r eproduce hypoglycemia. Anecdotally, some patients report improvement in symptoms after alte ring diets to increase intake of protein and complex carbohydrates in smaller portions dist ributed throughout the course of the day. y g o o n i r c o d n E l Thyroid function tests Physiology Thyrotropin releasing hormone (TRH) secreted by the hypo- thalamus stimulates secretion of TSH from thyrotroph cells in the ante- rior pituitary. TS H binds to receptors on thyrocytes in the thyroid gland, stimulating (a) uptake of iodine, (b) organification of iodine with thyroid peroxidase and thyroglobulin (TG) to, (c) produce thyroxine (T4) and triiodothyronine (T3), followed by (d) secretion of T4 and T3 from the thyroid gland. See Figure 9.1. Most of the T4 and T3 secreted by the thyroid gland bind to transportation proteins in the circulation. Free (unbound) T4 is converted to T3 by deiodin ase enzymes in peripheral tissues. Free T3 is the active form of thyroid hormone that binds to nuclear receptors to exert different regulatory effects in the target organ. Free T4 an d T3 exert nega- tive regulatory feedback on the secretion of TRH from the hypothalamus and the secretion of TSH from the anterior pituitary. There is a log-linear relationship betwe en thyroid hormone levels and TSH levels. The major- ity of abnormalities of thyroid functi on in the clinical setting stem from disorders that primarily involve the thyroid gland its elf. As such, TSH is an intrinsic assay that provides the most sensitive index of thyroid g land function. See Table 9.9. Table 9.9 Evaluation of suspected hypothyroidism 297 1 Check a TSH level Normal = euthyroid Elevated = likely primary hypothyroidism Low = possible central (seconda ry) hypothyroidism, although rare 1 If the TSH level is elevated, check an unbound (free T4 ) thyroxine \212 \212 \212 level \212 \212 Elevated TSH + low free T4 =primary hypothyroidism Elevated TSH + normal free T4 = subclini cal hypothyroidism 3 If the TSH level is low, check an unbound (free T4) thyroxine level \212 Low TSH + low free T4 = possible central (secondary) hypothyroid- ism (defect in hypothalam us or pituitary) 4 To confirm diagnosis of autoimmune-mediated hypothyroidism (most common, Hashimoto \200 \231s thyroiditis), check antithyroid peroxidase and antithyroglobulin antibody titers \212 Elevated antithyroid peroxidase and/or antithyroglobulin antibody titers = autoimmune thyro iditis. Negative antibody titers do not rule out autoimmune disease. Table 9.10 Evaluation of suspected hyperthyroidism 1 Check a TSH level \212 \212 \212 Normal = euthyroid Low = thyrotoxicosis Elevated = possible central (secondary) hyperthyroi dism 2 If the TSH level is low, check an unbound (free T4) thyroxine level and a total triiodothyronine (T3) level \212 \212 \212 Low TSH + elevated free T4, or T3 = thyrotoxicosis Low TSH + normal free T4, and T3 = subcl inical thyrotoxicosis Elevated TSH + elevated free T4, or T3 = central (secondary) hyper- t hyroidism (defect in hypothalamus or pituitary) 3 Check for findings consistent with manifestations of Graves \200\231 disease (goiter, dermopathy, symptoms and signs of thyroid eye disease) 4 If no findings consistent with manifestations of Graves \200\231 disease are evident, che ck a radionuclide thyroid uptake and scan study and a thy- roglobulin level \212 Increased, diffuse bilateral uptake (+/ \200\223 visible pyramidal lobe) = Graves \200\231 hyperthyroidism Normal to increased uptake, focal, \200\234hot \200\235 areas of distribut ion = toxic nodule or toxic multinodular goiter Low uptake + elevated or normal thyroglobul in = thyroiditis Low uptake + low thyroglobulin = ingestion of thyroid hormone (factitious hyperthyroidism) \212 \212 \212 Hyperthyroidism Definitions Thyrotoxicosis is a systemic syndrome resulting from the manife stations of exposure to excessive levels of thyroid hormone. Hyperthyroidism is defined as thyrotoxicosis caused by increased produc- tion and secretion of thyroid hormone from funct ional thyroid tissue. See Table 9.10. Symptoms of thyrotoxicosis May include weight loss, h eat intolerance, diaphoresis, palpitations, increased appetite, increased frequency of bowe l movements, amenorrhea or oligomenorrhea, tremulousness, anxiety, insomnia, and irritabili ty. Signs of thyrotoxicosis May include resting tachycardia, atrial arrhyth- mias, warm moi st skin, thinning of the hair, onycholysis, low bone mineral density (BMD), proximal muscle weakness, hyperreflexia, a resting tremor, lid lag (defined as a delay in the descent of t he upper eyelids on downward gaze; see Table 9.11), and (rarely) hypercalcemia. Causes of h yperthyroidism Common causes include Graves \200\231 disease, toxic multinodular goiter, to xic adenoma, and exposure to large amounts of iodine (IV contrast loads, amiodarone). Rare causes of hyperthyroidism include struma ovarii, metastatic thyroid cancer, and TSH-secreti ng pitu- itary adenoma (central hyperthyroidism). Graves \200\231 disease Autoimmune disord er characterized by endogenous pro- duction of antibodies that bind to and stimulate TSH re ceptors (also knows as thyroid-stimulating immunoglobulins). Marked female predominance. St imulation of TSH receptors may cause significant enlargement of the thy- roid gland evident as a goiter with a palpable pyramidal lobe. Increased vascularity of the thyroid gland may be detected as an audible bruit or palpable thrill. Complications believed to be caused by inflammation and 298 y g o o n i r c o d n E Figure 9.1 Hypothalamic-pituitary-thyroid axis l 299 antibody-mediated stimulation of fibroblast growth include dermopathy (pretibial myxedema), acropachy, and thyroid eye disease (Graves \200\231 oph- thalmopathy). Hyperthyroidism may be effectively treated with antithyroid drugs, radioactive iodine ablation, or thyroidecto my. Radioactive iodine treatment may exacerbate active thyroid eye disease. Pretreatment wi th systemic glucocorticoids may reduce risk. Graves \200\231 disease may be associ- ated wi th other autoimmune conditions in the same patient (T1DM, vitiligo, premature graying of th e hair, etc.). Toxic multinodular goiter Results from the growth of multiple autono- mously functioning hyperplastic thyroid nodules. Hyperthyroidism due to multinodular goiter is mo re common among older individuals and may develop in the setting of a previously euthyroid multinodular goiter. Growth of the thyroid gland substernally may cause compressive thoraci c outlet symptoms. Hyperthyroidism in a previously euthyroid patient may be precipitated by exposure to large amounts of iodine. Hyperthyroidism secondary to a multinodular goiter ma y be treated with radioactive iodine ablation, surgical resection, or antithyroid drugs. To xic adenoma A \200\234hot nodule \200\235 and resultant hyperthyroidism is due to progress ive growth of a single autonomously functioning thyroid nod- ule. Usually quite large, the nodule may be treated with antithyroid drugs, although radioactive iodine ablation or surgi cal resection are preferred and definitive. See also Table 9.12. Table 9.11 Thyroid eye disease Complication of Graves \200\231 disease believed to be caused by antibody-mediated stimulat ion of fibroblast growth and inflammation in soft tissues of the orbits and eyelids. Inflam mation may cause swelling of the eyelids, conjunctival injection, and chemosis. Affected pa tients may report excessive tearing, ocular irritation, and persistent foreign body or \200\234gritty \200\235 sensation of the eye. Swelling of the soft tissues in the orbits ma y cause protrusion of the eyeballs (proptosis), entrapment of the extraoc- ular muscles wit h impaired motion, and compression of the optic nerve. Affected patients may report problem s with excessive dryness of the eyes, diplopia, and disruptive changes in visual acuity. Ri sk of developing thyroid eye disease may be increased in patients who smoke. Evaluation For mal neuro-ophthalmologic evaluation required. Imaging with orbital CT scanning may help to define degree of proptosis and extent of extraocular muscle involvement. Treatment Manageme nt of mild symptoms involves protecting the cor- neas from exposure and abrasion with artif icial tears and ointments to provide adequate lubrication. High-dose systemic glucocorticoi ds may help to attenuate active inflammation. Progressive diplopia and disrup- tive changes in visual acuity may require surgical decompression of the orbits. Staged strabismus surge ry and eyelid surgery may be consid- ered. Treatments based on the use of orbital irradiati on, immunosup- pressive agents, and plasmapheresis have been tried with some success. Patie nts with persistent diplopia may need to wear glasses with correc- tive prismatic lenses. T hyroidectomy to improve thyroid eye disease is controversial. Causes of non-hyperthyroid thyrotoxicosis Include ingestion of phar- macologic and nonpharm acologic preparations of thyroid hormone, sub- acute thyroiditis, and autoimmune thyroiditi s. Subacute thyroiditis Granulomatous inflammation of thyroid tissue. Onset often preceded by a nonspecific viral illness. Patients present with pain localized to thyroid gland that may radiate upward to neck and jaw. The thyroid gland may be slightly enlarged and exquisit ely tender to palpa- tion. Inflammation may spread from one lobe to the other. Lab tests ma y reveal an elevated erythrocyte sedimentation rate (ESR). Thyroid function test profiles t ypically reveal a hyperthyroid phase (suppressed TSH, elevated free T4 and T3) lasting 1 \200\2234 wks caused by release of thyroid hormone, fol- lowed by a resolving hypothyroid p hase (normal to elevated TSH, low free T4 and T3)lasting 1 \200\2233 months, caused by impa ired production of thyroid hormone. Hypothyroid phase may be permanent. May require treatme nt with (a) -blockers to attenuate thyrotoxicosis and (b) systemic glucocor- ticoids to alleviate discomfort associated with inflammation. Subclinical hyperthyroidism Profile of t hyroid function test results char- acterized by a decreased TSH level with normal T4 and T3 levels. Indications for treatment are controversial. Arrhythmias and bone loss associated with TSH <0.1 IU/mL in elderly individuals, a threshold warranting treatment. Consider m ild -blockade or low-dose antithyroid medications in those with hyperthyroid symptoms to test for amelioration with normalization of thyroid function tests. 300 y g o o n i r c o d n E Table 9.12 Treatment of hyperthyroidism l \222 -Blockers May help to attenuate symptoms of thyrotoxicosis while other treatment moda lities are being planned or taking effect. Commonly used preparations include propranolol ( Inderal 10 \200\22340 mg tid, Inderal LA 60 \200\223120 mg/d) and atenolol (Tenormin 25 \200\223100 mg/d). -blocker dose should be titrated to relief of symptoms (palpitatio ns, tremulous- ness) instead of resting heart rate. Antithyroid drugs Thioamides that inhib it thyroid hormone produc- tion and release from the thyroid gland. Available preparations include methimazole (Tapazole 10 \200\22360 mg/d) and propylthiouracil (PTU 50 \200\223200 mg bid-tid). Methimazole offers advantage of once-daily dosing. PTU may be safer during pre gnancy and may reduce peripheral conversion of T4 to T3. Doses should initially be titrated to reduce T4 and T3 levels to within normal ranges. Return of suppressed TSH levels to nor mal range may be delayed. Limiting side effects of both methimazole and PTU may include pru ritic rash and hepatotoxicity with elevated transaminase levels or jaundice. Reversible agr anulocytosis may develop as a rare complica- tion of methimazole use. Patients should be in structed to stop treatment pending further evaluation if they develop a fever or severe pha ryngitis (symptoms of agranulocytosis). Radioactive iodine ablation Administration of a sin gle oral dose of iodine-131 may be definitive therapy for hyperthyroidism, although mul- ti ple doses are sometimes required. Isotope is taken up and organified by hyperfunctioning th yroid tissue. Over time, locally acting radiation gradually destroys thyrocytes. Calcula ted doses used to treat Graves \200\231 dis- ease based on thyroid gland volume and uptake. High incidence of postab- lative hypothyroidism requiring lifelong thyroid hormone replace ment. Calculated doses may be used to treat toxic adenomas. Higher-range empiric doses are usually used to treat toxic multinodular goiters. Thyroid surgery Procedures vary depending on indication. Toxic ade- nomas may be resected, leaving the remainder of the thyroid inta ct. Toxic multinodular goiters usually require total thyroidectomy, especially when subster nal extension may be contributing to compressive symptoms. Subtotal thyroidectomy may be co nsidered in cases of Graves \200\231 disease when antithyroid drugs and radioactive iodine are contraindicated or hyperthyroidism is life-threatening (thyroid storm, below). Thyroid storm Classified based on symptoms or signs (tachycardia/ arrhythmias, fever, transaminitis , altered mental status, GI symptoms, and heart failure); requires aggressive therapy with steroids, lithium, super-saturated potassium iodine (SSKI) in addition to -blockade/anti - thyroid drugs. 301 Hypothyroidism A systemic syndrome caused by a deficiency of thyroid hormone. Primary hypot hyroidism represents a deficiency of thyroid hormone caused by intrinsic dysfunction of the thyroid gland itself. Central (secondary) hypo- thyroidism represents a deficiency of thyr oid hormone caused by dysfunc- tion of the hypothalamus or pituitary gland. Symptoms May in clude weight gain, cold intolerance, dyspnea, constipa- tion, myalgias, arthralgias, fatigu e, lethargy, and amenorrhea. Signs May include bradycardia, pericardial effusion, cool dry skin, hair loss, brittle nail s, delayed terminal relaxation of peripheral reflexes, nonpitting edema caused by depositio n of glycosaminoglycans(myxedema), anemia, and hyponatremia. Causes of primary hypothyroidi sm Common causes include auto- immune thyroiditis, previous radioactive iodine or external beam radiation-induced ablation of thyroid tissue, surgical removal of thyroid tissue, and drug-mediated inhibition of thyroid hormone production and release. Rare causes include con genital absence of thyroid tissue and resistance to thyroid hormone. Most common cause worl dwide is iodine deficiency (rare in the United States due to abundant dietary supplementati on). Autoimmune thyroiditis Also known as Hashimoto \200\231s thyroiditis. Chronic lymphocy tic inflammation often associated with progressive destruction of functioning thyroid tissu e. Marked female predominance. Increased preva- lence with age. Autoimmune hypothyroidism i s the cause of 95% of cases of primary hypothyroidism. Elevated titers of antithyroid perox idase and antithyroglobulin antibodies may confirm a suspected diagnosis. May be associated with other autoimmune disorders including T1DM, autoimmune adrenalitis, and vitiligo. Trea tment Thyroid hormone replacement based on administration of pharmacologic preparations of levothyroxine, or T4 (brand name ver- sions include Levothroid , Levoxyl , Synthroid , U nithroid ; taken daily; available in 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, an d 300 mcg color-coded preparations). Usual daily replacement dose is approximately 1.6 mcg/ kg body weight. Elderly patients may only require 1 mcg/kg body weight. Preparations of thy roid hormone replacement including T4 and T3 also available (Armor ), although content is variable and TSH harder to monitor. T4 preparations are preferred. Levothyroxine may be sta rted at full replacement doses in patients <50 without evidence of heart disease. In patien ts with known or suspected heart disease, treatment should be started at a dose of 12.5 \200\22325 mcg/d, and should be increased gradually by 12.5 \200\22325 mcg increments at 4- wk intervals based on changes in TSH levels. A TSH level should be checked 6 wks after star ting a dose or 4 wks after adjusting a dose to assess the adequacy of replacement. Treatmen t should target maintenance of TSH levels within reference ranges. Coadministration of larg e doses of calcium supplements, iron supplements, and bile acid res- ins may inhibit absorp tion of levothyroxine. Subclinical hypothyroidism Profile of thyroid function test results char- acterized by an elevated TSH level with normal T4 and T3 levels. Indications for trea tment are controversial. Concomitant evidence of hypercholester- olemia or underlying autoi mmune thyroiditis may provide a rationale for starting treatment with thyroid hormone repla cement. 302 Nonthyroidal illness When thyroid function tests are checked in the setting of severe nonth yroi- dal illness (i.e., during prolonged hospitalization), secondary changes in TSH and th yroid hormone levels may return profiles that appear to be consis- tent with primary thyroi d dysfunction. T3 levels usually decline during the early stages of severe non-thyroidal il lness. As illness progresses, T4 levels may also decline. TSH levels are usually normal or suppressed during the early stages of severe non-thyroidal illness. They may rise above the upper limit of the normal range during recovery, producing a profile that may be mistaken for primary hypothyroidism. If thyroid function tests are checked in severely ill patients, clinical correlation is important. The presence of a goiter, history of radioactive iodine treatment, history of pituitary disease, or findings consistent with prior thyroid surgery may help to establish a correct diagnosis. For patients without findings consistent with underlying thyroid dysfunc tion, retesting 6 \200\2238 wks after recovery may be recommended before starting therapy. y g o o n i r c o d n E l Hyperparathyroidism Physiology Parathyroid hormone (PTH) secreted by the parathyroid glands in response to circulating blood calcium levels. PTH stimulates (a) increased breakdown of bone through activation of osteoclasts, (b) increased reabsorption of calcium (Ca 2+ ) and decreased reabsorption of phosphate (PO 4 \200\223 ) in the distal tubule of the kidney, and (c) increased pro- duction of 1,25-dihydroxyvitamin D. The overall effect is to increas e Ca 2+ levels while decreasing PO 4 \200\223 levels. Negative feedback exerted by increas ed Ca 2+ levels regulates secretion of PTH. See Table 9.13. Primary hyperparathyroidism Ina ppropriate autonomous secretion of PTH due to hyperplastic growth of one or more parathyroi d glands. Approximately 80% of cases associated with growth of a solitary adenoma, 15% with hyperplasia of all four glands, 4% with growth of multiple ade- nomas, and <1% with malign ant growth of parathyroid carcinoma. Patients often present with asymptomatic hypercalcemia . Confirmation based on finding an elevated blood Ca 2+ level in conjunction with an elevat ed or inappropriately normal PTH level. Complications associated with progres- sive disease may include (a) osteoporosis and fracture, (b) nephrolithia- sis, (c) precipitation or exa cerbation of psychiatric symptoms, and (d) GI symptoms. Variants presenting with hyperplasi a of all four glands associated with specific MEN syndromes (MEN-1 and -2a). Treatment invo lves surgi- cal resection of autonomously functioning parathyroid tissue. Surgery is indica ted in patients presenting with (a) severe or life-threatening hyper- calcemia, (b) osteopo rosis or fractures, (c) impaired renal function, or (d) recurrent nephrolithiasis. In asymp tomatic cases, evaluation of measured or estimated GFR and dual energy x-ray absorptiometry (DXA) scanning with inclusion of spine, hip, and distal forearm BMD may to help to determi ne which patients should be referred for surgery. 4 See Table 9.14. Planned operations may involve exploration and comparison of all four glands to identify hypertrophic tissue or ta rgeted resection of specific glands based on attempted preoperative localization. Studies c ommonly utilized for preoperative localization include sestamibi scans, MRI scans, CT scans , and neck ultrasonography. Intraoperatively, PTH levels may be measured to track changes f ollowing resection of suspect tissue. Solitary adenomas are usually resected in isolation. Confirmed hyperplasia of all four glands 303 Table 9.13 Indications for surgical treatment of asymptom- atic primary hyperparathyroidism \212 Calcium level >1 mg/dL above lab reference range upper limit of normal Bone density T-score at the hip, lumbar spine, or distal radius <-2.5 and/or previous fragility fracture Measur ed or estimated GFR of <60 mL/min Age <50 years \212 \212 \212 4 Bilezikian JP et al. Guidelines for the management of asymptomatic primary hyperparathyro id- ism: Summary statement from the Third International Workshop. J Clin Endocrinol Metabol . 2009. 94(2):335 \200\223339. may require resection of up to three and a half glands with reimplantation of residual tiss ue in an accessible location (forearm, sternocleidomastoid muscle). Familial hypocalciuric hypercalcemia (FHH) Lab profile may resemble that of primary hyperparathyroidism (elevated vs. inappropriately normal PTH, elevated calcium).Caused by autosomal dominant mutations in the calcium-sensing receptor found in both the parathyroid glands and renal tubules.May be confirmed with positive family history, hypercalcemia at young age, and low 24 h urine cal cium level measurement in patient. Ca/Cr clearance ratio <0.01 in 80% of patients. FHH is a symptomatic and without manifestation of end-organ damage (bone loss, kidney disease, etc.) .Does not need treatment. Secondary hyperparathyroidism Presents with a profile of an eleva ted PTH level in conjunction with a low or normal Ca 2+ level. Commonly due to vitamin D de ficiency (decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D leads to d ecreased suppression of PTH secre- tion and decreased intestinal absorption of Ca 2+ ). Rel ative hypocalcemia also stimulates increased secretion of PTH to restore and maintain nor- mal Ca 2+ levels. Secondary hyperparathyroidism also common in patients with chronic kidney disease once estimated GFR declines to <40 mL/ min. May respond to treatment with calcium supplementation, phosphate restriction,administration of potent 1,25-dihydroxyvitamin D ana logs or calcimimetic drugs like cinacalcet (Sensipar 60 \200\223180 mg/d). Tertiary hyper parathyroidism In patients with chronic kidney disease, prolonged severe secondary hyperpar athyroidism may lead to hyperplasia of autonomously functioning parathyroid tissue. Inappro priate secretion of PTH in this setting may lead to hypercalcemia with extracellular Ca 2+ deposition evident as cutaneous calcification. In extreme cases, this may lead to extremity gangrene as part of a life-threatening syndrome known as calciphylaxis . Urgent parathyroi dectomy may be required. Table 9.14 Multiple endocrine neoplasia syndromes 304 Multiple endocrine neoplasia type 1 (MEN-1) Clinical manifesta- tions include primary hyper parathyroidism, pancreatic tumors, and pitu- itary adenomas. Autosomal dominant loss-of-fun ction mutation of the MEN-1 tumor suppressor gene. Penetrance of primary hyperparathy- roid ism characterized by four-gland hyperplasia is 95%. Most common pancreatic tumors are gastr inomas (associated with the Zollinger-Ellison syndrome) and insulinomas. Pituitary adenomas may secrete prolactin or growth hormone or may be nonfunctional. Multiple endocrine neopla sia type 2a (MEN-2a) Clinical manifesta- tions include medullary thyroid carcinoma (MTC), p heochromocytoma, and primary hyperparathyroidism. Autosomal dominant mutation of the RET pr oto-oncogene. Different mutations identified in different kindreds. MTC may be diagnosed in 80 \200\223100% of affected individuals. Tends to be multicentric. Preceded by hyperplasia of parafollicular C-cells. Pheochromocytomas may develop in 50% of affected individuals. O ften bilateral. Rarely malignant. RET proto-oncogene screening is available as a commercial test. Multiple endocrine neoplasia type 2b (MEN-2b) Clinical manifesta- tions include MTC, pheochromocytoma, and mucosal neuromas (lesions that may be discernible as submucosal mass es on the lips, cheeks, tongue, glottis, eyelids, and visible corneal nerves). Affected ind ividuals may present with a characteristic marfanoid habitus. MTC tends to be more aggressi ve than in MEN-2a, mandating earlier diagnosis and treatment. Hypoparathyroidism Characterized by decreased secretion of PTH. Patients may present with s ymptoms and signs of hypocalcemia including perioral numbness, digital paresthesias, carpop edal spasm, and tetany. Confirmation is based on find- ing a decreased Ca 2+ level in conju nction with a low or inappropriately normal PTH level. Commonly due to a complication of su rgical proce- dures that inadvertently lead to removal or destruction of a critical mass of parathyroid tissue. Postoperative hypoparathyroidism may be transient or permanent. Idiopa thic hypoparathyroidism caused by autoimmune destruc- tion of parathyroid tissue may develo p in conjunction with autoimmune adrenalitis and mucocutaneous candidiasis as part of the t ype I polyglandu- lar autoimmune syndrome. Treatment Acute hypocalcemia may require treatme nt with IV infusions of calcium chloride (272 mg of elemental calcium per 10 mL) or calcium gluconate (90 mg of elemental calcium per 10 mL). Doses of 200 mg of elemental calcium may be administered over several minutes. Prolonged infusions of 400 \200\2231,000 mg of eleme ntal calcium may be administered over 24 h. Chronic hypocalcemia may require treatment with calcium supple- mentation and vitamin D analog therapy. Patients may require 1,500 \200 \2233,000 mg of elemental calcium daily in divided doses. Vitamin D analogs that may be use d to promote absorption of elemental calcium include calcitriol (Rocaltrol 0.25 \200\2231 .0 mcg daily \200\223bid) and ergocalciferol (50,000 IU daily to weekly). Treatment should target maintenance of calcium levels in low nor- mal ranges. Serum calcium should be closel y monitored in cases of possible of transient hypoparathyroidism, as parathyroid gland reco very can lead to dangerous hypercalcemia. y g o o n i r c o d n E l Osteoporosis Characterized by a loss of bone mass and/or microarchitecture associated with an increased risk of fracture. Proximate cause of >1.5 million fractures annually in the Un ited States. Individuals with osteoporosis and number of fractures will continue to rise as population ages.Up to 40% mortality in the first year following hip fracture. Most common sites of fragility fracture are the vertebral bodies, wrist, and hip. Risk factors Principa l risk factor associated with development of osteopo- rosis is advancing age. More common i n Caucasians and Asians than other ethnic groups. Other risk factors include female sex, lo w BMI, early meno- pause, amenorrhea, smoking, alcohol abuse, family history, and a history of minimally traumatic fractures. Iatrogenic risk factors include immobilization, treatmen t with anticonvulsants, thiazolidinedione use, and prolonged treat- ment with supraphysiolo gic doses of glucocorticoids. Disorders associated with development of osteoporosis include primary hyperparathyroidism, T1DM, T2DM, thyrotoxicosis, Cushing \200\231s syndrome, rheum atoid arthritis and other chronic inflammatory diseases, malabsorption syndromes (celiac di sease, gastric bypass, etc.), hypogonadism, anorexia nervosa, and connec- tive tissue disor ders that disrupt synthesis of bone matrix (osteogenesis imperfecta, Ehlers \200\223Danlos syndrome, Marfan \200\231s syndrome). Diagnosis Reliable diagnosis and quantification of bo 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